I WANT TO WELCOME THE MEMBERS OF THE BOARD OF THE SCIENTIFIC ADVISORS AND THE NATIONAL CANCER ADVISORY BOARD, NCAB, EX-OFFICIO MEMBERS, LIAISON REPRESENTATIVES, NCI STAFF AND MEMBERS OF THE PUBLIC. AND A SPECIAL WELCOME TO THE NEW BSA MEMBERS AND A SPECIAL SPECIAL WELCOME TO THE WAITING TO RETIRE, NCA MEMBERS, LIKE MYSELF. [ LAUGHS ] SO, ALSO I WANT TO WELCOME DAFNA, JOINING ME IN CO-CHAIRING, SHE IS NOW THE CHAIR OF THE BSA AND TO THANK NED, SO FOR THE FIRST TIME THERE IS TWO WOMEN CHAIRING. [ APPLAUSE ] SO THESE ARE REQUIRED ANNOUNCEMENTS. MEMBERS OF THE PUBLIC MAY WISH TO EXPRESS VIEWS REGARDING ANY ITEMS DISCUSSED DURING THIS MEETING. THEY MAY DO SO BY WRITING TO PAULET GRAY, OUR EXECUTIVE SECRETARY AT THE BOARD, WITHIN 10 DAYS AFTER THE MEETING. ANY WRITTEN STATEMENTS BY MEMBERS OF THE PUBLIC, WILL RECEIVE CAREFUL CONSIDERATION. AS BOARD MEMBERS, I WANT TO REMIND YOU THAT YOU MUST ABSENT YOURSELF DURING SPECIFIC DISCUSSIONS WHENEVER YOU'RE PARTICIPATION, DELIBERATIONS ON A PARTICULAR PRODUCT, PROGRAM OR OTHER SPECIFIC MATTER, WOULD CONSTITUTE A CONFLICT OF INTEREST OR CREATE THE APPEARANCE OF ONE. IT IS INCUMBENT UPON YOU TO ADVISE THE EXECUTIVE SECRETARY AND ABSTAIN FROM ANY PARTICIPATION AND DISCUSSION OR ACTION REGARDING THAT MATTER. IN LIGHT OF POLICIES GOVERNING CONFLICT OF INTEREST BASED ON FINANCIAL HOLDINGS OF SPECIAL GOVERNMENT EMPLOYEES WHICH INCLUDES ALL MEMBERS OF BOTH BOARDS, WE MUST DEPEND ON YOU TO VOLUNTARILY ABSENT YOURSELF DURING ANY AND ALL DISCUSSIONS OF MATTERS THAT COULD CONCEIVABLY IMPACT THE STATUS OF THOSE HOLDINGS. WE TRUST YOUR JUDGMENT IN THESE INSTANCES. DURING ANY CLOSED SESSION, ANY MATERIALS OR DISCUSSIONS OF A CONFIDENTIAL NATURE, DELIBERATED ON TODAY ARE PRIVILEGED INFORMATION AND ARE MADE AVAILABLE TO YOU ON A NEED TO KNOW BASIS. SUCH DELIBERATIONS ARE PRIVATE AND THEIR CONTENT SHOULD NOT BE DIVULGED. FUTURE MEETING DATES ARE LISTED ON THE AGENDA AND ARE IN THE BOOKS. SO SEE FUTURE MEETING DATES TAB IN YOUR BOOK. THE PRESUMABLY RETIRED NCAB MEMBERS WILL MORE LIKELY THAN NOT BE RETIRED IN FEBRUARY, 2019. THIS IS NEWS TO ME. OKAY. PLEASE KEEP THE DATE ON YOUR CALENDAR. IF YOU RECALL THE MINUTES FROM THE JUNE 2018 JOINT BSA-NCAB MEETING, WERE ELECTRONICALLY APPROVED AND A COPY OF THE SIGNED MINUTES IS IN THE BOOKS AND IS POSTED. NOW WE NEED TO APPROVE THE AUGUST 2018, NCAB VIRTUAL MEETING MINUTES. I NEED ALL NCAB MEMBERS TO VOTE. CAN I GET A MOTION TO ACCEPT? ALL THOSE IN FAVOR SAY YEA ANYONE OPPOSED? THOSE MEETING MINUTES ARE ACCEPTED. SO CELL PHONES AND OTHER ELECTRONIC DEVICES SHOULD BE TURNED OFF OR SET ON VIBRATE, PLEASE. WHEREVER THESE INSTRUMENTS GO OFF, THEY ARE QUITE DISRUPTIVE. AND OTHERS IN THE ROOM. BY LAW, WE NEED A QUORUM OF BOARD MEMBERS FOR EACH INSTANCE IN WHICH A VOTE OCCURS, WHETHER IN OPEN OR CLOSED SESSION. DURING THIS MEETING A MINIMUM OF 24 APPOINTED MEMBERS MUST BE PRESS TONIGHT VOICE YOUR VOTES. SINCE WE CAN'T PREDICT THE TIME NOR OCCURRENCE OF ANY MOTION, YOUR PRESENCE IN THE ROOM FOR ALL SEGMENTS OF THE MEETING IS A MUST. IT SHOULD BE NOTED THAT WHEN WE DO THE CONCEPTS LATER TODAY WHILE BOTH BOARDS CAN PARTICIPATE IN THE DISCUSSION, ONLY BSA MEMBERS WILL BE COUNTED IN THE VOTE. THUS FOR THAT, THE QUORUM WILL BE NINE. -- I'M SORRY, 16. ANY VOTES BY THE NCAB SHOULD BE NINE. SORRY ABOUT THAT. WE WILL NOW BEGIN TODAY'S AGENDA AND NED, YOU'RE GOING TO GIVE US THE NCI DIRECTOR'S REPORT. THANK YOU. >> DR. SHARPLESS: I WILL TRY TO BE QUICK TO GET US BACK ON TIME. I APOLOGIZE FOR THE LAST MINUTE CHANGES IN SCHEDULE. I APPRECIATE EVERYONE'S WILLINGNESS TO ACCOMMODATE THE LAST-MINUTE CHANGE. I THINK IT'S PROBABLY IMPORTANT TO START OUT BY REMEMBERING OR BY SAYING WHY THIS HAPPENED, AND THAT IT IS BECAUSE THE DEATH OF A GREAT MAN, PRESIDENT BUSH, A DEDICATED CAREER CIVIL SERVANT AND A LEADER AND THE FRIEND OF THE NIH IN CANCER RESEARCH. AS YOU'RE AWARE, ONE OF HIS CHILDREN DIED OF LEUKEMIA. A PATIENT THAT MAY HAVE A BETTER PROGNOSIS TODAY THAN SHE HAD THEN. FOR THOSE OF YOU WHO HAVE BEEN INVOLVED IN THE CEO ROUNDTABLE YOU HEARD THE STORY ABOUT HOW THIS AFFECTED HIS THINKING AND LED HIM TO BECOME A CHAMPION FOR CANCER RESEARCH. A SAD DAY FOR AMERICA BUT HAVING WEDNESDAY OFF IS NOT THE WORSE THING IN THE WORLD FOR THE NCI DIRECTOR, BECAUSE IT'S BEEN BUSY. BUT, SO BECAUSE OF THE CHANGES, WE WILL HAVE A PACKED DAY TODAY AND WE WILL ENDEAVOR TO FINISH ON TIME NONETHELESS. ONE PIECE OF NEW BUSINESS, THERE ARE SEVERAL NEW BSA MEMBERS. I'D LIKE TO BRIEFLY INTRODUCE THEM. SO MARY BECKERLY IS THE JOHN HUSBAND MAN PRESIDENTIAL ENDOWED CHAIR, CEO OF THE HUNTSMAN CANCER INSTITUTE. DR. BECKERLY'S RESEARCH HAS DEFINED NOVEL PATHWAYS THAT REGULATES CELL MOTILITY AND HER LAB IS FOCUSED ON UNDERSTANDING THE IMPACT OF THIS PATHWAY ON TUMOR REGRESSION. I SAW MARY. OTIS IS A WELL-KNOWN FIGURE AT THE NCI FOR HIS WORK AT THE AMERICAN CANCER SOCIETY AND NOW HE'S A PROFESSOR OF HEMATOLOGY AND ONCOLOGY AT EMORY. HE IS FOR MORE THAN 20 YEARS WAS A COMMISSIONED OFFICER IN THE U.S. PUBLIC HEALTH CORPSE AND WAS A LONG TIME NCIER. KEITH FLAHERTY, HE IS THE DIRECTOR OF THE CENTER FOR TARGETED THERAPY AND DIRECTOR OF THE CLINICAL RESEARCH AT NGH. THE DEPUTY CHAIR OF BIOMARKER SCIENCE AND CHAIR OF DEVELOPMENT THERAPEUTICS FOR ECOG. A WORLD-RENOWNED SCIENTIST WHOSE RESEARCH FOCUSES ON UNDERSTANDING THE CONSEQUENCES OF INHIBITING ONCOGENES AND ONCOGENIC PATH WAY AND MELANOMA WAS ESTABLISHING APPROACHES AND CONSTRUCTING COMBINATORIAL THERAPIES. KARIN IS THE HILLARY ENDOWED PROFESSOR AND CHAIR OF THE DEPARTMENT OF CANCER BIOLOGY AND THE DIRECTOR OF THE SIDNEY KIMMEL CANCER CENTER AT THOMAS JEFFERSON. LEADING EXPERT IN THE HORMONE AND CANCER DEVELOPMENT AND PROGRESSION WITH A SPECIAL FOCUS ON DEVELOPING NEW MEANS TO TREAT PROSTATE CANCER. KIM IS THERE. KIM IS THE CORNELIUS CRAIG PROFESSOR OF THE DEPARTMENT OF MEDICINE AND DIRECTOR OF THE DIVISION OF HEMATOLOGY AND ONCOLOGY AT VANDERBILT, CREATING A CLINICAL PROGRAM THAT SUPPORTS EACH OF THE CANCER PROGRAMS AT VANDERS BUILT AND AS A ONCOLOGIST, SHE LEADS THE ONCOLOGY DISEASE GROUP AND CLINICAL RESEARCH PROGRAM WHERE SHE FOCUSES ON RENAL CELL CARCINOMA AND THE LAST MEMBER IS LES. CHAIRMAN OF THE DEPARTMENT OF EPIDEMIOLOGY AND CANCER CONTROL AT ST. JUDE. AS ASSOCIATE DIRECTOR OF THE COMPREHENSIVE CANCER CENTER, HE HAS BEEN A LEADING INVESTIGATOR IN THE ISSUE OF SURVIVORSHIP, CHILDHOOD CANCER SURVIVORSHIP LEADING MANAGER MULTI-INSTITUTIONAL STUDIES OVER DECADES THAT DEFINED THE LONG-TERM CONSEQUENCES OF CANCER THERAPY IN KIDS. NOT HERE TODAY BUT I'LL INTRODUCE NEXT TIME WHEN THEY ARE IS MICHELLE, PAM, DAVID, ALEXIS AND BOB. SO THOSE ARE THE NEW MEMBERS. AND NOW ON TO THE UPDATE. | SO, FIRST I WOULD LIKE TO START WITH APPROPRIATIONS THIS IS THE GOOD NEWS PORTION OF THE TALK WE CONTINUE TO HAVE STRONG BIPARTISAN SUPPORT FOR CANCER RESEARCH IN PARTICULAR IN BIOMEDICAL RESEARCH IN JANUARY FROM THE CONGRESS THIS IS NOW OUR SORT OF FOURTH STRONG BUDGETARY INCREASE IN A ROW ONE CAN SEE THE FUNDING FOR THE NCI INCLUDING THE MOONSHOT, HAS INCREASED BY MORE THAN A BILLION DOLLARS SINCE 2015 PER YEAR THE ORANGE BAR SHOWS MOONSHOT FUNDING, WHICH IS ON TOP OF OUR APPROPRIATION, AND ONE CAN SEE ALSO THIS IS THE HIGH WATER MARK OF THE MOONSHOT FUNDING 1.8 BILLION DOLLARS OVER SEVEN YEARS PEAKING THIS YEAR AT 400 MILLION DOLLARS NEXT YEAR GOING TO 200 MILLION DOLLARS SO THAT IS GREAT NEWS THE TOTAL INCREASE IN 2019 IS ABOUT 170 MILLION DOLLARS, 70 MILLION TO OUR GENERAL APPROPRIATION AND 100 MILLION DOLLAR INCREASE TO THE MOONSHOT COMPARED TO 270 MILLION DOLLARS LAST YEAR WHILE A VERY GOOD YEAR THIS YEAR, NOT AS GOOD AS LAST YEAR THE OTHER THING TO NOTE IS THE FISCAL YEAR BUDGET WAS ENACTED ON TIME ON THE FIRST DAY OF THE FISCAL YEAR FIRST TIME THIS HAPPENED IN 22 YEARS THIS IS VERY IMPORTANT FOR THE NCI ALLOWING US A FULL YEAR TO PLAN THE BUDGET AND TO MAKE SOME TOUGH CHOICES WHERE NECESSARY A FEW SUCCESSES FROM 2018 THIS SUPPORT FROM CONGRESS ALLOWED IN ADDITION TO STARTING A NUMBER OF NEW PROJECTS THAT WE CAN TALK ABOUT ANOTHER TIME, FOR THE RPG POOL, THE RESEARCH PROJECT GRANT POOL, THAT FUNDS RO1S AND PO1s, WE HAVE LARGEST INCREASE SINCE 2003 THIS ALLOWED US ALSO TO MAKE A REAL PRIORITY OF FUNDING WE WILL SURPAS THAT GOAL WHEN THE NUMBERS OF DONE. AND THEN WE ALSO HAD INCREASE IN THE NUMBER OF NEW AWARDS UP FROM 2017, AND THE NUMBER OF NEW RO1s OTHERS HAS GROWN STEADILY. THIS REMINDS ME ONE THING. SADLY, BECAUSE OF THE CHANGE IN SCHEDULE, WE POSTPONED THE ORIENTATION FOR THE NEW MEMBERS UNTIL NEXT TIME. BUT I WANTED TO -- AS A BRIEF ADVICE FOR ORIENTATION, THREE THINGS. ONE IS -- THIS IS AN OPEN MEETING SO ANYTHING YOU SAY CAN AND WILL BE USED AGAINST YOU. TWO, THIS IS SOMETIMES WE WILL LAPSE INTO FED SPEAK, UNFORTUNATELY, A LANGUAGE I RECENTLY LEARNED. AND THERE WILL BE A BEWILDERING NUMBER OF ACRONYMS LIKE, RPG AND ESI, AND IF AT ANY POINT YOU DON'T UNDERSTAND WHAT WE ARE TALKING ABOUT, PLEASE STOP AND ASK. THAT IS PERFECTLY APPROPRIATE THING TO DO AND YOU'LL FIND A NUMBER OF OTHER PEOPLE ARE CONFUSED AS WELL. LASTLY, IF THERE IS ANYTHING THAT -- WE ASKED YOU TO COME FOR YOUR FRANK OPINIONS. IF THERE IS ANYTHING WITH WHICH YOU DO NOT AGREE, PLEASE SPEAK UP AND LET US KNOW. DO NOT BE AFRAID TO SHARE YOUR OPINIONS. WE WANT A FORTHRIGHT AND HONEST AND FRANK DISCUSSION FROM THE BOARD. SO THOSE ARE MY -- CONSIDER YOURSELF ORIENTATED. ALSO GOING ON -- SO AS I MENTIONED, THERE ARE SOME REALITIES OF THE BUDGET THAT WE HAVE TO TALK ABOUT TODAY REGARDING 2019. AND I ALREADY ALLUDED TO THIS THAT THE 180 MILLION DOLLAR INCREASE IN 2019 IS GREAT NEWS, BUD 100 OF THAT IS FOR THE MOONSHOT AND WE WILL PRESERVE THE MOONSHOT FUNDING. AND FOR THOSE PURPOSES. THAT MEANS IT'S 80 MILLION DOLLARS FOR GENERAL APPROPRIATION, WHICH IS LESS THAN WE NEED TO PUT IN THE RPG POOL TO KEEP UP WITH EXPENSES AND ON TOP OF THAT, THERE ARE OTHER COST REALITIES WE HAVE TO MENTION. SO RENT AND UTILITIES INCREASED FOR THE NCI. WE HAVE MANDATORY ASSESSMENTS, TRANSFERS TO THE NIH AND THE HHS THAT ARE NOT UNDER OUR CONTROL. STIPEND INCREASES IS AN IMPORTANT THING TO SUPPORT. GENERALLY THE TRENDS IN THE NCI HAS BEEN INCREASING AWARD SIZES WITHIN A MECHANISM LIKE RO1 AND THEN WE SEEN A SHIFT FROM SOME MECHANISMS AWAY FROM R21S THAT OVERALL INFLUENCE THE WORK SIZE. AND THEN WE HAVE NONCOMPETING COMMITMENTS IN THE RPG POOL. SO AS I MENTIONED, THE POOL OF GRANTS INCREASES EVERY YEAR. SO, THAT MEANS THAT THERE IS A SIGNIFICANT SET OF COSTS FOR 2019 THAT ARE GOING TO PROVIDE PRESSURE TO THE 80 MILLION DOLLAR INCREASE IN OUR APPROPRIATIONS. SO, ONE OF THE THINGS THAT IS REALLY IMPORTANT TO KNOW ABOUT THE RPG POOL -- AND THESE DATA ARE VERY SURPRISING TO ME. AND THIS SHOWS THE NUMBER OF APPLICATIONS TO THE NCI SINCE 20 THIRTEEN, THE GROWTH OF THAT POOL COMPARED TO THE ENTIRE NIH. SO INCLUDING THE NCI, BY THE WAY, SO THE TOTAL NUMBER IS HERE. SO THE NUMBER OF APPLICATIONS HAS GONE UP 10% TO THE NIH BUT TO THE NCI SINCE 2013, IT'S GONE UP CLOSER TO 50%. AND THE ACTUAL NUMBERS ARE HERE. YOU CAN SEE THE TOTAL INCREASE ON THE ORDER OF 3000 MORE RO1 APPLICATIONS AND SOME 2000 OF THOSE ARE GOING TO THE NCI. SO, THE MASSIVE GROWTH THE NCI IS SEEING IS NOT SEEN IN OTHER INSTITUTES. IT'S AN INTERESTING QUESTION WHY THIS IS HAPPENING. I THINK IT REFLECTS A NUMBER OF FACTORS. WE BELIEVE SOME OF THE INCREASE STARTS WELL BEFORE THE MOONSHOT STARTED. SO I SUSPECT THE MOONSHOT KEPT THE MOMENTUM GOING BUT IT'S NOT THE ONLY FACTOR. THERE ARE A LOT OF GREAT SCIENTISTS WITH NEW IDEAS MOVING TO OUR FIELD. AND I THINK THIS IS A TESTIMONY TO THE VIBRANCY OF THE EXTRAMURAL COMMUNITY. AND I THINK FRANKLY, ALSO I BELIEVE THIS IS PARTLY ATTRIBUTABLE TO THE CANCER CENTERS. I THINK THIS DEMONSTRATES THE SUCCESS OF THE CANCER CENTER PROGRAM OF CREATING AN ENVIRONMENT WHERE JUNIOR FACULTY WHEN THEY COME,SADE THERE IS ALL THIS INFRASTRUCTURE AND SUPPORT FOR MY RESEARCH. AND I THINK THAT PROBABLY HAS HAD AN AFFECT. SO THIS IS A GOOD PROBLEM. THIS IS GOOD NEWS FOR THE NCI THAT WE ARE GETTING ALL THESE GREAT IDEAS AND YOUNG SCIENTISTS AND MORE ESTABLISHED SCIENTISTS COMING TO OUR FIELD. BUT, YOU CAN JUST IMAGINE THE EFFECTIVENESS ON PAY LINES, BECAUSE PAY LINES ARE A NUMBER OF FUNDED APPLICATIONS DIVIDED BY THIS NUMBER. NOW OUR NUMBER OF FUNDED APPLICATIONS GOES UP EVERY YEAR BUT IT DOESN'T GO UP 50% OVER THIS PERIOD. SO, THIS IS WHY PAY LINES ARE LOWER THAN WE WOULD LIKE IN THE NCI AND I SUSPECT IN 2019 WILL BE LOWER THAN THEY WERE IN 2018. SO THE GUIDING PRINCIPLES FOR 2019 WILL BE THESE. FIRST, WE TO THE EXTENT POSSIBLE, WANT TO PRESERVE THE RPG POOL. I DON'T THINK WE CAN KEEP PAY LINES EXACTLY AS HIGH BUT WE WILL MAE EVERY EFFORT TO DO SO. I THINK THE PAY LINES WHEN YOU START TALKING ABOUT NUMBERS LIKE 8 AND 9%, BECOME DEMORALIZING FOR THE EXTRAMURAL COMMUNITY AND SO TO THE ABILITY WE CAN, WE WILL TRY AND KEEP THAT PRESERVED. WE WILL NOT RAID THE MOONSHOT FUNDS TO SOLVE PROBLEMS. THE MOONSHOT HAD A GOOD VISION. IT'S WELL ON ITS WAY AND I THINK IT IS AIMING TO ACHIEVE ITS GOALS. BUT WE WILL EAT THE MONEY THAT WAS ALLOCATED FOR THE MOONSHOT PURPOSES OF THE MOONSHOT. AND LASTLY, WE CONTINUE TO UNDERSTAND IN THESE TIMES OF VERY TOUGH FUNDING ENVIRONMENTS, THAT EARLY STAGE INVESTIGATORS REALLY DO HAVE A GREATER CHALLENGES AND THEREFORE THEY NEED SOME SUPPORT THROUGH ENHANCED PAY LINES. THIS MEANS WE WILL DO A FEW THINGS. SO WE WILL HAVE AN ACROSS-THE-BOARD 5% REDUCTION TO THE DIVISIONS AND CENTERS WITHIN THE NCI. SO THE DOCS WILL BE FUNDED DIVISION AND CENTER AND OFFICE DOC WILL BE FUNDED AT 95% OF 2018. 2018 WAS A GOOD NUMBER AND HAD BIG INCREASE. SO THIS IS A CUT TO A GOOD NUMBER. THIS WILL NOT INCLUDE KITS TO GRANTS AND PERSONNEL WITHIN THE DOCS BUT IT WILL DECREASE THEIR OPERATING COSTS. WE WILL HAVE TO HAVE REDUCTION TO NONCOMPETING AWARDS. SO WITHIN THE R APPROXIMATE. RPG POOL, WE WILL NOT BE ABLE TO FUND AT 100% BECAUSE WE NEED TO USE MONIES TO SUPPORT NEW INVESTIGATORS TO AUGMENT PAY LINES. SO THERE WILL BE A 3% CUT TO NONCOMPETING RENEWALS IN THE HPG POOL. THIS WILL NOT APPLY TO MOONSHOT GRANTS. THIS WILL NOT APPLY TO THE CANCER CENTERS. BUT JUST ABOUT EVERYTHING -- AND WILL NOT APPLY TO NRSA AND TRAINING AWARDS BUT IT WILL APPLY TO THE VAST MAJORITY OF EVERYTHING ELSE OUT OF THE RPG POOL. I'M SURE THERE LUCK QUESTIONS WE CAN TALK ABOUT IN A MOMENT. LET ME MENTION A FEW HIGHLIGHTS OF 2018. EYE LIKE TO SHOW THE DATA ON CANCER STATISTICS, A VARIETY OF SOURCES. THIS IS THE MOST COMPREHENSIVE IS THE ANNUAL REPORT, A DOCUMENT CREATED BY THE AMERICAN CANCER SOCIETY, CDC AND THE NCI EVERY YEAR. AND IT SHOWS A STEADY GOOD TREND THAT IN AGGREGATE, CANCER MORTALITY AND CANCER INCIDENTS DECLINING IN THE UNITED STATES. REALLY REMARKABLE IMPROVEMENT FOR THINGS LIKE LUNG CANCER AND COLON CANCER. BUT, PROGRESS IS UNEVEN. SO OVERALL MORTALITY IS DECLINING, THERE ARE A FEW AREAS WHERE WE ARE SEEING INCREASING MORTALITY FOR OBESITY-ASSOCIATED CANCERS. THIS IS BOTH THE GOOD NEWS OF THE MODERN CANCER RESEARCH THAT WE ARE MAKING STRONG PROGRESS. BUT THAT PROGRESS IS ALSO UNEVEN AND THE NCI CAN'T ACCEPT THAT. WE HAVE TO MAKE PROGRESS FOR ALL PATIENTS WITH CANCER. YOU HAVE A COPY OF THE BYPASS BUDGET. THIS IS -- OR THE PROFESSIONAL JUDGMENT BUDGET THAT DESCRIBES THE PRIORITIES OF THE NCI GOING FORWARD FOR A YEAR IN ADVANCE. THIS IS FOR FISCAL YEAR 20 AND STARTING WORK ON THE 2021 DOCUMENT. WE HAVE THESE TOPICS TO BE COMPREHENSIVE AND USE THIS DOCUMENT TO DESCRIBE TO THE CONGRESS WHAT WE WOULD DO, WHERE EXTRA SUPPORT IS AVAILABLE. THIS DOCUMENT IS CREATED IN COMPLIANCE WITH THE NATIONAL CANCER ACT AS A REQUEST OF THE NCI PROVIDED BY PAST BUDGET ANNUALLY. IT'S BEEN A GOOD YEARS FOR IMMUNOTHERAPY. I THINK THAT BOTH WITHIN THE INTRAMURAL AND EXTRAMURALLY, A LOT OF EXCITEMENT IN THIS FIELD. WE HAVE SEEN NEW IMPRESSIVE CELLULAR APPROACHES LIKE STEVE ROSENBERG'S PAPERS IN SOLID TUMOR MALIGNANCIES BREAST CANCER REPORT THIS YEAR. WE HAVE SEEN A NOBEL PRIZE FOR THE CHECKPOINT INHIBITORS THIS YEAR. AND I HAVE JUST BEEN REMARKING TO MANY THAT AS YOU GO TO THESE NATIONAL MEETINGS, I JUST CAME FROM ASH, ASCO, OR ACR, EVERYONE OF THESE MEETINGS HAS MANY LARGE, WILDLY POSITIVE RANDOMIZED TRIALS IN THEIR PRACTICE. A DECADE AGO IN MY CAREER, I DON'T REMEMBER MEETINGS BEING LIKE THIS. IT'S THE RATE OF PROGRESS IN CERTAIN DISEASES IS SO FAST AND I THINK IF YOU LOOK AT WHAT IS DRIVING A LOT OF THOSE SUCCESSES, THEY ARE COMBINATION THERAPIES FOR CHECKPOINT INHIBITORS FOR EXAMPLE. SO REAL PROGRESS THERE AND CHALLENGES TO FIGURE OUT HOW TO EXPAND THESE TERRIFIC CELLULAR IMMUNOTHERAPIES TO GREATER POPULATIONS AND TO HOW TO BEST USE THESE MULTIPLE AGENCY WE HAVE AVAILABLE. BUT AGAIN, A GOOD PROBLEM TO HAVE IN SOME DISEASES WHERE WE USED TO HAVE NO REAL OPTIONS. THE INTRAMURAL PROGRAM CONTRIBUTED TO THE SIGNIFICANTLY APPROVAL OF A NEW DRUG FOR HAIRY CELL THIS YEAR. THIS IS A CD22 ANTI-BELIEVED COUPLED TO A TOXIN AND REFLECTS DECADES OF WORK IN THE INTRAMURAL PROGRAM. SO IT IS A TESTIMONY TO THE KIND OF WORK THAT THE REAL SORT OF LEADING WORK THAT THE INTRAMURAL PROGRAM CAN DO IN A RARE DISEASE LIKE HAIRY CELL WHERE IT'S HARDER TO DO CLINICAL TRIALS FOR MANY REASONS. THIS STUDY IS AN INTERESTING RESULT JOINTLY FUNDED BY THE NIA AND NCI SHOWING THAT THE USE OF DAILY ASPIRIN IN PATIENTS OVER THE AGE -- SECRETARIES OVER THE AGE OF 70 WAS NOT ASSOCIATED WITH A BENEFIT IN TERMS OF CANCER PREVENTION OR SURVIVAL. IN FACT THERE WAS INCREASE IN CANCER ASSOCIATED MORTALITY IN THE TRIAL. THIS TRIAL WAS SET UP TO LOOK AT MANY ENDPOINTS, CARDIOVASCULAR AND ALZHEIMER'S. IN AGGREGATE IT'S A NEGATIVE STURDY, THIS WHOLE ISSUE OF THE NEW ENGLAND JOURNAL WAS STUDIES OF ASPIRIN CHEMO PREVENTION OR -- FOR MORTALITY REDUCTION. AND GENERALLY, THE RESULTS WERE, I WOULD SAY, CONCLUSIVE THAT ASPIRIN, PROPHYLAXIS IN NO POPULATION PROVIDES A BENEFIT. FOR TREATMENT OF PEOPLE WHO HAD A STROKE OR HEART ATTACK THAT IS DIFFERENT BUT FOR PRIMARY PROPHYLAXIS IT'S NOT BENEFICIAL. I THINK THIS COMES ON THE HEELS OF SIMILAR RESULTS WITH VITAMIN D. IF YOU GO BACK A LONG TIME, IS LIN YUM AND RETINOIDS AND FISH OIL AND SOMETHING ELSE. WE HAVE A TRIAL LIKE THIS STILL GOING WITH METFORMIN. BUT THESE RESULTS MAKE IT CLEAR HOW CHALLENGING IT IS TO DO ALL COMER SCHEMA PREVENTION IN THE GENERAL POPULATION. IF EVEN A DRUG LIKE ASPIRIN TOO TOXIC FOR THIS APPLICATION, ONE HAS TO WONDER WHETHER CHEMO PREVENTION WITH THE NCI. WE SPENT A LOT OF TIME TALKING ABOUT PREVENTION AND SHOULD TRIALS BE MORE TARGETED AND FOCUSED ON HIGH-RISK INDIVIDUALS, FOR EXAMPLE. WE ARE VERY EXCITED BY THE APPROVAL OF THIS HIGHLY-ACTIVE KINASE INHIBITOR FOR PEDIATRIC AND ADULT CANCERS FEATURING TREK FUSIONS. THE NCI IS PARTICULARLY PROUD OF THIS RESULT. IT WAS INTRAFUSIONS DISCOVERED BY THE INTRAMURAL PROGRAM. FREDRICK NATIONAL LAB BACK IN THE 80s. IT'S LIKE THE THIRD ONCOGENE DISCOVERIES AND THE FIRST FUSION ONCOPROTEIN DISCOVERED. AND THAT GREAT SCIENCE THEN DECADES LATER, TRANSLATES INTO A HIGHLY-ACTIVE THERAPY FOR KIDS AND ADULTS THAT HARBOR THESE EVENTS. WE ALSO HAVE HAD THIS AGENT IN BOTH PEDIATRIC MATCH AND THE ADULT MATCH TRIALS, AND SO WE HAVE OUR FIRST-HAND EXPERIENCE WITH LOW FREQUENCY OF THESE EVENTS. WE SEQUENCED THOUSANDS OF PATIENTS ON MATCH, FOR EXAMPLE, TO THIS TRIAL. BUT THEY HAVE BEEN ACCRUING. SO THIS IS SORT OF BOTH THE PROMISE AND PROBLEM OF PRECISION ONCOLOGY. THESE DRUGS CAN BE HIGHLY ACTIVE BUT FROM SOME INSTANCES THEY WILL BE HIGHLY RARE PATIENTS. THIS IS HOT OFF THE PRESS AT ASH. ONE OF THESE WAS RELEASED YESTERDAY AND THE OTHER TWO DAYS AGO. WILDLY-POSITIVE RANDOMIZED TRIALS USING CLL -- BOTH TRIALS REPORT ESSENTIALLY CHEMOTHERAPY FREE-REGIMENS SO IN LIEU OF DRUGS, INSTEAD WITH RITUXIMAB OR I WILL IBRUTINIB, VERY REMARKABLE SURVIVAL BENEFITS AND BENEFIT TO THE PATIENTS. SO HIGHLY-ACTIVE REGIMENS THAT ARE MINIMALLY TOXIC FOR THIS IMPORTANT HUMAN CANCER. AS I SAID, THIS IS WHAT I WAS ALLUDING TO WHEN YOU GO TO THESE MEETINGS AND THESE KINDS OF TRIALS. ALMOST DON'T MAKE THE NATIONAL MEDIA BUT BECAUSE THEY ARE -- IT'S JUST FREQUENT OCCURRENCE NOW IN ONCOLOGIC RESEARCH. BUT HIGHLY SUCCESSFUL RESULTS AND VERY MEANINGFUL FOR PATIENTS. WE AT NCI HAVE BEEN THINKING A LOT ABOUT PEDIATRIC CANCER AND MORE TO COME ON THIS TOPIC. AS I ALLUDED TO, THERE IS SEVERAL IMPORTANT ADVANCES. I MENTIONED LARRY. WE'VE HAD A REALLY IMPORTANT SET OF STUDIES DONE IN THE INTRAMURAL PROGRAM LOOKING AT MEK INHIBITORS IN PATIENTS WITH F1 DEFICIENCY. PEDIATRIC MATCH IS ACCRUING QUITE WELL. CLOSE TO 400 PATIENTS NOW. AND THIS CD22, CD19 CAR T REPORT THAT WAS AT ASH, FOR EXAMPLE. WE HAVE FUNDED THROUGH THE MOONSHOT AND OTHER SOURCES A BUNCH OF NEW INITIATIVES IN PEDIATRIC ONCOLOGY, SO INCLUDING A DISCOVERY NETWORK, FUSION ONCOPROTEIN AWARDS AND SOME ACROSS THE LIFESPAN RESEARCH. AND THERE HAS BEEN RELEVANT LEGISLATION TO PEDIATRIC ONCOLOGY TWO OF THE MOST RECENT SHOWN IN THIS. NOT A COMPREHENSIVE LIST. SO THE RACE ACT IS AN ACT THAT REQUIRES MANUFACTURERS AT THE TIME OF REGULATORY FILING WITH THE FDA, TO DESCRIBE HOW THEY WILL STUDY THEIR AGENT IN PEDIATRIC CANCERS IF THE TARGET IS RELEVANT TO PEDIATRIC DISEASE TO, COME UP WITH A LIST OF RELEVANT TARGETS, THE NCI WORKED WITH THE FDA IN A IMPORTANT SET OF STUDIES. THE STAR ACT ASKS THE NCI TO DO A NUMBER OF THINGS RELATED TO VAS IN PEDIATRIC ONCOLOGY BY SPECIMEN STORAGE AND ACCRUAL AND THEN CHILDHOOD SURVIVORSHIP. WE HAVE BEGUN TO IMPLEMENT ASPECTS OR PLANS FOR THE STAR ACT AND I BELIEVE WE WILL SAY A WORD OR TWO ABOUT IT LATER. THE MOONSHOT, AS I MENTIONED, I THINK IS GOING QUITE WELL. WE ARE NOW THREE YEARS INTO THE MOONSHOT AND STARTING TO SEE THE FRUITS OF THESE LARGE NEW FUNDING EFFORTS AND THE NETWORKS HAVE BEEN CREATED AND THE GREAT NEW SCIENCE THAT IS BEING SUPPORTED BY THE MOONSHOT. WE HAD AN UPDATE WITH A BLUE RIBBON PANEL THAT WENT WELL AND TALKED ABOUT THE SUCCESSES AND THE PROGRESS TO DATE ON THIS. AS MENTIONED, THE FUNDING PATTERN FOR THE MOONSHOT IS SHOWN HERE. SO, HIGH WATER MARK THIS YEAR, THEN WHO00 MILLION DOLLAR DECREASE AND THEN 200 MILLION DOLLAR DECREASE. THESE CUTS, QUOTE/UNQUOTE, ARE A GOOD PROBLEM TO HAVE. WE KNEW THIS WAS GOING TO HAPPEN SO WE HAVE BEEN ABLE TO BUDGET AND PLAN ACCORDINGLY. ALSO THE FUNDS IN THE MOONSHOT WERE AWARDED AS ANY-YEAR MONEY NOT FISCAL YEAR-RESTRICTED MONEY. THAT IS VERY NICE. THAT ALLOWS US TO FULLY-FUND THE GRANTS INITIALLY AND THEN CARRY OVER FUNDS IN FISCAL YEARS. SO THAT HAS MADE THIS EASIER TO DEAL WITH. I THINK IT'S IMPORTANT TO SAY, THOUGH, THAT THE MOONSHOT IS LEADING TO THE CREATION OF SOME GREAT NETWORKS AND INFRASTRUCTURE AND RESEARCH PROGRAMS AND GROUPS AND THOSE THINGS ARE GOING TO LIVE ON BEYOND 2023 AND AT SOME POINT, THE NC LIMIT HAVE TO FIGURE OUT HOW TO FUND THEM AND PROBABLY WILL COME OUT OF OUR GENERAL APPROPRIATION. SO THESE HAVE REAL IMPLICATIONS FOR HOW WE PLAN IN THE FUTURE. AS MENTIONED, THIS INCREASE WILL BE USED FOR THE MOONSHOT PRIORITIES. IF YOU KNOW THAT THESE GRANTS THAT WE AWARDED IN 17, 18 AND 19, HAVE OUT-YEAR COSTS AND THE MONEY DECLINES TO 200 MILLION GOING ON, YOU CAN I THINK FER THAT MOST OF THE NEW STUFF WILL BE DONE IN THE FIRST THREE YEARS. AND THIS YEAR, THERE ARE A FEW RFAs OPEN RIGHT NOW AND FUSION ONCOPROTEINS AGAIN, AT-RISK INDIVIDUALS WITH INHERITED CANCER SYNDROMES AND IMMUNO-ONCOLOGY NETWORKS. THERE WILL BE A SIGNIFICANT NUMBER OF ADDITIONAL PROPOSALS OR FUNDING ANNOUNCEMENTS IN 2019. THEN WE ARE DOING SOME MANEUVERS TO TRY AND PRESERVE A LITTLE BIT OF FLEXIBILITY IN THESE FUTURE YEARS SO WE ARE ABLE TO DO SOME NEW STUFF IN 20 AND ON, ALTHOUGH I THINK THE NUMBERS OF NEW THINGS WILL BE SMALLER THAN THIS YEAR, FOR EXAMPLE. I ALSO WOULD LIKE TO MENTION THESE WORKING GROUPS THAT WE NOW STARTED. THIS WAS IN A WAY CAME OUT OF A SPORE RE-EVALUATION PROCESS. SO THE RE-EVALUATION SPORE RECOMMENDED THE NCI CONVENED THOUGHT LEADERS TO TALK ABOUT SPECIFIC TRANSLATIONAL OPPORTUNITIES THAT WOULD BE A GOOD FIT WITHIN -- OR FOR SUPPORT FOR THE NCI'S VARIOUS NETWORKS AND MECHANISMS. SO THAT IS THROUGH THE CTAP CLINICAL TRIALS AND ADVISORY COMMITTEE. AND WE HAVE ALREADY CONVENED -- WE THOUGHT ABOUT THIS FOR A WHILE AND DECIDED THAT IT MIGHT BE NICE TO HAVE FOCUS TO THESE WORKING GROUPS RATHER THAN TO SAY WHAT IS COOL IN TRANSLATION. AND SO THE FIRST OF THESE IS DEDICATED TO THE TOPIC, GLIOBLASTOMA, LED BY WALLY. THE RADIATION ONCOLOGY ROSTERS DEVELOPMENT SHOULD KICK OFF VERY SOON. I DO NOT ENVISION THESE ARE THE LAST TWO WE DO. WE WILL LIKELY MOVE IT TO OTHER TOPICS. AND THEN LASTLY, SOME IMPORTANT LEADERSHIP TRANSITIONS, NCI'S HIRING AT A FE NARRUOUS CLIP AND I HOPE THOSE WHO KNOW GOOD CANDIDATES FOR THESE JOBS WILL REFER THEM TO ME OR LEADERSHIP WITHIN THE NCI. THIS IS NOT AN EXHAUSTIVE LIST BUT WE ARE SHORT OF WINDING OUR WAY THROUGH THE FEDERAL PROCESS FOR DIRECTOR OF CGH. WE ARE A BIT FURTHER ALONG FOR DIRECTOR IN TERMS OF THE LEAD STRATEGY PERSON FOR BIG DATA AT THE NCI. JEFF ABRAMS RETIRED ABOUT TWO DAYS AGO, I THINK, FROM THE CTEP AND THIS IS A VERY IMPORTANT JOB, WHICH WILL FLOOD NEW LEADERSHIP. BARRY KRAMER, WHO IS HERE TODAY, ANNOUNCED HIS RETIREMENT BEGINNING OF NEXT YEAR. I'D LIKE TO POINT OUT BARRY HAD A TERRIFIC AND WONDERFUL SERVICE AS IN FEDERAL SERVICE AND IT IS A REAL LOSS TO THE NC TONIGHT LOSE HIS VISION AND LEADERSHIP AND I THINK BARRY DESERVES SOME APPLAUSE. [ APPLAUSE ] AND THEN LASTLY, WE ARE NEARING A NCI LEADERSHIP IN FREDRICK. AS MANY KNOW, TAKEN ON THE LEAD ROLE FOR LIDOS AND WILL BE A VERY IMPORTANT JOB IN HELPING TO DETERMINE HOW EAST FREDRICK NATIONAL LAB RUNS. SO THESE ARE THE KEY FOCUS AREAS I HAVE ENUNCIATED AND I'M HAPPY TO TALK ABOUT WORK IN ANY OF THESE SPECIFIC TOPICS IF THERE IS INTEREST BUT IN THE INTEREST OF TIME, AND TO ALLOW FOR A LONG AND ROBUST DISCUSSION, I'LL WIND UP THERE AND TAKE ANY QUESTIONS. THANK YOU. >> THANK YOU, NED. ANY QUESTIONS? >> USE THE MIC. >> -- INCREASE NUMBER OF RL1 APPLICATIONS AND COMPLAINING TO ME ABOUT PAYLINE FOR NCI AND I'M SURPRISED -- AND ALWAYS CONTRASTING TO AI. SO WHAT'S HAPPENING WITH NIAID? WHY ARE THEY NOT HAVING MORE FUNDING? >> I HAPPEN TO KNOW THE NUMBER FOR NIAID AND THEIR INCREASE OVER THE SAME PERIOD. THEY GO UP SOMEWHERE 10-15%. SO THAT IS NICE INSTITUTE OR CENTER THAT IS SEEING AN INCREASE IN SUBMISSIONS AS WELL. AND I'D SAY THAT IS CHARACTERISTIC. SOME ARE GOING UP A LITTLE BIT AND SOME ARE GOING DOWN A LITTLE BIT. ON AGGREGATE IT'S ABOUT 10% OVER ALL AND THEN THE NCI, THE LARGE -- SOME OF THE VERY SMALL ONES LIKE THE NATIONAL LIBRARY OF MEDICINE HAD BIG INCREASE BUT THE LARGE NIHs THAT GIVES A LOT OF AWARDS, THE NCI IS A OUTLIER BY MAYBE A FACTOR OF TWO. AND IT IS AN INTERESTING QUESTION WHY THAT HAPPENS. FROM OUR POINT OF VIEW, IT'S GREAT BECAUSE WE ARE GETTING ALL THESE GREAT VIBRANT APPLICATIONS BUT FROM THE EXTRAMURAL COMMUNITY WHO WORKS BASED ON PAY LINES, IT'S NOT GREAT NEWS. I WILL SAY ONE OF THE THINGS WE HAVE BEEN TRYING TO MARKET, I'LL MAKE TWO POINTS. FIRST OF ALL, PAY LINES AND SUCCESS RATES ARE DIFFERENT. SO WE USE SELECT PAY FOR SOME PORTION OF OUR APPLICATIONS MEANING THAT THE NCI CHOOSES TO FUND THINGS NOT STRICTLY BASED ON SCORE. SO OCCASIONALLY, WE WILL SEE SOMETHING THAT HAS 15 PERCENTILE AND PICK IT OUT AND SAY WE WANT TO FUND THAT. WE PRESERVE THAT FOR TWO REASONS. ONE IS THAT WHEN SCORES ARE HEAVILY COMPRESSED LIKE THIS, WE HAVE A WORRY THAT TRULY INNOVATIVE SCIENCE GETS IGNORED. WE WANT TO RESERVE THE RIGHT TO SAY THAT IS A GREAT DESPITE WHAT THE REVIEWERS SAID. AND SECONDLY, OR IN PART, ONLY PARTLY IGNORING WHAT THE REVIEWER SAID, NOT TOTALLY. SECONDLY, WE NEED TO HAVE RESEARCH ACROSS THE PORTFOLIO OF CANCER. IF WE GET TOO MANY GRANTS IN ONE DISEASE AND NOT ENOUGH IN ANOTHER THEN WE NEED TO DO SOME BALANCING. SO SUCCESS RATES WILL BE OR HAVE BEEN OVER 10% AND I THINK WE ARE WORKING ON THE 2018 NUMBERS BUT THEY WILL BE ON THE ORDER OF 12% FOR LAST YEAR AND I SUSPECT WILL BE ABOUT THE SAME OR A TAD LOWER THISSER. SO SUCCESS RATES ARE A BETTER NUMBER BUT STILL QUITE LOW. THE OTHER POINT TO MAKE ABOUT THIS THAT AS I TRY TO EXPLAIN THIS TO THE CONGRESS, WHO IS VERY CONCERNED ABOUT PAY LINES AND THE DEMORALIZATION OF JUNIOR INVESTIGATORS, A NUMBER OF AWARDS THE NCI IS FUNDING HAS GONE UP A LOT AND WILL GO UP IN 2019. THE NUMBER WILL INCREASE. BUT NOT AS FAST AS THE NUMBER OF NEW APPLICATIONS. >> I HAD A QUICK QUESTION. SO EARLY CAREER INVESTIGATORS, HAS THAT PAY LINE STILL GONE UP OR STAYED UP? AND WHAT WILL HAPPEN WITH THE PAY CUTS? >> RIGHT. SO, WE ARE GOING TO TRY TO PRIORITIZE ESI'S AGAIN. SO IN 2018, WE FUNDED A LOT MORE ESIs THAN 2017. SO THAT INCREASED ON THE ORDER OF -- MORE THAN 25%, THE FINAL NUMBERS -- IT'S MORE LIKE 30%, I THINK. SO IF WE GAVE OUT 100 AWARDS IN 2017, IT WAS MORE LIKE 130-ISH IN 2018. THAT INCLUDES THIS R37, THE 7-YEAR AWARD I TOLD YOU ABOUT BEFORE. SO THE RO1 EQUIVALENT NUMBER HAS GONE UP AND THAT TRANSLATED INTO A SUBSTANTIAL INCREASE IN THE PAY LINES FOR ESI. SO 2017, I WILL NOT GET THE EXACT NUMBERS RIGHT BUT IT WAS PROBABLY AN -- THE ESTABLISHED INVESTIGATOR VERSUS THE ESI DELTA WAS ON THE ORDER OF A COUPLE PERCENTS LIKE 3% AND LAST YEAR MORE LIKE ON THE ORDER OF 8%. SO THE BONUS YOU GET FOR BEING ESI IS HIGHER. THIS REMINDS ME TO TAKE HOME TWO MESSAGES TO THE JOURNAL FACULTY MENTOR. ES SYMPT A BONUS. DON'T GIVE IT UP. WE SEE JUNIOR INVESTIGATORS GETTING ROPED INTO MULTI-PI PROPOSALS WHERE NAY LOSE THEIR ESI STATUS. ADVISE THEM NOT TO DO THAT. AND R21s MAY BE ABOUT THE HARDEST GRANT TO GET AT THE NCI. THE PAY LINE IS NOT GOOD AND CERTAINLY I WOULD NOT RECOMMEND TO ANY JUNIOR SCIENTIST THEY USE THAT AWARD AS A STARTER AWARD. THAT SHOULD APPLY FOR ESI RO1. R21S ARE NOT TO GET A CAREER STARTED. >> ARE YOU GOING TO DO THE 3% CUT FOR EARLY CAREER AS WELL? OR IS THAT SOMETHING YOU CAN PREVENT? BECAUSE IT SEEMS LIKE IT'S COUNTER PRODUCTIVE. >> 3% CUTS WILL GO TO RO1s IN THE RPG POOL. I'M LOOKING AT YOU TO HELP ME REMEMBER. SO BY THE WAY, I SHOULD MENTION THERE IS ALSO A CUT AT THE BEGINNING OF THE AWARD, WHICH IS 17%. IT'S NOW GOING TO BE 19%. THAT IS SMALLER FOR MODULAR GRANTS. SO THEY TAKE A SMALLER CUT. SO, EARLY STAGE PEOPLE DO NOT USE THE MODULAR GRANT AT A GREATER FREQUENCY THAN ESTABLISHED INVESTIGATORS AND MAY HAVE A BENEFIT. DO YOU WANT TO EXPLAIN? >> NO, I THINK YOU HAVE GONE OVER. >> OKAY. [ LAUGHS ] >> KARIN? >> YES, HAVE YOU CONSIDERED OR HAS THERE BEEN CONSIDERATION OF WHAT THE IMPACT IS OF THE CHANGE IN POLICY FOR ASSIGNING CANCER FOCUS AT THE CENTERS? IT CERTAINLY IS AN INCENTIVE TO APPLY SPECIFICALLY TO NCI GRANTS THE WAY THAT IS CURRENTLY STRUCTURED AND COULD THAT BE DRIVING SOME OF THE INCREASE IN NCI SUBMISSIONS? >> YES, I THINK SO AS YOU'RE AWARE, MOST GRANTS ARE REVIEWED BY THE CENTER FOR SCIENTIFIC REVIEW, CSR, A DIFFERENT NIH. AND THEY GET REFERRED TO THE ICs BASED ON THE TOPIC REFLECTS BY THE ABSTRACT. IF IT HAS THE WORD CANCER, IN THE ABSTRACT, OFTEN UPON THOSE WILL GO TO THE NCI. I DO NOT BELIEVE THERE IS ANY CHANGE IN THE CODING OR REFERRAL PRACTICES THAT WOULD EXPLAIN THIS. I THINK THIS IS PROBABLY MORE REFLECTION OF THE GRANTS THAT ARE GOING TO CSR. >> I'M SEEING THE OTHER WAY. INCENTIVE TO DRIVE SOMETHING TOWARDS NCI INTENTIONALLY INCLUDE CANCER IN THE ABSTRACT AND OTHER BECAUSE IT BENEFITS THE CENTER FOR THE GRANT COMES FROM NCI. IS THAT RIGHT? >> SO YOU'RE SAYING THE CANCER CENTER, CCSG PROGRAM -- WELL, THAT WOULD BE GOOD IF THAT HAPPENED. I MEAN, I THINK THAT WAS SORT OF THE VISION OF THE CANCER CENTERS WAS TO INCREASE PEOPLE WORKING IN CANCER RESEARCH. >> SO NED, NOT TO BELABOR KARIN'S POINT BUT SEVERAL CENTER DIRECTORS ARE HERE AND WITH THE NEW GUIDELINE CHANGES THE CULTURE HAS CHANGED WITHIN THE CENTERS PRETTY INTENTLY TO PUSH OUR INVESTIGATORS TO GO TO NCI BECAUSE IT HELPS OUR FUNDING BASIS. SO I THINK THAT'S A GOOD THING. >> THAT'S PART OF THE REASON WE CREATED THE CANCER CENTER WAS TO DO THAT. THAT'S A FEATURE NOT A BUG. I WOULD LIKE TO -- >> I DON'T THINK WE ARE SAYING IT'S A BAD THING, I'M SAYING IT MAY DRIVE THAT EVEN HARDER. IT MAY BE MORE DISPROPORTIONATE GIVEN THE RULE CHANGE, THE IDEA THAT NCI MAY ANTICIPATE THAT. >> I THINK WHEN I SAID THE CANCER CENTERS MAY BE PART OF THE REASON FOR THIS, THAT'S SORT OF WHAT I MEANT. >> AND LAST YEAR THERE WAS DISCUSSION ABOUT EXTENDING EARLY-STAGE INVESTIGATORS TO THE RENEWAL OF THE FIRST RO1 OR SECOND. HAS ANY OF THAT BEEN IMPLEMENTED OR IS THAT STILL IN DISCUSSION? >> SO THAT IS EXPENSIVE ENDEAVOR. SO GIVING THE ESI BONUS TO PEOPLE ON THEIR FIRST RENEWAL HAS -- WOULD END UP DECREASING THE BONUS THAT WE COULD GIVE THE ESIs AND WE HAVE DATA THAT ESTABLISHED INVESTIGATORS, WHETHER THEY ARE RENEWING THEIR FIRST RO1 OR FIFTH, THEY DO ABOUT THE SAME. THERE IS NOT THE SUCCESS RATE FOR FIRST RENEWALS IS COMPARABLE FOR MORE SENIOR INVESTIGATORS. WE FELT LIKE THEY DIDN'T NEED THE SPECIFIC -- THAT WAS A SURPRISE TO ME. THE CANCER CENTER DIRECTOR, I HAD A SENSORY NEWING YOUR FIRST RO1 WAS PARTICULARLY CHALLENGING BUT RENEWING ANY RO1 AT THE NCI IS PARTICULARLY CHALLENGING. SO WE DECIDED WHEN WE SAW THE DATA WE WOULD EXTEND THE PRIORITY REALLY JUST TO THE PEOPLE IN THE ESI STATUS. NOW, THE PERIOD BY WHICH ONE SHOULD BE CONSIDERED IN ESI, THERE IS THAT -- THAT IS UNDER DISCUSSION. THE NCI'S DATA BELIEVES THAT 10 YEARS IS PROBABLY TOO SHORT. BUT WE -- I CAN TELL YOU THERE IS A COMMITTEE ADVISING FRANCIS COLLINS TO THE NIH THAT IS CONSIDERING THIS ISSUE RIGHT NOW AND THE NCI DECIDED NOT TO GO IT ALONE BUT WAIT TO SEE WHAT THE REST OF THE NIH DECIDES AND THE RECOMMENDATIONS SHOULD BE FORTHCOMING AND THE TWO-YEAR AWARD SEEMS TO BE -- THE 7-YEAR AWARD WITH THE EXTRA TWO YEARS, IT SEEMS TO BE GOING PRETTY WELL. WE GAVE OUT SORT OF ON THE ORDER OF HALF OF THE NEW ESI AWARDS WE GAVE OUT IN 2018, WERE R37s AND THE PEOPLE ARE GETTING THOSE AWARDS ARE HAPPY ABOUT IT AND UNDERSTAND AND IT'S BECOME DESIRABLE THING NOW. THAT WILL BY THE WAY, WE WILL CONTINUE IN 2019. WE WILL CONTINUE TO USE THE R37 FOR A WHILE LONGER. >> I THINK WE ARE GOING TO MOVE ON TO THE NEXT SESSION. THANK YOU. >> THANK YOU. >> NEXT IS THE PRESIDENT'S CANCER PANEL REPORT FROM DR. BARBARA RIMER. >> DR. RIMER: WELCOME TO THE NEW MEMBERS AND THANK YOU FOR HAVING ME HERE TODAY TO SPEAK TO YOU. SO I WANT TO FIRST GIVE YOU A LITTLE BIT OF BACKGROUND, ESPECIALLY FOR NEW MEMBERS ON THE PRESIDENT'S CANCER PANEL AND THEN TALK ABOUT RECENT REPORTS THAT WE HAVE BEEN DOING. SO, JUST AS KIND OF AN OVERVIEW, THE PANEL IS AUTHORIZED BY THE PUBLIC HEALTH SERVICE ACT AND IT REQUIRES THAT THE PANEL MONITOR THE DEVELOPMENT AND EXECUTION OF ALL THE ACTIVITIES OF THE NATIONAL CAPSER PROGRAM. SO THAT IS REALLY EVERYTHING -- CANCER PROGRAM -- EVERYTHING THAT HAPPENS IN CANCER, AND REPORT DIRECTLY TO THE PRESIDENT ABOUT DELAYS OR BLOCKAGE IN THE RAPID EXECUTION OF THE PROGRAM. SO THIS IS A BIG TASK AND ONE HAS TO MAKE IT MANAGEABLE. SO, WHEN THE PREVIOUS -- I'LL EXPLAIN THAT THERE WERE THREE PEOPLE ON THE PANEL. NOW THERE IS 1, ME. SO I'M THE LAST PERSON STANDING FROM A THREE-PERSON PANEL THAT ALSO INCLUDED HILL HARBOR AND OWEN WHITE. I THINK IT WAS -- THEY WERE REALLY GREAT PEOPLE TO HAVE AS PART OF THIS AND WHEN WE WERE NAMED TO THE PANEL, WE DECIDED THAT THE ONLY WAY TO REALLY MAKE THIS MEANINGFUL WAS TO ADOPT A SET OF CRITERIA ABOUT HOW WE WOULD SELECT TOPICS TO WORK ON. AND I THINK THE MOST IMPORTANT CRITERION WE CHOSE WAS ACTIONABLE RECOMMENDATIONS. SO THE THREE OF US AGREED THAT WE DIDN'T NEED TO DO THIS. WE WANTED TO DO IT. ONCE WE WERE NOMINATED, BUT THAT WE HAD TO DO SOMETHING MEANINGFUL. AND SO, FOCUSING ON ACTIONABLE RECOMMENDATIONS, AND WE HAD AN EARLY CONVERSATION WITH DOUG AND HAROLD VARMUS WHEN WE EVOLVED THESE RECOMMENDATIONS. AND WE REALLY STUCK TO THEM THROUGHOUT. AND WE ALSO WANTED TO MAKE SURE THAT OUR REPORTS WERE OF THE LENGTH THAT WOULD BE READ. OWEN WANTED THEM TO BE -- I THINK 10 PAGES OR SOMETHING LIKE THAT. WE ENDED UP WITH MORE THAN THAT, BUT IT WASN'T 500 OR ANYTHING REALLY. SO LONG THEY WOULDN'T BE READ. AND WE PRODUCED FOUR DIFFERENT REPORTS. THE FIRST WAS ON ACCELERATING HPV UPTAKE AND THEN CONNECTED HEALTH, WHICH REALLY FOCUSED ON ALL THE OPPORTUNITIES IN THIS CURRENT CONNECTED WORLD. AND THEN PROMOTING VALUE, AFFORDABILITY AND INNOVATION IN CANCER DRUG TREATMENT. AND THEN WE RECENTLY RELEASED AN UPDATE ON HPV VACCINATION. AND I'LL TALK TO YOU TODAY ABOUT THE LAST TWO REPORTS ON CANCER DRUG COSTS AND ON HPV VACCINATION FOR CANCER PREVENTION. AND PLEASE FEEL FREE TO INTERRUPT ME IF YOU HAVE QUESTIONS OR COMMENTS. AND I JUST WANT TO ADD ALSO THAT THE INPUT OF PEOPLE THROUGHOUT THE INSTITUTE -- AND ESPECIALLY CENTER DIRECTOR -- DIVISION DIRECTORS, AND HAROLD VARMUS, DOUG AND NED, HAVE REALLY BEEN CRITICAL TO PRODUCING WHAT I THINK ARE REALLY HIGH-QUALITY REPORTS. SO WE RELEASED IN THE SPRING. NED, ABI AND I WENT TO THE WHITE HOUSE AND SPOKE WITH ANDREW BREAM BERG, WHO IS NO LONGER THERE, ABOUT OUR REPORT AND OUR RECOMMENDATIONS. AND AT THE SAME TIME, THEY WERE REALLY INVOLVED IN A SET OF RECOMMENDATIONS AROUND DRUG PRICING THAT THEY WERE PRETTY INVESTED IN. SO THERE WERE SOME AREAS OF COMPLIMENTIARITY BUT REALLY DIFFERENT FOCUSES OVERALL. SO, THE MOTIVATION FOR DOING THIS REPORT WAS THE REAL SUBSTANTIAL INCREASE IN CANCER DRUG PRICING, PARTICULARLY IN ALIGNMENT WITH THE NEW CANCER DRUGS, WHICH ARE REMARKABLE IN THEIR POTENTIAL IMPACT, BUT ALSO WE HAVE SEEN AN INCREASE IN PRICING SO THAT $100,000 A YEAR IS PRETTY MUCH THE STANDARD NOW. AND THAT MEANS THAT DRUG COSTS HAVE ACCELERATED ABOVE OTHER ASPECTS OF MEDICAL CARE AND HAVE BECOME OUT OF RANGE FOR SOME PATIENTS. SO AT ONE OF OUR MEETINGS, WE HAD A PATIENT STAND UP AND HOLD UP A PILL, AND SAY CANCER PATIENTS ARE NOW SAYING, IT'S YOUR MEDICINE OR YOUR MORTGAGE. THAT IS REALLY AN UNSUSTAINABLE POSITION TO BE IN. BUT I JUST WANT TO EMPHASIZE THAT WE ARE ELATED BY THE KINDS OF OUTCOMES THAT NED TALKED ABOUT TODAY. IT'S JUST PLACING US IN A DILEMMA AS A COUNTRY, ABOUT HOW WE PAY FOR ALL OF THIS. SO WE LOOKED AT FINANCIAL TOXICITY WHICH IS REALLY SOMETHING THAT HAS COME OUT OF RESEARCH DONE BY NCI AND OTHERS, AND WE UNDERSTAND THAT THE COST OF DRUGS AND THE IMPACT ON PATIENTS FINANCIAL STATUS CAN HAVE REAL PHYSICAL OUTCOMES IN TERMS OF SHORT SURVIVAL, SKIPPED DOSES OF MEDICINE, WHICH PEOPLE USED TO THINK NEVER OCCURRED IN CANCER, AND NOW WE KNOW THEY DO. AND DEBT. WE HEARD FROM PATIENTS WHOSE FAMILIES WENT OR TOOK OUT SECOND MORTGAGES, WENT INTO DEBT, GAVE UP JOBS. IT'S IT HAS IMPACT NOT JUST ON THE PATIENT BUT ON THE WHOLE FAMILY. AND YOU ALL KNOW THAT. AND NEARLY -- AND ONE OF THE FINDINGS WE LEARNED WAS REALLY THAT A LOT MORE PATIENTS WANT TO TALK ABOUT THE COST OF DRUGS WITH THEIR DOCTORS AND PROBABLY HAS BEEN RECOGNIZED IN THE PAST. NEARLY 66% OF CANCER PATIENTS SAY THEY WANT TO TALK TO THEIR DOCTORS ABOUT CANCER COSTS. WE KNOW PHYSICIANS AREN'T TRAINED TO TALK ABOUT THIS. IT'S NOT NECESSARILY THE -- NOT NECESSARILY THE BEST PEOPLE TO HAVE THOSE DISCUSSIONS. BUT SOMEBODY HAS TO HAVE THOSE DISCUSSIONS. AND ABOUT 27% OF CANCER PATIENTS AND LESS THAN HALF OF ONCOLOGISTS, REPORT HAVING HAD CANCER-RELATED DISCUSSIONS, COST-RELATED DISCUSSIONS. IT'S NOT SURPRISING. THEY ARE HARD. THEY ARE NOT JUST DIFFICULT TO HAVE BUT IT'S HARD TO GET A HANDLE ON WHAT THE COST WILL BE FOR ANY ONE PATIENT. SO, WE HAD SEVERAL RECOMMENDATIONS, INCLUDING TO PROMOTE VALUE-BASED PRICING AND USE, WHICH IS DONE NOW IN MANY COUNTRIES. IT'S DONE IN SOME SETTINGS IN THE UNITED STATES, SOME INSURANCE COMPANIES BUT NOT ROUTINELY. WE WERE VERY FIRM IN THIS REPORT THAT IT'S CRITICAL TO PROVIDE ACCESS TO CANCER DRUGS, WE HAVE BEEN THEY ARE HIGH-PRICED DRUGS, WHEN THEY HAVE REAL VALUE. BUT WE ARE ALSO PAYING FOR DRUGS THAT DON'T HAVE REAL VALUE THAT EXTEND LIFE BY DAYS OR WEEKS, COMPARED TO THE KINDS OF DATA THAT NED WAS TALKING ABOUT TODAY. WE THOUGHT IT WAS REALLY IMPORTANT TO HAVE COMMUNICATION ABOUT TREATMENT COSTS AND OPTIONS. SO THE PATIENTS ARE FULLY INFORMED. SO THEY MAKE CLEAR, INFORMED DECISIONS BEFORE I THAT SAY GO OUT AND TAKE THAT SECOND MORTGAGE ON THEIR HOUSE. WE MINIMIZE CONTRIBUTIONS OF DRUG COSTS TO FINANCIAL TOXICITY, STIMULATE GENERICKING AND BIOSIMILAR MARKET COMPETITION. WE KNOW THAT THERE ARE A NUMBER OF BARRIERS. A NUMBER OF WAYS THAT GENERICS ARE INHIBITED, THAT BIOSIMILARS ARE INHIBITED AND IT'S REALLY IMPORTANT TO HAVE OPEN COMPETITION. AND WE FELT STRONGLY THAT IT WAS CRITICAL THAT THE FDA HAVE ADEQUATE RESOURCES IN ITS CANCER PROGRAM. AND THAT WE AS A COUNTRY CONTINUE TO INVEST IN BIOMEDICAL RESEARCH. AND I THINK SOME OF WHAT YOU HEARD FROM NED TODAY REALLY IS PROOF FOR THIS. SO OUR CONCLUSIONS WERE THAT RISING DRUG COSTS ARE A SIGNIFICANT PROBLEM, NOT NEWS TO ANYBODY HERE. AND THAT THE CONSEQUENCES FOR FAMILIES MEANT PATIENCE AND SOCIETY AS A LARGE, ARE TOO GREAT TO IGNORE. THAT AFFORDABLE ACCESS TO DRUGS WILL BE THE DIFFERENCE BETWEEN LIFE AND DEATH FOR MANY PATIENTS. AND THAT WE IDENTIFIED THREE PRINCIPLES THAT SHOULD GUIDE ACTION. CANCER DRUG PRICES SHOULD BE ALIGNED WITH VALUE TO PATIENTS. AND THAT SEEMS PRETTY OBVIOUS BUT WE KNOW THAT WE ARE PAYING FOR BOTH DRUGS THAT ARE HIGHLY EFFECTIVE, POTENTIALLY CURATIVE, AND THOSE THAT ARE ONLY MARGINALLY EFFECTIVE. THAT ALL PATIENTS SHOULD HAVE AFFORDABLE ACCESS TO APPROPRIATE DRUGS, AND THAT THERE MUST BE INVESTMENTS IN SCIENCE TO DRIVE FUTURE INNOVATION. SO, I THINK THESE WERE REALLY IMPORTANT AND SIGNIFICANT CONCLUSIONS AND REALLY ALIGN WITH WHAT ASCO, MANY OTHER ORGANIZATIONS HAVE BEEN SAYING. SO I WANT TO MOVE ON THEN TO THE REPORT THAT WE JUST RELEASED IN NOVEMBER, WHICH IS ON HPV VACCINATION AND SOME OF THE MOONSHOT EFFORTS THAT HAVE BEEN AROUND THIS TOPIC. THERE HAS BEEN A LOT OF NCI INTEREST AND COMMITMENT TO THIS ABOUT DIVISION, DIVISION OF CANCER PREVENTION, THE INTRAMURAL AND EXTRAMURAL PROGRAMS. AND THIS HAS REMAINED A VERY IMPORTANT AND EVOLVING FIELD SINCE WE RELEASED OUR REPORT IN 2012. SOME OF THE CHANGES HAVE BEEN ABOUT HOW MANY DOSES ARE NEEDED AND I'LL SAY A LITTLE BIT ABOUT THAT. AND THE EVOLVING DATA ABOUT THE VACCINE. WE JUST REALLY EXCITING AS A CANCER VACCINE. AND DOUG LOWY AND JOHN SCHILLER FROM THE INTRAMURAL PROGRAM, HAD MUCH TO DO WITH THIS DISCOVERY OF THIS, AND REALLY IMPLEMENTATION. AND DOUG HAS BEEN A GREAT REVIEWER. IF YOU WANT TO COMMENT AT ANY POINT, PLEASE JUST JUMP IN. AND I ALSO WANT TO THANK NOEL BREWER AT THE GILLING SCHOOL AND REALLY ONE OF THE INTERNATIONAL EXPERTS TO THE VACCINE. AND THERE HAVE BEEN A LOT OF PEOPLE WHO CONTRIBUTED. I WON'T READ ALL THE NAMES. WE REACHED OUT TO PEOPLE WITHIN THE INSTITUTE, AMERICAN CANCER SOCIETY, CDC, HHS, WE KNEW IT WAS IMPORTANT TO BRING PEOPLE TOGETHER. AND ONE OF THE IMPORTANT LESSONS WE LEARNED EARLY IS THAT THE IMMUNIZATION COMMUNITY AND THE CANCER PREVENTION CONTROL COMMUNITIES REALLY HAD VERY LITTLE TO DO WITH EACH OTHER AT THE BEGINNING. AND I THINK ONE OF THE THINGS WE DID WAS TO BRING THEM TOGETHER, AND THAT REALLY TOOK PEOPLE FROM NCI, CDC, AND, BEING WILLING TO LEARN EACH OTHER'S LANGUAGE AND PRIORITIES. SO WHEN WE STARTED -- AND HERE ARE SOME ADDITIONAL NAMES. WHEN WE STARTED, THE VACCINE HAD BEEN RECENTLY RELEASED AND APPROVED BY THE COMMITTEE ON IMMUNIZATION PRACTICES. THREE DOSES WERE REQUIRED SO THREE DIFFERENT TIMES PEOPLE HAD TO COME BACK FOR VACCINATION, AND RATES WERE REALLY LOWER THAN THEY SHOULD HAVE BEEN AND JUST BEGINNING FOR MALES WHO WERE APPROVED FOR USE OF THE VACCINE IN 2011. AND WE THOUGHT IT WAS -- WE REALLY WANTED TO KEEP THE FOCUS ON HPV VACCINATION BECAUSE EVEN NOW ABOUT 50% OF PEOPLE HAVE BEEN VACCINATED WITH ALL THREE DOSES. BUT ONE OF THE -- I THINK REALLY IMPORTANT THINGS THAT CHANGED SINCE OUR ORIGINAL REPORT, IS THAT NOW ONLY TWO DOSES ARE REQUIRED FOR MOST PEOPLE. SO, 15 OR LESS, AGE 15 OR LESS, TWO DOSES. AND FOR THOSE WHO INITIATE AFTER AGE THIRTEEN, IT'S STILL 3 DOSES. WE HOPE THAT WILL CHANGE. AND THE CHANGE IN RECOMMENDATIONS WAS BASED ON IMMUNE DATA SHOWING THAT THOSE WITH TWO VACCINE DOSES RESPONDED IN MOST CASES EVEN BETTER THAN THAN THOSE WITH THREE. AND THE FDA RECENTLY UPDATED ITS STANDARDS TO INCLUDE OR SAY WITH GUARDASIL 9, THE ONLY VACCINE USED IN THE UNITED STATES RIGHT NOW, THAT THE AGE CAN BE BROADENED TO INCLUDE THOSE 27-45. AND THAT IS REALLY A PROFOUND DIFFERENCE. THAT. WE EXPECT THAT THAT MAY HAPPEN IN THE FALL, BUT THAT MEETING HASN'T YET OCCURRED. I THINK THAT'S RIGHT. WE HAVEN'T TRACKED WITH HOW RECENTLY THE MEETING -- WHETHER IT HAS OCCURRED. I DIDN'T THINK IT HAD YET. HPV-RELATED CANCERS ARE MORE OF A PROBLEM THAN IN THE UNITED STATES, YOU CAN SEE THE WORLDWIDE AND UNITED STATES, IT'S A CAUSE OF MANY CANCERS BESIDES CERVICAL CANCER. AND ORAL CANCERS ARE INCREASING OUTCOMES. SO WHAT WE HAVE SEEN FROM THE BEGINNING OF THE RELEASE OF THE VACCINE, IS THAT VACCINE UPTAKE FOR HPV IS LESS THAN FOR OTHER ADOLESCENT VACCINES. YOU CAN SEE THAT IN THE DIFFERENT CURVES. BUT THERE HAS BEEN PROGRESS. SO ABOUT -- THERE IS INCREASE OF ABOUT FIVE PERCENTAGE POINTS EVERY YEAR FROM 2013 TO 17. AND THEY HAVE BEEN PARTICULARLY PRONOUNCED AMONG MALES. BUT THERE ARE ALSO IMPORTANT GEOGRAPHIC DIFFERENCES ACROSS THE UNITED STATES. SO THERE ARE A FEW STATES WITH VERY HIGH PENETRATION OF THE VACCINE AND SOME STATES IN GRAY WITH VERY LOW VACCINATION RATES. SOME PEOPLE HAVE JUST CHARACTERIZED THIS AS RURAL VERSUS URBAN, BUT IT'S MUCH MORE COMPLEX THAN THAT. AND WE DON'T KNOW ALL THE REASONS FOR THE DIFFERENCES ELECTRA MIGHT WANT TO COMMENT ON THAT AT SOME POINT. SO WE SEE SOME CONTINUING CHALLENGES, VACCINATION RATES REMAIN LOWER THAN FOR OTHER ADOLESCENT VACCINES. LOWER THAN THAT IN OTHER COUNTRIES. SO AUSTRALIA HAS OVER 70% OF AGE-ELIGIBLE MALES AND FEMALES HAVING BEEN VACCINATED. BUT AUSTRALIA IS A COUNTRY THAT DOES COUNTRY-WIDE CAMPAIGNS. THEY ARE ABLE TO GO INTO SCHOOLS AND VACCINATE IN SCHOOLS. THEY ARE ABLE TO DO THINGS THAT IN OUR COUNTRY, WHICH HAS SCHOOLS REGULATED LOCALLY AND STATEWIDE, WE JUST CAN'T DO. AND THOSE CENTRAL STRATEGIES CAN OFTEN BE VERY EFFECTIVE. SO UPTAKE IS VERY UNEVEN ACROSS THE UNITED STATES. AND THE DISTRICT OF COLUMBIA HAS A RATE OF 78% VERSUS MISSISSIPPI, WHICH IS 29%. WAY TOO LOW. SO WHEN WE ISSUED OUR REPORT IN 2012, WE CONCLUDED THAT HPV -- THAT UNDERUSE OF THE VACCINE WAS A SERIOUS BUT CORRECTABLE THREAT TO PROGRESS AGAINST CANCER. AND CONVERSATIONS THAT WE HAD RECENTLY SUGGESTED THAT THERE WAS A NEED FOR US TO COMMENT AGAIN BECAUSE I'M THE ONLY PERSON ON THE PANEL, WE MADE IT A REPORT FROM THE CHAIR AND SINCE IT CAN'T HARDLY BE THE PANEL -- THIS IS A CHALLENGE BUT WE REALLY TRIED TO FINESSE THAT. WE DIDN'T HOLD MEETINGS BUT WE TALKED WITH KEY STAKEHOLDERS. WE LOOKED AT THE RECENT LITERATURE AND NOEL BREWER WORKED WITH US VERY CLOSELY ON THE REPORT. SO THE ORIGINAL GOALS WERE TO REDUCE MISSED CLINICAL OPPORTUNITIES, TO INCREASE PARENTS, CAREGIVERS AND ADOLESCENCE ACCEPTANCE OF VACCINES, TO MAXIMIZE ACCESS, AND PROMOTE GLOBAL UPTAKE. THE KINDS OF REASONS THAT THE PEOPLE AREN'T BEING VACCINATED ARE VERY MUCH LIKE OTHER CANCER CONTROL STRATEGIES LIKE SMOKING, MAMMOGRAPHY, OTHER KINDS OF CANCER SCREENING, THAT PEOPLE NEED STRONG, CLEAR RECOMMENDATIONS FROM PROVIDERS. WE NEED SYSTEMS CHANGES. IT NEEDS TO BE A PART OF SYSTEMS THAT ADOLESCENTS GET ASKED AND ASSESSED AND HEALTH CARE PROVIDERS HAVE TO GIVE STRONG RECOMMENDATIONS FOR VACCINATIONS. MOST PEOPLE, MOST PARENTS, WHEN THEY ARE GIVEN THAT KIND OF A RECOMMENDATION, ARE GOING TO HAVE THEIR CHILD VACCINATED. SO WE NEED COMMUNICATION CAMPAIGN IS PROMOTION AND MORE MUST BE DONE TO ASSURE THAT PARENTS HAVE ACCESS TO CLEAR, ACCURATE INFORMATION. WE NEED TO MAKE SURE THAT AS THE AFFORDABLE CARE ACT CHANGES OVER TIME, THAT VACCINATION IS KEPT AS SOMETHING THAT IS AFFORDABLE AND CONVENIENT. AND WE NEED TO MAKE SURE THAT THE COST COVERED FOR ADOLESCENCE ADOLESCENCE. SO, I HOPE THAT THIS WILL BE COVERED IN THE DISCUSSION ABOUT GLOBAL CANCER, BUT THE POTENTIAL IMPACT IS GREATEST IN LESS DEVELOPED COUNTRIES WHERE THE VAST MAJORITY OF CERVICAL CANCER CASES AND DEATHS OCCUR. SO WE SHOULD CONTINUE TO SUPPORT IMPLEMENTATION AND SUSTAINABILITY OF VACCINATION IN COUNTRIES AROUND THE WORLD, ESPECIALLY IN LOW AND MIDDLE-INCOME COUNTRIES. AND THEN THERE IS SOME AREAS FOR RESEARCH. ONE IS TO ESTABLISH THE NATURAL HISTORY OF ORAL HPV INFECTIONS. SO WE HAVE SEEN ABOUT AN 88% DECREASE IN ORAL CANCERS AMONG VACCINATED POPULATIONS IN THE UNITED STATES BUT STILL DON'T HAVE DEFINITIVE EVIDENCE, AND THAT IS SOMETHING THAT IS VERY MUCH-NEEDED. WE NEED TO UNDERSTAND INEQUITIES AMONG POPULATIONS WITH HIGH RATES. AND I THINK WE CONTINUE TO FEEL HOW IMPORTANT IT WAS TO USE SOCIAL MEDIA TO COMMUNICATE ABOUT HPV AND ABOUT VACCINATION, AND HOPEFULLY WE WILL GET TO THE POINT WHERE A SINGLE DOSE WILL BE SUFFICIENT FOR EFFICACY. SO, I'LL JUST SHARE THE OVERARCHING CONCLUSIONS, WHICH ARE ABOUT SYSTEM-LEVEL CHANGES, THE IMPORTANCE OF PARTNERSHIPS AND COLLABORATIONS, AND THAT PROGRESS AND MOMENTUM BUILT OVER THE PAST HALF DECADE CREATED A COMPELLING OPPORTUNITY TO INCREASE UPTAKE AND REDUCE HPV CANCERS. THIS IS A PLACE WHERE I THINK REALLY WELL AND HAVE WORKED TOGETHER. NCI HAS INVESTED IN THIS. THE CDC, ACS, IT'S BEEN A REALLY GOOD EXAMPLE OF THE VALUE OF PARTNERSHIPS. SO I WANT TO THANK A NUMBER OF PEOPLE FROM THE NCI WHO HAVE REALLY WORKED WITH US CLOSELY. I THINK ONE OF THE LESSONS I LEARNED FROM WORKING AT THE NCI WAS THAT IT'S REALLY IMPORTANT TO EVOLVE -- INVOLVE PEOPLE AT THE START, THAT GIVING THEM A REPORT AFTER ITS DONE AND ASKING STAFF TO SAY HOW THEY'LL MAKE IT ACTIONABLE, IS NOT THE WAY TO WORK WITH NCI STAFF. THERE IS SOME PHENOMENAL PEOPLE HERE AND THEY HAVE REALLY HELPED US TO DEVELOP REPORTS THAT I THINK ARE MEANINGFUL AND HAVE HAD IMPACT. AS MY TERM ENDS, I REALLY WANT TO TELL YOU AND THANK THE OUTSTANDING STAFF THAT WE HAD WORKING ON THIS AND CONTRACTORS AS WELL AND THEIR NAMES ARE LISTED UP HERE, FOR A SMALL TEAM OF PEOPLE, I THINK THEY GET A LOT DONE AND WE'VE BEEN ABLE TO DO WORK THAT MATTERS. AND IT'S REALLY FROM BEING FOCUSED ON WORKING VERY CLOSELY WITH PEOPLE FROM AROUND THE INSTITUTE. SO, I HOPE THAT IF THERE IS A NEW PANEL, WHEN THERE IS A NEW PANEL, THAT THEY WILL CONSIDER THE KINDS OF CRITERIA THAT WE ADOPTED SO THAT THE REPORTS CONTINUE TO BE MEANINGFUL AND THAT THERE IS A REAL ATTEMPT TO INVOLVE NECESSARY ORGANIZATIONS AND AGENCIES SO THAT THIS BECOMES, THE PRODUCTS ARE OWNED NOT JUST BY THE PANEL, BUT BY THE LARGER COMMUNITY. SO I WILL STOP THERE AND BE HAPPY TO TAKE QUESTIONS OR COMMENTS. >> THANK YOU BARBARA. >> I WANT TO THANK BARBARA FOR DOING THIS -- [ APPLAUSE ] THESE REPORTS ARE REALLY IMPORTANT AND COMMITMENT AND CONTINUATION OF WORK IS REALLY APPRECIATED. SO THANK YOU FOR YOUR SERVICE. I KNOW YOU HAVE A BUSY DAY JOB. >> YES, THANK YOU. >> QUESTIONS FOR BARBARA? >> SO BARBARA, I HAVE JUST A QUESTION I NOTED IN THE DATA YOU PRESENTED I HADN'T THOUGHT ABOUT, MAYBE IT'S -- WHEN YOU LOOK AT THE PATTERNS OF CANCERS RELATED TO HPV IN THE U.S. VERSUS WORLDWIDE, IT'S STRIKING THAT THE FREQUENCY OF CANCERS SO LOW. DO YOU THINK THAT IS JUST FAILURE TO SCREEN THOSE CANCERS FOR HPV VERSUS ACTUAL DIFFERENCES IN FREQUENCY? >> DR. RIMER: LET ME SEE IF WE CAN GET BACK TO THAT SLIDE. >> THE NCI ACTUALLY DCEG SPONSORED A RESEARCH WORKSHOP LAST WEEK. AND THIS WAS ONE OF THE QUESTIONS THAT CAME UP. I THINK THE ANSWER OF WHERE ARE WE GOING IN AREAS WITH LOW INCIDENCE OF ORAL PHARYNX CANCER, IS UNCLEAR. AND IT REMAINS TO BE SEEN WHAT THE TRAJECTORY IS GOING TO BE. IT'S COMPLICATED TO SOME DEGREE BECAUSE DATA THAT ARE AVAILABLE IN LOW AND MIDDLE-INCOME COUNTRIES ARE LESS ROBUST THAN WHAT WE HAVE IN HIGH-INCOME COUNTRIES AND IN ADDITION, TAKING A SNAPSHOT OF PREVALENCE AT ONE TIME POINT IS NOWHERE NEAR AS INFORMATIVE ABOUT THIS PARTICULAR KIND OF HPV-ASSOCIATED CANCER AS LOOKING AT THE TRAJECTORY OVER TIME. >> THANK YOU, DOUG. >> WONDERFUL WORK BARBARA. ALWAYS AMAZING. ONE QUESTION. YOU COMPARED AUSTRALIA TO THE UNITED STATES ABOUT THE NATIONAL SYSTEM. NOW WE'VE MANAGED TO GET OTHER YOUTH-RELATED VACCINES AT A MUCH HIGHER LEVEL OF PREVALENCE, PARTICULARLY THROUGH SCHOOL ENTRY REQUIREMENTS. SO HAD YOU CONSIDERED, FOR EXAMPLE, CDC RECOMMENDING THAT HPV BE PART OF THE PACKAGE OF VACCINES THAT YOUTH GET AS A CONDITION OF SCHOOL ENTRY? >> WE DID WHEN WE DID THE INITIAL REPORT AND WE HAD A LOT OF DISCUSSION ABOUT THAT. AND THERE WAS A LOT OF CONCERN THAT IT WAS GOING TO END UP WITH PEOPLE BEING VACCINATED OUTSIDE OF THE RECOMMENDATIONS FOR WHEN THE VACCINE WAS SUPPOSED TO BEGIN. I THINK THE PROBLEM WITH HPV VACCINATION WAS INITIALLY ITS LINKAGE TO SEX AND SEXUAL BEHAVIOR. AND ONE OF THE THINGS THAT OUR REPORT DID WAS TO -- AND PEOPLE REALLY WERE AT THE RIGHT POINT TO TALK ABOUT THIS. WAS REAL TOW REFRAME IT AS CANCER PREVENTION, NOT ABOUT SEXUAL BEHAVIOR. AND I THINK THE FACT THAT IT'S EARLY RELEASE AND DISCUSSIONS WERE SO OFTEN ABOUT SEXUAL BEHAVIOR AND READINESS FOR SEXUAL BEHAVIOR, THAT IT AFFECTED ITS EARLY TRAJECTORY. I THINK AT SOME POINT, MAKING IT PART OF REQUIRED SCHOOL DOCUMENTATION, WOULD MAKE A BIG DIFFERENCE, ALTHOUGH SOME PARENTS WOULD OPT-OUT, BUT IT WOULD HELP TO PUSH IT FURTHER ALONG. >> I THINK DEVIATING FROM SEX REALLY -- IT'S ONE OF OUR MOST EFFECTIVE CANCER PREVENTIONS. >> YES. IT IS A REMARKABLE VACCINE. >> LAST TIME YOU GAVE THE REPORT, BARBARA, YOU MENTIONED TWO THINGS AND REFERRED TO THEM AGAIN, ONE OF THEM AGAIN. EDUCATING THE PEDIATRICIANS WHO OFFER IT AND THE SECOND THING WAS, ACCESS AND HAVING ACCESS EASIER THROUGH PHARMACY, LOOKINGS SAY. HAS ANY PROGRESS BEEN MADE ON THOSE TWO AREAS? >> DR. RIMER: A LOT OF WORK HAS BEEN DONE AND FUNDED BY NCI ON MAKING IT A ROUTINE PART OF HEALTH CARE, OF MEDICAL CARE. AND STRENGTHENING RECOMMENDATIONS OF PEDIATRICIANS AND OTHER PHYSICIANS. THERE HAS BEEN A LOT OF WORK TO REFINE THE KIND OF WORDING THAT SHOULD BE USED, HOW IT SHOULD BE DONE, WHEN IT SHOULD BE DONE. SO PROGRESS IS REALLY BEEN MADE ON THAT. THE PHARMACY ISSUE HAS BEEN HARDER TO MOVE THE NEEDLE ON BECAUSE PHARMACY REGULATIONS ARE STATEWIDE. SO IT'S KIND OF LIKE TRYING TO GET INTO SCHOOLS. AND SOME STATES ALLOW IT AND SOME STATES DON'T. SO IT'S NOT LIKE THE FLU SHOT WHERE MANY OF US NOW GO TO THE PHARMACY FOR YOUR FLU SHOT BECAUSE IT'S SO EASY TO DO. IT REALLY HADN'T BEEN FACILITATED IN THAT WAY FOR PHARMACIES. AND I DON'T KNOW IF ANY OF THE OTHER PEOPLE WHO ARE WORKING IN THIS FIELD WANT TO COMMENT. >> SO BARBARA, I THINK YOU'RE RIGHT ON. AND PHARMACIES ARE REGULATED BY STATE AND IN SOME IS A LITTLE, FOR EXAMPLE, FILED AROUND - I'M JUST GOING TO THROAT OUT A NUMBER, 14 OR SO, STILL HAS TO HAVE A PRESCRIPTION TO BE ABLE TO GET THAT HPV VACCINE. BUT I THINK BARBARA IS EXTREMELY ON TRACK WITH EVERYTHING SHE SAID. AND I THINK WHAT WILL REALLY HELP US FOR THE UPTAKE OF HPV VACCINE IS TO HAVE A CHANGE IN THE CULTURAL NORMS ABOUT IT AWAY FROM SEX AND AWAY FROM CERVICAL CANCER AND MANY PEOPLE THINK THAT IT'S ONLY 10,000 WOMEN OR 3000 WOMEN WHO DIE FROM CERVICAL CANCER. THAT'S NOT MANY. BUT, THOSE ARE JUST THE CANCERS. WE HAVEN'T TALKED ABOUT THE PRE-CANCEROUS CONDITIONS, ET CETERA. AND I THINK WE HAVE TO START DRIVING HOME THE MAGNITUDE OF THIS IN ADDITION TO THE FACT THAT WE COULD PREVEN UP TO 30,000 PEOPLE EACH YEAR FROM SUFFERING WITH CANCER IN TERMS OF AS A CULTURAL NORM. AND I DON'T KNOW IF SENDING THIS TO THE PRESIDENT, BEING THE PRESIDENT'S CANCER PANEL L CHANGE HIS OPINION ABOUT HPV, BUT IT REALLY HAS TO START FROM THE TOP AND WE HAVE TO HAVE SOME NATIONAL CONVERSATIONS ABOUT THE TRUTH ABOUT HPV VACCINATION AND THESE CANCERS. >> THANK YOU ELECTRA. REALLY THE FACT THAT IT IS ALMOST TOTALLY PREVENTIBLE CANCER, THAT WE HAVE THE EXPORT TOW DO THIS AND WE HAVEN'T YET DONE IT, IS REALLY UNFORTUNATE. THIS IS SOMETHING UNDER OUR CONTROL. >> I THINK YOU COVERED MOST OF THE POINTS. BARBARA THANK YOU AGAIN FOR THE LEADERSHIP. >> THANK YOU. >> LOOKING AT THE SUCCESS? PLACES LIKE RHODE ISLAND OR THE DISTRICT HERE, HAVE YOU GUYS GONE TO LIKE THE GOVERNORS AND REALLY TAKEN THE EFFORT TO THE STATE LEVEL WHERE THERE CAN BE LEGISLATION FOR SCHOOL ENTRY AND CHANGING THE REQUIREMENTS OF PHARMACIES AND THINGS LIKE THAT? RECOGNIZINGRECOGNIZING THAT IT WILL NEED T O BE DECENTRALIZED AND FOCUS IN ON ONE OR TWO STATES IN THE LOWER QUARTILE WHERE WE MAY HAVE GOOD RELATIONS WITH THE GOVERNOR'S HOUSE. >> IT'S A GREAT SUGGESTION. I WISH WE COULD HAVE DONE THAT BUT WE BASICALLY WERE THREE PANEL MEMBERS AND THREE STAFF PEOPLE. SO THAT WAS BEYOND US. BUT I THINK IT'S SOMETHING THAT COULD BE CONSIDERED BY VARIOUS CANCER GROUPS. BECAUSE IT IS A SHAME THAT THERE IS -- THAT THE DECENTRALIZED SYSTEM KEEPS US FROM USING STRATEGIES THAT OTHER COUNTRIES DEMONSTRATED. SO THANK YOU FOR THAT. >> GREAT. THANK YOU. >> THANK YOU. >> ANY OTHER QUESTIONS? THANK YOU BARBARA. >> THANK YOU. AND I REALLY AM GRATEFUL FOR THE PRIVILEGE OF HAVING LED THIS PANEL. IT'S THE BEST CONTINUING EDUCATION I COULD EVER IMAGINE. >> THAT'S GREAT. WE WILL MOVE ON TO THE LEGISLATIVE REPORT AND MK HOLOHAN. >> Ms. HOLOHAN: GOOD MORNING. SO, THIS IS GOING TO BE A LITTLE ABBREVIATED GIVEN THE SCHEDULE THAT YOU HAVE TODAY. BUT I WANTED TO JUST SAY, AS ALWAYS, MY TEAM IS HAPPY TO TALK TO ANY OF YOU ON LINE, CALL US, E-MAIL US, HAVE YOUR STAFF CALL US. I WANTED TO MAKE SURE YOU KNEW MY DEPUTY AND I -- HOLLY GIBBONS IN THE POLKA DOTS, WE WILL BE HERE ALL DAY SO IF ANYONE WANTS TO CATCH US AT A BREAK, WE WOULD LOVE TO TALK TO YOU. UPDATE ON MIDTERM ELECTIONS AND COMMITTEE CHANGES IMPORTANT TO NIH FROM BOTH APPROPRIATIONS AND AUTHORIZING PERSPECTIVE. A LITTLE RECAP ABOUT FY19 APPROPRIATIONS WHICH IS DONE FOR US BUT NOT DONE FOR THE ENTIRE GOVERNMENT YET. A LITTLE NOTE ABOUT CONGRESSIONAL HEARINGS AND VISITS. DR. SHARPLESS HAS BEEN VERY BUSY WITH THESE THIS YEAR AND A LOOK AHEAD AT FY20 AND BUDGETED CAPS. WE HAVE MORE TO CONTEND WITH IN FY20 IN TERMS OF A BUDGET DEAL. SO LAST TIME WE MET, I SHOWED YOU THIS SLIDE WHICH REALLY IS DEPICTING THE HISTORY TELLS US THAT IN THE MIDTERM ELECTIONS, THE PRESIDENT'S PARTY LOSES SEATS. ALMOST ALWAYS IN THE HOUSE, SOMETIMES IN THE SENATE AS WELL. WHAT WE SAW IN YEAR WAS A LITTLE DIFFERENT. WE SAW PRESIDENT'S PARTY LOSING A LOT OF SEATS IN THE HOUSE, DEMOCRATS FLIPPED 42 SEATS FROM Rs TO Ds AND ENDED UP WITH A 40-SEAT GAIN AND THE REPUBLICANS GAINED TWO SEATS IN THE HOUSE. THIS MAY BE HAVE BEEN A BLUISH WAY BUT MAYBE OUTLINED PURPLE TO SLIGHT THE DIFFERENCE. THAT IS INTERESTING BECAUSE THAT IS NOT WHAT WE SAW IN ANY OF THE PRIOR MIDTERMS. SO AS EVERYONE KNOWS, THE DEMOCRATS CAPTURED THE HOUSE. THEY HAVE BEEN IN THE MINORITY IN THE HOUSE FOR THE PAST EIGHT YEARS. WITH PRETTY SUBSTANTIAL WIN. THE REPUBLICANS SAW THIS COMING AND I THINK THIS IS WIDELY EXPECTED. WITH A LITTLE SURPRISING THE REPUBLICANS INCREASED THEIR MAJORITY. THAT IS SOMEWHAT SIGNIFICANT INCREASE FOR A BODY THAT IS SO CLOSELY DIEDED AND ONLY 100 SLOYDS -- DIVIDED. THIS SLIDE SHOWS THE HOUSE, SENATE AND WHITE HOUSE CONTROL SINCE 2009. AND SO, WHAT THIS SHOWS THAT THE PLUS 35 AND THE FAR COLUMN FOR 2019, THAT IS THE MARGIN, THE DIFFERENCE, DELTA BETWEEN Rs AND Ds IN THE BODY. SO WHAT WE ARE SEEING IS A DIVIDED CONGRESS AND A REPUBLICAN ADMINISTRATION. OTHER PRESIDENTS HAVE DEALT WITH THIS AS WELL. BUT IT'S NOT AS COMMON IF YOU LOOK AT THE TRAJECTORY FOR THE PAST FEW YEARS IT'S A LITTLE BIT DIFFERENT. SO WHAT THIS MEANS IS, WE'LL SEE REQUIRES BOTH CHAMBERS TO ADVANCE LEGISLATION AND SO WE WILL SEE WHAT POINTS OF AGREEMENT CAN BE REACHED AND WHAT LEGISLATION WILL NOT HAVE A CHANCE. SO THIS IS NOT GOING TO IMPROVE THE PRODUCTIVITY OF THE CONGRESS BEING ABLE TO GET BILLS TO THE FINISH LINE. SOME OF THE LEADERSHIP CHANGES. EVERYONE HAS READ EXHAUSTIVELY ABOUT THE RACE FOR SPEAKER OF THE HOUSE. SO CONGRESSWOMAN PELOSI HAS GOTTEN THE INITIAL NOD FROM HER PARTY. SHE GOT ENOUGH VOTES IN THE LEADERSHIP MEETINGS WHEN CONGRESS CAME BACK AFTER THE THANKSGIVING RECESS. HOWEVER, THE SPEAKER OF THE HOUSE HAS TO BE NOMINATED AND VOTED ON BY THE ENTIRE CONGRESS. THAT'S IN THE CONSTITUTION. THIS IS THE THIRD LINE FOR THE PRESIDENCY SLOT AFTER THE VICE PRESIDENT. SO SPEAKER OF THE HOUSE. SO, SHE WILL HAVE TO HAVE A VOTE ON JANUARY 3. THE MAGIC NUMBER IS 218. PRESIDENT TRUMP HAS TWEETED THAT THERE WILL BE REPUBLICAN SUPPORT FOR HER. SHE IS DETERMINED TO WIN WITH DEMOCRATIC VOTES. THERE ARE SITUATIONS WHERE SHE MAY NOT NEED 218 VOTES. WHAT SHE NEEDS IS MAJORITY OF MEMBERS VOTING THAT DAY AND PRESENT. THERE MAY BE LESS THAN THE FULL CONGRESS ASSEMBLED TO VOTE, IN WHICH CASE THE NUMBER OF VOTES SHE WOULD NEED WOULD BE LOWER THAN 218. WE'LL SEE WHAT HAPPENS WITH THIS. THERE IS A PRETTY VOCAL DECENTING GROUP TO WANTING YOUNGER LEADERSHIP, DIFFERENT LEADERSHIP. THERE IS REALLY AT THIS POINT NO VIABLE CONTENDER. JOE CAROLLO FROM NEW YORK HAD LOOKED LIKE SORT OF THE MOST OBVIOUS SENIOR AND WELL SUPPORTED CHALLENGER BUT HE WAS DEFEATED IN HIS PRIMARY. SO, HE IS NO LONGER IN THE MIX. SO THE FIRST TABLE SHOWS YOU THE HOUSE LEADERSHIP FOR BOTH REPUBLICANS AND DEMOCRATS. THE SECOND SET OF DATA SHOWS YOU THE LEADERSHIP FOR HOUSE APPROPRIATIONS. WE HAVE A SITUATION THAT I THINK HAS NOT HAPPENED BEFORE IN EITHER THE HOUSE OR SENATE. WE HAVE THE INCOMING, NEXT CONGRESS, THE CHAIR OF THE HOUSE APPROPRIATIONS COMMITTEE WILL BE LOWY FROM NEW YORK WHO HAS BEEN IN CONGRESS SINCE 1988. AND RANKING MEMBER IS FROM TEXAS WHO HAS BEEN IN CONGRESS SINCE 1996. CONGRESSWOMAN LOWE AND CONGRESSWOMAN GRAINGER WORKED TOGETHER FOR MANY YEARS IN STATE AND FOREIGN OPS. BOTH IN LEADERSHIP POSITIONS ON THAT SUBCOMMITTEE, THE APPROPRIATIONS COMMITTEE FOR STATE AND FOREIGN OPS. SO THEY HAVE A LONGSTANDING CORPORATIVE COLLABORATION. THEY HAVE A PERSONAL FRIENDSHIP. THIS BODES WELL FOR THE APPROPRIATIONS COMMITTEE GETTING THEIR WORK DONE. ROSA DELORA FROM CONNECTICUT, LONGSTANDING MEMBER OF CONGRESS, ALSO OVARIAN CANCER SURVIVOR, WILL BE CHAIR OF THE HOUSE APPROPRIATIONS LABOR HHS COMMITTEE. TOM COLE, REPUBLICAN FROM OKLAHOMA WHO HAS BEEN CHAIRMAN OF THE COMMITTEE FOR THE PAST SEVERAL YEARS, WILL REMAIN AS RANKING MEMBER. HE WAS IN THE LEADERSHIP RACE FOR THE FULL COMMITTEE CHAIR WITH OTHER CARDINALS, SUBCOMMITTEE CHAIRS IN THE HOUSE. AND WE WERE A LITTLE WORRIED THAT HE MIGHT GET THAT JOB AND THEN NOT BE ABLE TO POSSIBLY NOT BE ABLE TOL STAY AS THE LABOR HHS RANKING REPUBLICAN, BUT THAT IS NOT THE CASE. AND WE REALLY THINK THESE TWO ALSO CONGRESSMAN DELOREO AND CONGRESSMAN COAL, KNOW EACH OTHER WELL. CONGRESSMAN COAL AS CHAIRMAN BROUGHT IN A VERY COLLABORATIVE COOPERATIVE DYNAMIC TO THE SUB COMMITTEE THAT HAD BEEN VERY FRACTIONED IN THE PAST PRE SAIDING SIX-EIGHT YEARS SO THIS REALLY BODES WELL FOR US AS WELL. THE AUTHORIZING COMMITTEES WE EXPECT TO SEE FRANK FROM NEW JERSEY AS THE CHAIR OF THE BIG ENERGY AND COMMERCE COMMITTEE AND CONGRESSWOMANNA FROM CALIFORNIA, WHO IS A HUGE SUPPORTER OF PANCREATIC CANCER RESEARCH AND HAD CONVERSATIONS WITH NCI IS THIS TOPIC. WE EXPECT HER TO BECOME CHAIR OF THE HEALTH SUBCOMMITTEE WHICH IS THE MAIN SUB COMMIT THEY NIH WOULD DEAL WITH FROM THE AUTHORIZERS IN THE HOUSE. SO, WHAT DOES THIS MEAN FOR US? WE HAD TREMENDOUS BIPARTISAN SUPPORT AND THIS IS NIH A POINT OF AGREEMENT AMONG THE Rs AND Ds ON THE APPROPRIATION SUBCOMMITTEE. WE EXPECT THAT TO CONTINUE AND WE HEARD SOME VERY ENCOURAGING THINGS FROM CONGRESSWOMAN LOWY AND CONGRESSWOMAN DELOREO. CONGRESSWOMAN DELOREO HAS BEEN VOCAL SHE IS LOOKING FOR A MUCH BIGGER ALOCATION FOR THE BILL. NIH IS NOT THE ONLY THING IN THIS BILL. THERE IS LABOR. THE ENTIRE DEPARTMENT OF LABOR, DEPARTMENT OF EDUCATION AND ALL OF HHS. SO THERE ARE OTHER PRIORITIES FOR THE DEMOCRATS THAT THEY HAVE MADE CLEAR THAT THEY HAVE NOT GOTTEN TO FUND AS THROUGHLY AND FULLY AS THEY WANT TO. AND AS THEY WOULD HAVE LIKED TO IN THE PAST FEW YEARS. SO, WE ARE HOPEFUL THAT THERE WILL BE A BIGGER APPROPRIATION FROM THE COMMITTEE TO DIVIDE AMONG THESE SUBCOMMITTEE BILLS BECAUSE THAT IS GOING TO BE IMPORTANT FOR NIH TO CONTINUE TO ENJOY THESE SUSTAINED INCREASES. SO FOR FY19, THE DEFENSE LABOR HH BILL WAS SIGNED INTO LAW ON SEPTEMBER 28 PROVIDING ANOTHER TWO BILLION DOLLARS, INCREASE FOR NIH AND WHICH ACQUITTED TO US 79.3 MILLION INCREASE FOR NCI. WE ALSO RECEIVED THE 400 MILLION ALOCATION FOR THE CANCER MOONSHOT. EVEN THE DEFENSE BILL HADN'T HAD ON TIME BUDGET SINCE 2008. THIS WAS A BRILLIANT STRATEGY STARTING IN THE SENATE WITH APPROPRIATORS WHO INSISTED THAT DEFENSE BE PUNISHED WITH LABOR. DEFENSE IS A MUST PASS. EVERYONE SUPPORTS IT. IT'S GOING TO GO. IT MAY NOT GO ON TIME BUT IT WILL BE FUNDED. LABOR H IS THE MOST CONTENTIOUS. THERE IS A LOT OF 308 SEE ISSUES. A GREAT DEAL OF DISAGREEMENT ABOUT IT. -- A LOT OF POLICY ISSUES. IT'S THE MOST COMPLICATED BILL TO GET DONE. COUPLING THESE, AND IT WAS ABSOLUTELY FROM WHAT WAS REPORTED AND WHAT WE HEARD FROM STAFFERS, IT WAS A NO QUESTIONS ASKED, THIS IS SET IN STONE AND IT IS GOING TO HAPPEN. THERE WERE MANY MEMBERS OF THE HOUSE PARTICULARLY FISCAL CONSERVATIVES WHO DIDN'T LIKE HAVING TO VOTE FOR LABOR H WHEN VOTING FOR DEFENSE BUT IT WAS NOT UP FOR DISCUSSION. AND SO THAT IS HOW WE ENDED UP GETTING OUR BILL SIGNED INTO LAW AND GETTING OUR APPROPRIATION BEFORE THE START OF THE FISCAL YEAR. SO ALSO IN 1996, THIS WAS YOUR PRESIDENT, SPEAKER AND VICE PRESIDENT, HERE IS -- I DIDN'T KNOW DR. VARMUS HAD A BEARD AT ONE POINT. THIS IS AL GORE SHAKING HANDS WITH NIH COMMUNICATIONS DIRECTOR AND DR. VARMUS WITH THE BEARD. DR. CLASSNER WAS THE DIRECTOR OF NCI. JIM ALLISON PUBLISHED THIS PAPER IN SCIENCE. THAT'S WHAT AN APPLE COMPUTER LOOKED LIKE, A DESKTOP. AND THE FIRST MISSION IMPOSSIBLE MOVIE CAME OUT. SO WHERE FISCAL YEAR 2019 APPROPRIATIONS STAND. FOR US, WE ARE DONE. WE ARE ENACTED INTO LAW. THERE IS 12 SPENDING BILLS, 12 SUB COMMITTEES. 5 OF THEM HAVE BEEN PASSED. THOSE 5 AMOUNT TO 75% OF THE ENTIRE FEDERAL BUDGET BUT 7 MORE BILLS THAT ENCOMPASS 313 BILLION DOLLARS ARE STILL BEING WORKED ON. THEY ARE CURRENTLY FUNDOD A CR THAT RUNS THROUGH DECEMBER 7 AND THERE IS A DEAL UNDERWAY TO EXTEND THIS TO THE 21st OF DECEMBER. LAWMAKERS THOUGHT THEY WERE GOING HOME ON THE 14th SO THERE IS SOME RETIRING MEMBERS WHO WERE NOT SO HAPPY ABOUT THIS. THE OUTSTANDING BILLS INCLUDE AGRICULTURE, WHICH IS WHERE FDA GETS THEIR FUNDING. THEIR APPROPRIATION COMES THROUGH A DIFFERENT BILL SO THAT IS OBVIOUSLY VERY IMPORTANT TO MANY OF THE CANCER RESEARCH ENTERPRISE EFFORTS INTERIOR ENVIRONMENT AND FINANCIAL SERVICES, THIS IS THE BILL WHERE IF THERE IS A FEDERAL PAY RAISE IT WILL BE ADVANCED THROUGH THAT BILL. THAT IS IMPORTANT FOR MANY OF US AS FEDERAL EMPLOYEES. 1.9%. BUT ALSO IT'S A COST THAT DR. SHARPLESS HAS TO CONSIDER. HE IS LOOKING AT THE BUDGET IF THAT BILL IS ADVANCED. TRANSPORTATION HUD, COMMERCE, JUSTICE, SCIENCE, THAT IS WHERE NSF, NATIONAL SCIENCE FOUNDATION GETS THEIR FUNDING. STATE AND FOREIGN OPS AND THE BIG DIFFICULT BILL THIS YEAR, HOMELAND SECURITY, THAT IS NOW THE HOT POTATO BILL. LABOR, HHS NOT SO MUCH BECAUSE OF BORDER INFRASTRUCTURE AND FUNDING FOR THE WALL. HOUSE INCLUDED IN THEIR HOMELAND SECURITY BILL 5 BILLION DOLLARS FOR THE WALL WHICH IS WHAT THE WHITE HOUSE REQUESTED. THE SENATE INCLUDED ONLY 1.6 BILLION SO THERE IS A FAIRLY BIG DELTA THEY NEED TO COVER THERE. SO IT'S NOT JUST APPROPRIATIONS HEARINGS. THIS YEAR, DR. SHARPLESS DID HOUSE APPROPRIATION HEARINGS. I THINK I ALREADY SHOWED YOU PICTURES. IN JULY THERE WAS A HEARING OF ENERGY AND COMMERCE SUBCOMMITTEE ABOUT EMPITATION OF THE 21ST CENTURY CURES ACT AND HE IS SHOWN WITH DR. COLLINS. DR. STEPHANIE DEVAINY WHO WORKS ON THE ALL OF US RESEARCH PROGRAM AND FDA COMMISSIONER, SCOTT GOTTLIEB. AND THEN TO OUR HORROR, THERE WAS AN AUGUST HEARING IN THE SENATE AND THE HEALTH EDUCATION LABOR AND PENSIONS COMMITTEE AND I SAY TO OUR HORROR BECAUSE AUGURY SAYS IS THE TIME WHEN ALL THE STAFFERS GO ON VACATION AND THE TIME WE GO ON VACATION, AND THERE IS NEVER HEARINGS IN AUGUST EXCEPT WHEN THERE IS. AND THIS YEAR THERE WAS BECAUSE MA GEORGEY LEADER McCONNELL DECIDED HE WAS GOING TO KEEP THE SENATE AND SESSION IN AUGUST. - AUDIO MAJORITY LEADER. SO HOLLY TOOK CARE OF THIS, BLESS HER HEART BECAUSE I WAS ON VACATION. DOCTOR SHARPLESS MADE THE HEARING. THESE ARE GOOD OPPORTUNITIES FOR MEMBERS TO EXPRESS SUPPORT FOR NIH TO LEARN ABOUT RESEARCH. MEMBER VISITS. WE HAVE A LOT OF MEMBER VISITS. JUST SHING YOU TWO HERE. ONE WAS REPRESENTATIVE KEVIN YODER, REPUBLICAN FROM KANSAS, WHO DID NOT WIN RE-ELECTION. WHICH IS UNFORTUNATE IN THAT HE WAS A BIG SUPPORTER OF CANCER RESEARCH. HE WAS PART OF THE HOUSE CANCER CAUCUS. HE IS SHOWN HERE WITH DR. SHARPLESS AND MEMBERS OF OUR PEDIATRIC ONCOLOGY BRANCH AND THEN A PICTURE OF DR. SHARPLESS MEETING REPRESENTATIVE GK BUTTER FIELD, DEMOCRAT FROM NORTH CAROLINA, A BIG SUPPORTER OF CHILDHOOD CANCER RESEARCH. LEGISLATIVE IMPLEMENTATION. SO DR. SHARPLESS MENTIONED RACE FOR CHILDREN ACT SIGNED INTO LAW IN 2017. FDA IN CONSULTATION WITH NCI AND OTHER STAKEHOLDER GROUPS DEVELOPED TWO LIST OF MOLECULAR TARGETS. THE LAW REQUIRED IT BE CATEGORIZED AS RELEVANT AND NON-RELEVANT AND POSTED TO THE FDA'S WEBSITE IN AUGUST 2018. NCI WILL CONTINUE TO BE ENGAGED ON THIS ISSUE AND WORK WITH THEM ON UPDATES. CHILDHOOD SCANSER STAR ACT, SURVIVORSHIP TREATMENT AND RESEARCH WAS SIGNED INTO LAW IN 2018. RESEARCH PROVISIONS DIRECTED TOWARDS CDC, NIH, NCI, OFFICE OF SECRETARY AT HHS, OUR PORTION FOCUSES ON ON CHILDHOOD ADD LESSENT AND YOUNG ADULT CANCERS, SURVIVORSHIP RESEARCH AND BIOSPECIMEN COLLECTION AND RESOURCES. IMPLEMENTATION PLANNING IS UNDERWAY. THAT'S A PROCESS OF IMPLEMENTATION OF ANY LEGISLATION THAT HAPPENS AT THE DEPARTMENT AND AGENCY LEVEL. YOU WILL HEAR THIS AFTERNOON FROM DR. DANIEL DAY ABOUT ONE OF THE SURVIVOR SHIP PROPOSALS, OUR FIRST STEP TOWARDS IMPLEMENTING THAT. WE HAVE THE RETURN OF BUDGET CAPS AND THE DEBT CEILING ISSUES IN FY20. SO, IN MARCH 19, THE DEBT CEILING IS REINSTATED. THERE WAS A DEBT CEILING -- TO RAISE THE DEBT CEILING BUT THAT EXPIRES. IN OCTOBER OF 2019 THE RETURN OF BUDGET CAPS FROM THE BUDGET CONTROL ACT OF 20 LEVEL WOULD WE HAVE BEEN HERE BEFORE. -- - 2011. IF CONGRESS DOES NOTHING, THERE WILL NEED TO BE A 50 BILLION DOLLAR REDUCTION IN OVERALL ALLOCATION, GOVERNMENT WIDE, FOR NON-DEFENSE DISCRETIONARY SPENDING AND THAT WOULD AFFECT NIH AND MANY, MANY OTHER DEPARTMENTS. WE HAVE BEEN HERE BEFORE. THERE HAVE BEEN THREE TIMES THAT CONGRESS FACED THIS CLIFF. THEY HAVE PASSED LEGISLATION TO EITHER EXTEND DEADLINES TO KICK THE CAN DOWN THE ROAD, TO RAISE CAPS, TO FIND OFFSETS AND THEY HAVE DONE IT WITH PARITY BETWEEN DEFENSE AND NON-DEFENSE ACCOUNTS. SO, THAT IS WHAT I WOULD EXPECT TO HAPPEN. I THINK THAT WILL PROBABLY BE THE FIRST ORDER OF BUSINESS FOR THE 116th CONGRESS. WHAT WE HEAR FROM STAFFERS IS THAT THEY ARE NOT PROCEEDING TO BREAK BILLS TO THE BUDGET CONTROL ACT NUMBERS BECAUSE THE NUMBERS ARE FAR TOO LOW AND THEY COULDN'T DO IT. THIS IS THE TEAM THAT DID THE LAST BUDGET DEAL IN 2018 WHICH WAS FOR 2017 AND 2018. PAUL RYAN WILL BE GONE. KEVIN McCARTHY, THE YOU NOO MINORITY LEADER FOR THE REPUBLICANS IN THE HOUSE WILL BE PLAYING THAT ROLE. I WANTED TO CLOSE WITH, I DIDN'T KNOW UNTIL I WAS DOING READING ABOUT FORMER PRESIDENT BUSH 41, LAST NIGHT, THAT HE ATTENDED -- AT NIH FOR THE RIBBON CUTTING IN 1990 OF THE CHILDREN'S INN AND GAVE A REALLY LOVELY TALK THERE ABOUT HOW INSPIRING HE FOUND THE WORK AND RECOGNIZED DR. PHIL PEASO INSTRUMENTAL IN DEVELOPING THE INN AND I THOUGHT THIS WAS A TERRIFIC WAY TO REMEMBER HIM. THAT WAS HIS 90th BIRTHDAY AND HE DID IT IN THE PAST FOR 85 AND FOR 80 AND I'M PETEY SURE HE WOULD HAVE DONE IT NEXT YEAR IF HE WAS AROUND. THANK YOU VERY MUCH. HAPPY TO TAKE ANY QUESTIONS. I THINK WE ARE ON THE CLOCK. [ APPLAUSE ] >> ANY QUESTIONS? >> CATCH YOU AT COFFEE BREAK >> OUR NEXT PRESENTATION IS ON GENETIC SUSCEPTIBILITY TO PROSTATE DANCER IN MEN OF AFRICAN-AMERICAN ANCESTRY. >> THANKS AGAIN AND WELCOME TO ALL THE NEW BOARD MEMBERS AND THE DISCUSSION ABOUT THE LATE PRESIDENT, PUBLIC SERVICE, HAS BEEN A LOT OF DISCUSSION. SO WE APPRECIATE YOUR PUBLIC SERVICE AND AGREEING TO SERVE ON THESE BOARDS. SO, SOME OF YOU RECALL THEN IN PREVIOUS MEETINGS OF THIS BOARD, WE HAD DISCUSSIONS ABOUT THE MOONSHOT AND ABOUT HEALTH DISPARITIES AND ABOUT INTERFACE BETWEEN THOSE TWO DOMAINS. SO WE THOUGHT IT MIGHT BE HELPFUL TO GIVE AN EXAMPLE OF AN INVESTIGATOR WHOSE BEEN FUNDED BY A SPECIAL MOONSHOT INITIATIVE THAT HE'LL BE TALKING ABOUT PROSTATE CANCER. AND THERE IS MANY DIFFERENT CANDIDATE DISPARITIES WE COULD TALK ABOUT, OF COURSE AND MANY OF YOU HE WORKED IN THOSE BUT WE THOUGHT THE BLACK-WHITE DISSIPATER NEPROSTATE CANCER MORTALITY IS ONE OF THE MOST LARGEST AND PROMINENT AND IN TERMS OF POPULATION IMPACT ONE WITH THE GREATEST DISPARITIES WE ARE DEALING WITH. AND AS A SCIENTIFIC CHALLENGE, IT'S A MORAL CHALLENGE, A CLINICAL CHALLENGE. AND THIS IS WHY WE CHOSE AS PART OF THE MOONSHOT INITIATIVE TO MAKE A SPECIAL INVESTMENT IN THIS AREA. SO CHRIS HAIM EN HAS BEEN FUNDED IN THIS AREA, NOT JUST BY THE MOONSHOT BUT I WANTED TO MENTION BY WAY OF BACKGROUND, HE IS PROFESSOR OF PREVENTIVE MEDICINE AT UFC, AFFLEC CHAIR OF CANCER RESEARCH, AND LEADS THE CANCER PROGRAM AT THE CANCER CENTER AT USC AND HE IS GENETIC EPIDEMIOLOGIST IN ETHNIC DISPARITIES. SO A LOT OF YOU ARE AWARE OF MULTI-ETHNIC COHORT. THIS HAS BEEN ONE OF OUR LARGE AND MOST SUCCESSFUL EPIDEMIOLOGICAL INVESTMENTS IN DISPARITIES WORK AND GENERATED A WEALTH OF EVIDENCE. CHRIS HAS ALSO BEEN THE LEADER OF THE AFRICAN ANCESTRY PROSTATE CANCER CONSORTIUM. WE JUST HAD A BIG MEETING HERE LAST WEEK OF OUR INTERNATIONAL COHORT'S CONSORTIUM. THIS IS A GROUP THAT POOLS DATA FROM ACROSS PROJECTS, ACROSS SITES AND COUNTRIES AND CHRIS HAS BEEN ONE OF THE SIGNIFICANT PLAYERS IN THAT EFFORT. HE OFFERED MORE THAN 450 PEER-REVIEWED PUBLICATIONS AND WE ARE REALLY WELCOMING -- GLAD WE CAN WELCOME HIP HIM HERE TODAY TO GIVE YOU UPDATE ON THIS IMPORTANT TOPIC. CHRIS? >> THANKS, BOB FOR THAT INTRODUCTION. AND THANK YOU PAULET FOR THE INVITATION TO SPEAK WITH YOU HERE TODAY ABOUT THE WORK WE HAVE BEEN DOING OVER THE LAST DECADE IN STUDYING GENETIC SUSCEPTIBILITY IN PROSTATE CANCER IN MEN OF AFRICAN ANCESTRY. THIS IS SUPPORTED BY A NUMBER OF INSTITUTIONS, NHGRI, NCI, AND WORK CARRIED OUT THROUGH A NUMBER OF LARGE-SCALE CONSORTIA. STARTING IN GENEVA, THE GAME ON CONSORTIUM AND THEN THE AFRICAN ANCESTRY PROSTATE CANCER CONSORTIUM. AND AT THE END OF THE TALK, I'LL SPEAK TO HOW THIS EFFORT IS NOW BEING EXPANDED REALLY QUITE SUBSTANTIALLY THROUGH THE NEW RESPOND INITIATIVE. SO, SHOWN HERE ARE DATA FROM SEER, WHICH HIGHLIGHT A LONGSTANDING ETHNIC AND RACIAL DISPARITY FOR PROSTATE CANCER AND INCIDENTS RATES BEING 70% HIGHER IN AFRICAN-AMERICAN MEN. AFRICAN-AMERICAN MEN ARE MORE LIKELY TO BE DIAGNOSED EARLIER WITH MORE AGGRESSIVE TUMORS AND HAVE A TWO FOLD INCREASE OF DYING FROM PROSTATE CANCER COMPARED TO MEN FROM OTHER POPULATIONS. THERE ARE MANY FACTORS THAT HAVE BEEN DEMONSTRATED OR SUGGESTED TO CONTRIBUTE TO THESE DISPARITIES, INCLUDING SOCIODEMOGRAPHICS, RISK FACTORS AND ACCESS TO CARE, WHICH INCLUDES VARIATIONS, RATES OF SCREENING AND DETECTION AND TREATMENT, BUT WITH RESPECT TO DIFFERENCES IN INCIDENCE, ONE THING THAT IS STREETING WITH PROSTATE CANCER, THERE IS RELATIVELY FEW ESTABLISHED RISK FACTORS, AGE, FAMILY HISTORY, AND RACE, WHICH REALLY ASKED THE QUESTION IS TO WHAT CONTRIBUTES TO THIS UNDERLYING VARIATION AND COULD GENETIC FACTORS HELP EXPLAIN DISPARITIES IN PROSTATE CANCER INCIDENTS? SO THIS IS WORK, A QUESTION WE SET OUT TO ADDRESS THROUGH A NUMBER OF STUDIES STARTING WITH ADD MIXTURE MAPPING OVER 12 YEARS AGO. THIS WAS WORK LED BY DAVID AND MATT FROM HARVARD. AND SO THIS IS AN APPROACH THAT,TA LAOS YOU TO IDENTIFY RISK ALLELES THAT TRACK WITH LOCAL GENETIC ANCESTRY IN AN ADD MIX POPULATION. SO IN AN ADD MIXTURE SCAN OF 1600 AFRICAN-AMERICAN MEN FROM THE MULTIETHNIC COHORT STUDY, WE IDENTIFIED REGION OF THE GENOME HERE AT AQ24, A SIGNIFICANT ACCESS OF AFRICAN ANCESTRY AMONG AFRICAN MEN WITH PROSTATE CANCER AND THROUGH DENSE FINE MAPPING THIS REGION AND POPULATIONS FROM THE MULTIETHNIC COHORT AS WELL. WE IDENTIFIED SEVEN INDEPENDENT RISK VARYIENTS AND ASSOCIATED WITH PROSTATE CANCER RISK. SO THEY SPANNED ABOUT 600 KILOBASE REGION ACROSS AQ24. AND ALTHOUGH THIS IS ONLY ONE REGION, IT WAS THE FIRST EVIDENCE OF COMMON GERMLINE VARIATION CONTRIBUTING TO PROSTATE CANCER RISK AND THE IMPORTANCE OF THIS REGION OF THE GENOME ACROSS MULTIPLE RACIAL AND ETHNIC POPULATIONS. AND SO, TAKING A CLOSER LOOK AT THE INDEPENDENT RISK ALLELES FOUND HERE AT AQ24, IT WAS ASTONISHING HOW STRIKING THE DISPARITY WAS AND THE INCIDENCE AND THE ALLELE FREQUENCY. THIS IS ONE EXAMPLE HERE SHOWN HERE AT THE TOP. TWICE AS COMMON IN POPULATIONS OF AFRICAN AN CESSORY COMPARED TO OTHER POPULATIONS -- ANCESTRY -- AND THESE ARE FREQUENCY INFORMATION FROM THE 1000 GENOMES PROJECT. SO BASED ON THIS OBSERVATION, WE DEVELOPED A POLYGENIC RISK MODEL FOR PROSTATE CANCER THAT TAKES INTO ACCOUNT THE FREQUENCY AND AFFECT SIZE. WHAT WE OBSERVED AS THESE VARIANTS MAKE A MUCH GREATER CONTRIBUTION TO PROSTATE CANCER RISK AMONG MEN OF AFRICAN ANCESTRY WHICH IS SHOWN HERE COMPARING AFRICAN-AMERICANS COMPARED TO WHITES IF YOU COMPARE THE POLYGENIC RISK MODEL DISTRIBUTIONS. SO THIS REALLY BEGGED THE QUESTION, AS TO WHAT OTHER VARIANTS IN THE GENOME MIGHT THERE BE TO CONTRIBUTE TO RACIAL AND ETHNIC DIFFERENCES IN PROSTATE CANCER RISK? IT WAS PROVIDED STRONG JUSTIFICATION FOR A LARGER INITIATIVE. SO IN 2007, WE BEGAN THE AFRICAN ANCESTRY PROSTATE CANCER CONSORTIUM WHICH INCLUDES MAINLY STUDIES FROM THE UNITED STATES BUT ALSO STUDIES FROM CANADA, THE U.K., FRANCE AND FROM AFRICA AND FROM THE CARIBBEAN. AND IN TOTAL, 10,000 PROSTATE CANCER CASES AND 10,000 CONTROLS THAT HAVE BEEN INCLUDED IN A GENOME-WIDE ASSOCIATION STUDY OF PROSTATE CANCER AND THIS NUMBER SEEMS QUITE IMPRESSIVE OF 10,000 PROSTATE CANCER CASES. THIS IS APPROXIMATELY ONE TENTH THE SIZE OF CURRENT GENOME-WIDE ASSOCIATION STUDIES IN MEN OF EUROPEAN ANCESTRY. AND WHAT WE FOUND IN THIS GENOME-WIDE ASSOCIATION STUDY HERE IS AQ24, WHICH REALLY STANDS HEAD AND SHOULDERS AT REST AS THE STRONGEST REGION IN THE GENOME, AND AS I MENTIONED, A LOT OF ACTIVITY IN THIS REGION HARBORING MULTIPLE INDEPENDENT RISK ALLELES FOR PROSTATE CANCER. BUT I WANT TO DRAW YOUR ATTENTION TO ONE VARIANT IN PARTICULAR. IT'S A NON-CODING VARIANT THAT HAS A 6% FREQUENCY AMONG MEN OF AFRICAN ANCESTRY AND NOT OBSERVED IN ANY OTHER RACIAL AND ETHNIC POPULATION. IT'S PROBABLY ONE OF THE MOST IMPORTANT RISK VARIANTS FOR PROSTATE CANCER THAT HAS BEEN IDENTIFIED TO DATE. SHOWN BELOW HERE, IS THE RISK ESTIMATES AND THE ALLELE FREQUENCIES FOR CARRIERS OF THIS VARIANT WHERE 11% OF MEN HARBOR ONE VARIANT WHICH IS ASSOCIATED WITH A TWO-FOLD INCREASE IN PROSTATE CANCER RISK WITH THE RISK ELEVATED CLOSE TO 3 FOR MEN WHO ALSO HAVE A FAMILY HISTORY OF PROSTATE CANCER. FOR HOMOZYGOUS CARRIERS OF THIS VARIANT, RELATIVELY RARE IN THE POPULATION FOR A MAN TO CARRY TWO OF THESE ALLELES. ESPECIALLY MORE COMMON IN CASES ASSOCIATED WITH A 5-FOLD ELEVATED RISK OF PROSTATE CANCER BUT THE RISK OF,Y APPROACHING OVER EIGHT FOR MEN WHO ALSO HAVE A FAMILY HISTORY OF PROSTATE CANCER. SO JUST TO GIVE YOU SOME PERSPECTIVE ON THIS, THE MOST WELL-ESTABLISHED HIGH PENETRANCE VARIANT FOR PROSTATE CANCER IS MUTATION IN HOCKS B13. IT'S RARE IN WHITES IN THE POPULATION ASSOCIATED WITH A 3-FOLD INCREASE IN RISK AMONG CASES UNSELECTED FOR FAMILY HISTORY. ESTIMATED TO ACCOUNT FOR ABOUT 5% OF HEREDITARY PROSTATE CANCER. THIS VARIANT HERE AT AQ24 HAS SIMILAR RELATIVE RISKS RANGING FROM 3-5 DEPENDING ON GENOTYPE CLASS. WHAT IS DIFFERENT HERE IS IT'S 30 TIMES MORE COMMON IN THE POPULATION. SO LIKELY TO MAKE A GREATER CONTRIBUTION TO PROSTATE CANCER RISK THAN IN POX B13. AND RISK WITHIN FAMILIES IS SOMETHING HASN'T BEEN LOOKED AT BUT WE NEED TO ESTABLISH. WE ALSO OBSERVED IN THIS GENOME-WIDE ASSOCIATION STUDY AMONG MEN OF AFRICAN ANCESTRY, IS THAT MOST OF THE TOP SIGNALS WE SEE ACROSS THE GENOME ARE OBSERVED WITH ALLELES THAT ARE ONLY FOUND IN MENTAL OF AFRICAN ANCESTRY. AND THESE ARE THREE REGIONS THAT WE HAD POWERED ON CHROMOSOMES 13, 17 AND 22. THESE VARIANTS HAVE ALLELE FREQUENCIES RANGING FROM 2-5% AGAIN ONLY IN AFRICAN ANCESTRY POPULATIONS AND ASSOCIATED WITH RELATIVE RISKS ON THE ORDER OF ABOUT 1.6 PER ALLELE. SO WHAT THIS MEANS IS ABOUT 10% OF MEN OF AFRICAN ANCESTRY CARRY ONE OF THESE VARIANTS THAT INCREASES THEIR RISK BY 60% COMPARED TO ALL OTHER MEN IN THE POPULATION BECAUSE THEY DON'T CARRY THESE RISK ALLELES. SO WHAT THESE OBSERVATIONS AND POPULATION-SPECIFIC ALLELES, AT AQ24 AND IN THESE REGIONS OF THE GENOME REALLY HIGHLIGHT, IS THE IMPORTANCE OF GENETIC STUDIES INANT VEST RALLY DIVERSE POPULATIONS. HOWEVER, AS WE ARE ALL AAWARE, THE VAST MAJORITY OF GENOME ASSOCIATION STUDIES HAVE BEEN CONDUCTED PRIMARILY IN EUROPEAN AN VEST RE. THIS INCLUDES STUDIES THROUGH 2016. THIS GENERAL PATTERN IS CONSISTENT TODAY. AND THIS HIGHLIGHTS OVERWHELMING OVER REPRESENTATION OF EUROPEAN ANCESTRY SAMPLES INCLUDED IN GENOME-WIDE ASSOCIATION STUDIES OF CANCER FOR EACH OF THE DIFFERENT CANCER SITES SHOWN HERE. IT'S NOT SURPRISING THAT THE MAJORITY OF LOCI IDENTIFIED FOR CANCER HAVE COME FROM OR IDENTIFIED IN STUDIES IN WHITES. WITH ONLY 15% OF RISK LOCI IDENTIFIED IN ASIAN POPULATIONS AND ONLY ABOUT 4% OF RISK LOCI FIRST IDENTIFIED IN POPULATIONS WITH LATINO OR AFRICAN ANCESTRY. AND JUST SHOWING HERE IS A STRIKING IMBALANCE FOR PROSTATE CANCER NOTED AS WELL WITH A RED BAR HERE INDICATING THE NUMBER OF CASES FROM THE AFRICAN ANCESTRY PROSTATE CANCER CONSORTIUM. SO WE KNOW ABOUT GENETICS SUSCEPTIBILITY TO PROSTATE CANCER IS MAINLY THROUGH GWAS STUDIES IN MEN OF EUROPEAN ANCESTRY, EFFORTS LED PRIMARILY THROUGH THE PRACTICAL CONSORT YUP, INTERNATIONAL CONSORTIUM INCLUDES 130 STUDIES GLOBALLY, THE MOST RECENT PUBLICATION CAME OUT EARLIER THIS YEAR AND SCANNED 140,000 MEN IN EUROPEAN ANCESTRY IDENTIFYING SEA NEW LOCI FOR PROSTATE CANCER BRINGING THE TOTAL NUMBER OF RISK VARIANTS UP TO 181. MORE THAN 80% FOUND IN POPULATIONS OF EUROPEAN ANCESTRY AND ESTIMATED TO EXPLAIN ON THE ORDER OF CLOSE TO 40% IN FAMILIAL RISK OF PROSTATE CANCER. WE KNOW THE EFFECTS OF VARIANTS ARE MODEST. HOWEVER, IN AGGREGATE, WE FIND THAT THEY CAN DO A RELATIVELY GOOD JOB IN STRATIFYING PROSTATE CANCER RISK IN THE POPULATION. AND SO THIS IS A POLYGENIC RISK SCORE WHICH WE ESTIMATED IN WHITES USING THESE 181 RISK VARIANTS AND YOU CAN SEE THAT THE -- COMPARE TO THE MEN WHO IN THE 25th-70 PERCENTILE WERE MEN AT AVERAGE RISK. WE SEE THE POLYGENIC RISK SCORE IDENTIFIES THE TOP 25% OF MEN WHO HAVE HAY TWO FOLD OR MORE INCREASE IN RISK AND TOP 10% WHO HAVE OVER FOURFOLD INCREASE IN RISK. SIZEABLE FRACTION OF THE POPULATION BUT CONSIDERABLE RISK. SO, IT'S NOT SURPRISING THAT THIS POLYGENIC RISK SCORE LOOKS SO NICELY IN WHITES AS MOST OF THE VARIANTS WERE IDENTIFIED IN WHITES. IMPORTANT PUBLIC HEALTH QUESTION, IMPORTANT TOPIC. FIELD IS CAN A POLYGENIC RISK SCORE DEVELOPED IN ONE POPULATION, CAN IT BE USED TO IDENTIFY MEN IN ELEVATED RISK IN OTHER POPULATIONS? SO THIS IS SOMETHING THAT WE HAVE BEGUN TO LOOK AT HERE AND THIS SHOWS A POL GENEIC RISK SCORE SUMMARY USING 181 RISK PARENTS AND FOR THOSE INTERESTED IN POLYGENIC RISK SCORES, THIS IS A WEIGHTED POLYGENIC RISK SCORE USING ESTIMATES IN WHITES AS THE WEIGHT FOR EACH OF THE VARIANTS SINCE THE AFFECT ESTIMATES WITH WHITES IS MORE LIKELY TO REPRESENT THE UNDERLYING TRUE CAUSAL VARIANT IN EACH REGION. SHOWN HERE IS COMPARING MEN OF ASIAN, AFRICAN AND LATINO ANCESTRY COMPARED TO WHITES T DOES A GOOD JOB IN STRATIFYING RISK IN THESE OTHER POPULATIONS. BEING ABLE TO IDENTIFY AT LEAST THE TOP 10% OF MEN ACROSS ALL POPULATIONS WHO HAVE A 3 FOLD OR MORE INCREASE IN RISK BUT AS YOU œSCORE WORKS BETTER IN MANY OFSK EUROPEAN ANCESTRY. THIS OBSERVATION OF INCOMPLETE TRANSFERABILITY OF POLYGENIC RISK SCORE ACROSS POPULATIONS IS NOT SOMETHING THAT IS UNIQUE TO PROSTATE CANCER. IT'S BEEN OBSERVED FOR OTHER CANCERS AND DISEASES AS WELL. IT INDICATES THE NEED FOR LARGER AND MORE COMPREHENSIVE STUDIES OF I CAN'T REMEMBER LINE VARY NATION MINORITY POPULATIONS TO IDENTIFY THE VARIANTS TO IMPROVE RISK PREDICTION ACROSS POPULATIONS. THIS IS SOMETHING THAT WE ARE CURRENTLY WORKING ON AND I'LL GET TO IN JUST A MOMENT. BUT FIRST I WANT TO GET BACK TO THE INITIAL QUESTION THAT I RAISED AT THE BEGINNING OF THIS TALK. DO GENETIC RISK FACTORS CONTRIBUTE TO POPULATION DIFFERENCES IN PROSTATE CANCER RISK? WHICH WAS THE INITIAL HYPOTHESIS WE OBSERVED EVIDENCE WITH INITIAL FINDINGS OF AQ24. WE GET A SINCE OF COMPARING POLYGENIC DISTRIBUTIONS ACROSS POPULATIONS. SO SHOWN HERE ON THE LEFT IS A COMPARISON OF THE POLYJENISK RISK SCORE COMPARED TO MEN OF EUROPEAN AND AFRICAN ANCESTRY. THIS IS LIMITED TO AQ24. NOW THERE IS 14 KNOWN INDEPENDENT RISK VARIANTS FOR PROSTATE CANCER JUST IN THIS AQ24 REGION. AND YOU CAN SEE HERE THAT THE DISTRIBUTION FOR MEN OF AFRICAN ANCESTRY IS SHIFTED TO THE RIGHT COMPARED TO MEN OF EUROPEAN ANCESTRY. WE OBSERVED THIS 10 YEARS AGO. MAINLY BECAUSE THESE VARIANTS ARE MORE COMMON IN AFRICAN ANCESTRY BASED ON THESE 14 RISK ALLELES. NOW ON THE RIGHT IS WHAT WE SEE TODAY. AMONG ALL 181 COMMON RISK ALLELES FOR PROSTATE CANCER AND THESE DISTRIBUTIONS PRETTY MUCH OVERLAP SO IT SUGGESTS THAT THESE 181 VARIANTS DO NOT IN AGGREGATE, DO NOT CONTRIBUTE TO THE GREATER RISK OF PROSTATE CANCER THAT WE OBSERVED IN MEN OF AFRICAN ANCESTRY. THERE IS A MAJOR CAVEAT HERE AND THE CAVEAT IS WHAT I SAID BEFORE. THESE VARIANTS WERE THE MOST SIGNIFICANT VARIANTS GENOME-WIDE FROM GENOME-WIDE ASSOCIATION STUDIES AND FINE MAPPING STUDIES IN MEN OF EUROPEAN ANCESTRY. WE HAVE YET TO IDENTIFY AN EQUIVALENT SET OF MARKERS TO SERVE AS AN OPTIMAL SET FOR POLYSCORE FOR MEN OF EUROPEAN -- AFRICAN ANCESTRY. UNTIL THIS IS DONE, I DON'T THINK WE'LL BE ABLE TOL FAIRLY ANSWER THIS QUESTION. SO OVER THE PAST FEW MONTHS, WE HAVE BEEN LOOKING AT WAYS TO TRY TO IMPROVE THE PREDICTION OF THIS POLYGENIC RISK SCORE ACROSS POPULATIONS. AND WE HAVE BEEN DOING THIS THROUGH MULTI-ETHNIC STUDIES, GWAS AND FINE MAPPING. AND SO WHAT WE HAVE BEEN COMBINING GWAS DATA WITH THE GOAL BEING TO IDENTIFY A MUCH STRONGER SIGNALS IN KNOWN REGIONS AS WELL AS NOVEL VARIANTS THAT HAVE ETHNIC EFFECTS ON RISK. VARIANTS THAT HAVE ETHNIC EFFECTS ON RISK ARE MORE LIKELY TO BE CONTRIBUTING TO POLYGENIC RISK SCORE PREDICTION ACROSS POPULATIONS. AND SO TO DATE, WE HAVE COMBINED DATA FOR CLOSE TO 240,000 MEN ACROSS THE DIFFERENT POPULATIONS AND THESE RESULTS ARE PRELIMINARY. ALTHOUGH WE FEEL RELATIVELY CONFIDENT IN BEING 60 NOVEL RISK VARIANTS FOR PROSTATE CANCER COMING FROM THIS MULTIETHNIC SCAN BRINGING TOTAL NUMBER UP TO 240. AND FINE MAPPING OF 181 KNOWN SIGNALS IN 90, KNOWN INDEX VARIANT THAT WAS INITIALLY REPORTED IN MEN OF EUROPEAN ANCESTRY HAS BEEN REPLACED BY A DIFFERENT MARKER, EXACTLY WHAT WE WANTED TO SEE BECAUSE OF THE CONTRIBUTIONS FROM THE OTHER POPULATION. SO WE ARE CURRENTLY GOING BACK NOW AND INCORPORATING THIS GENETIC INFORMATION INTO OUR POLYGENIC RISK SCORE ESTIMATION AND WE BELIEVE THAT THESE NEW MARKERS WILL NOW SUBSTANTIALLY IMPROVE THE RISK PREDICTION IN MOST IF NOT ALL OF THESE POPULATIONS. SO AN IMPORTANT QUESTION RELATED TO POLYGENIC RISK SCORES IS THE CLINICAL UTILITY. AS I HAVE SHOWN YOU, THE CURRENT POLYGENIC RISK SCORE CAN IDENTIFY ABOUT TOP 10% OF MEN WHO CROSS POPULATIONS THAT HAVE A 3-FOURFOLD INCREASE RISK OF PROSTATE CANCER. WHICH IS IMPORTANT. BUT UNFORTUNATELY, THESE COMMON RISK ALLELES AND THE POLYGENIC RISK SCORE CAN'T DISCRIMINATE BETWEEN A MAN'S RISK OF DEVELOPING AGGRESSIVE VERSUS NON AGGRESSIVE PROSTATE CANCER, WHICH IS A PROBLEM. THERE ARE A NUMBER OF ONGOING SCREENING STUDIES THAT NOW INCORPORATE THIS POLYGENIC RISK SCORE UNDERWAY IN THE U.K. AND SWEDEN AND SPECIFICALLY DESIGNED TO ADDRESS THE SENSITIVITY FOR DETECTING AGGRESSIVE PROSTATE CANCER AMONG THOSE AT VERY HIGH GENETIC RISK AND WHETHER TARGETED SCREENING OF THESE MEN COULD REDUCE THE NUMBER OF BIOPSIES AND OVER DIAGNOSIS, WHICH IS A MAJOR ISSUE WITH PSA TESTING. BUT WHAT IS REALLY CRITICALLY NEEDED AND WILL DRAMATICALLY IMPROVE THE UTILITY OF A POLYJENISK RISK SCORE WILL BE IDENTIFYING MARKERS OF AGGRESSIVE DISEASE WHICH UNFORTUNATELY HAS BEEN DIFFICULT TO DO. STUDIES AT BRCA1 AND 2. 1% OF PROSTATE CANCER CASES ARE FOUND WITH CLEAR INDICATIONS IN THESE GENES ASSOCIATED WITH SIZEABLE RISK AND AGGRESSIVE TUMORS AND CARRIERS HAVE POOR SURVIVAL. AND IN A RECENT STUDY BY PRICHARD AND COLLEAGUES OF METASTATIC PROSTATE CANCER CASES, THEY ALSO NOTED QUITE SIZEABLE RELATIVE RISKS WITH BURDEN TESTING OF PATHOGENIC MUTATIONS IN BRCA1 AND 2. BUT THEY ALSO FOUND STRONG ASSOCIATIONS IN LARGE RELATIVE RISKS ASSOCIATED WITH A NUMBER OF OTHER GENES. IN TOTAL, 12% OF METASTATIC CASES WERE FOUND TO CARRY PATHOGENIC MUTATION COMPARED TO ONLY 3% OF CONTROLS. SO BASED ON THESE STUDIES AND MANY OTHERS IN THE FIELD, IT'S BECOMING QUITE CLEAR THAT THESE RARE PATHOGENIC MUTATIONS IN DNA REPAIR PATHWAY GENES ARE IMPORTANT MARKERS OF SUSCEPTIBILITY FOR PROSTATE CANCER. WE ADDRESSED A SIMILAR QUESTION LOOKING AT THE IMPACT OF RARE CODING VARIANTS IN RELATIONSHIP TO PROSTATE CANCER RISK IN MEN OF AFRICAN ANCESTRY, SOMETHING THAT'S NOT YET BEEN ADDRESSED. THIS WAS A STUDY THAT INCLUDED AFRICAN-AMERICAN PROSTATE CANCER CASES AND CONTROLS FROM THE MULTIETHNIC COHORT STUDY IN L.A. AND CASES AND CONTROLS FROM ONGOING CASE CONTROL STUDY THAT WE HAVE IN UGANDA. AND SO WE EVALUATED A VERY SIMILAR PANEL OF DNA REPAIR IN CANCER SUSCEPTIBILITY GENES AND WE ARE TALKING ABOUT PATHOGENIC MUTATIONS SO RARE TRUNCATING MUTATIONS OR VARIANTS IDENTIFIED AS BEING PATHOGENIC. AND WE OBSERVED ABOUT 2% OR 4% OF CASES BEING MUTATION CARRIER'SIERS AND 2% CONTROLS. -- CARRIERS. OUR STUDY IS UNSELECTED FOR DISEASE AGGRESSIVENESS. BUT THIS ASSOCIATION WAS DRIVEN MAINLY BY FOUR GENES, BRCA2, COMPARISON OF -- [ INAUDIBLE ] WELL-KNOWN AND ESTABLISHED BREAST CANCER SUSCEPTIBILITY GENES. TAKING A CLOSER LOOK AT THESE FOUR GENES, THIS IS THE BURDEN FREQUENCY AND CONTROLS VERSUS CASES. EACH OF THESE GENES WERE ASSOCIATED WITH A 3-FOURFOLD RELATIVE RISK FOR OVERALL PROSTATE CANCER BUT THE BURDEN FREQUENCE WAS GREATER IN MEN WHO HAD MORE AGGRESSIVE TUMORS. SO RELATIVE RISK APPROACHING 7-8 FOR ATM AND FOR BRCA2. WHAT ABOUT METASTTIC PROSITS KATE CANCER? LOOKING AT METASTATIC DISEASE, WE HAD SMALL NUMBERS OF NUMBER OF CASES IN AFRICAN-AMERICAN SET AND UGANDANS WE DIDN'T HAVE INFORMATION ABOUT STAGE BUT WE HAD INFORMATION ABOUT PSA AT THE TIME OF DIAGNOSIS AND ROUGHLY 1/3 OF THE CASES IN OUR UGANDAN CASE CONTROL HAD A PSA LEVEL ABOVE 100. USING THIS AS AN INDICATOR, WE LOOKED AT THE BURDEN FREQUENCY OF THESE VARIANTS AND AS SHOWN HERE, THE RESULTS ARE QUITE STRIKING. RELATIVE RISKS ON THEED OF 15 FOR BOTH BRCA2 AND ATM. THE RELATIONSHIP BETWEEN THESE VARIANTS IN METASTATIC DISEASE ESTIMATED THAT THESE METASTATIC CASES OF 5% OF THEM CARRY INDIN JUST WONG OF THESE 2 GENES. THESE RESULTS ARE CONSISTENT IN WHAT IS REPORTED IN WHITES AND PATHOGENIC MUTATIONS IN DNA REPAIR PATHWAY GENES HAVE MAJOR IMPACT ON SUSCEPTIBILITY TOW PROSTATE CANCER IN MEN OF AFRICAN ANCESTRY. SO WE RECENTLY EXPANDED OUR SEARCH FOR RARE VARIANTS AND CONTRIBUTING TO AGGRESSIVE PROSTATE CANCER THROUGH EXOME SEQUENCING. THIS IS A PROJECT WE HAVE UNDERWAY IN MEN OF EUROPEAN ANCESTRY. IT'S A MULTI-STAGE PROJECT WITHIN THE FIRST STAGE WE EXOME SEQUENCED 5500 PROSTATE CANCER CASES. HALF AGGRESSIVE AND 4568 NON AGGRESSIVE AND THIS IS SOME OF THE RESULTS FOR THIS FIRST STAGE WE SEE SOME OF THE EXPECTED ASSOCIATIONS BETWEEN BURDEN FREQUENCIES OF THE PATHOGENIC MUTATIONS AND KNOWN GENES BEING ASSOCIATED WITH AGGRESSIVE DISEASE. BUT AS YOU CAN SEE HERE, THERE IS A HUGE NUMBER OF OTHER SUGGESTIVING ISNALS ACROSS THE GENOME WHICH WE ARE WORKING ON NOW TO VALIDATE IN A SECOND STAGE OF 14,000 CASES HALF AGGRESSIVE AND HALF NON AGGRESSIVE AND EXPECT THESE RESULTS TO BE COMING IN SOMETIME LATER IN THE SPRING. BASED UPON ON WHAT WE KNOW ABOUT THE IMPORTANCE OF RARE AND ETHNIC VARIATION, A STUDY LIKE THIS IS CLEARLY WARRANTED FOR MEN OF AFRICAN ANCESTRY. UNFORTUNATELY WE DON'T HAVE THE NUMBER OF CASES TO DATE FOR SUCH A WELL-POWERED STUDY. THIS IS ONE OF THE MAIN REASONS AND MOTIVATIONS FOR THE RESPONSE SITE. SO RESPOND STANDS FOR RESEARCH ON PROSTATE CANCER IN MEN OF AFRICAN ANCESTRY, DEFINING ROLES OF GENETICS, TUMOR MARKERS AND SOCIAL STRESS INITIALLY SUBMITTED AS A PROGRAM PROJECT GRANT WITH FOUR PROJECTS AND SINCE BEEN CONVERTED TO A U19 INCLUDING COLLABORATION OF DCEG INTRAMURAL INVESTIGATORS. THE PRIMARY GOAL IS TO RECRUTE 10,000 AFRICAN-AMERICAN MEN WITH PROSTATE CANCER. THESE DATA AND SPECIMENS WILL BE USED TO ADDRESS A NUMBER OF SCIENTIFIC QUESTIONS RELATED TO AGGRESSIVE PROSTATE CANCER. THE FIRST PROJECT WILL FOCUS ON GENETIC SUSCEPTIBILITY AND CONTINUING GENOME-WIDE ASSOCIATION STUDIES AND OVERALL PROSTATE CANCER AND AGGRESSIVE DISEASE AND EXOME SEQUENCING. SECOND PROJECT WILL FOCUS ON SOCIAL FACTORS THAT CONTRIBUTE TO LIFETIME STRESS. SOCIAL FACTORS RELATED TO ADVERSITY MAY BE MORE COMMON IN AFRICAN-AMERICAN COMMUNITIES AND THEY CAN BE MEASURED ON THE INDIVIDUAL LEVEL, NEIGHBORHOOD LEVEL AND LOOKING AT THEM IN AGGREGATE TO SEE HOW THE AGGREGATE SOCIAL STRESSORS MAY BE CONTRIBUTING TO AGGRESSIVE PROSTATE CANCER. WE WILL BE MEASURING INFORMATION, LIFESTYLE FACTORS AND HEALTH BEARS AND MEDICAL CARE RELATED FACTORS AND THEN TWO PROJECTS THAT FOCUS ON TUMOR-RELATED FEATURES TO CHARACTERIZE SOMATIC MUTATION PROFILES AND ONCOGENIC STATES USING RNA EXPRESSION PROFILING TO SEE HOW THEY VARY BETWEEN AGGRESSIVE AND NON AGGRESSIVE TUMORS AND LOCAL INFLAMMATION IN THE TUMOR MICRO-ENVIRONMENT BETWEEN AFRICAN-AMERICANS AND WHITES AND AGGRESSIVE AND NON AGGRESSIVE DISEASE. THIS FOURTH PROJECT ON LOCAL INFORMATION WAS ACTUALLY DROPPED DUE TO BUDGET CUT BUT WE ARE HOPING THE PROSTATE CANCER FOUNDATION WILL COME THROUGH WITH FUNDING TO BRING IT BACK INTO THE PROGRAM. THERE ARE FOUR CORES FOR THIS EFFORT AND FUNDING PROVIDED BY NCI, NIMHD AND THE PROSTATE CANCER FOUNDATION, HOPEFULLY. SO FOR THIS WORK, WE ESTABLISHED A TEAM UMULTIDISCIPLINARY TEAM OF INVESTIGATORS WITH EXPERTISE IN PROSTATE CANCER RESEARCH, HEALTH DISPARITIES RESEARCH, AND WITH EXPERIENCED AND SUCCESSFULLY RECRUITING AFRICAN-AMERICAN CASES AND EPIDEMIOLOGICAL STUDIES. SO THIS INCLUDES EPIDEMIOLOGISTS, CLINICAL RESEARCH, ON COPGISTS AND PATHOLOGISTS AND INDIVIDUALS WITH BACKGROUND IN BIOIN FOREMALTICS AND BIOSTATISTICS WHO OVERSEE THE INTERGRATION OF THE OMICS AND NON OMIC DATA. AND WEIS HAVE A ADVISORY COMMITTEE RECENTLY FORMED AS WELL WHO REPRESENTED REAL KEY LEADERS IN PROSTATE CANCER RESEARCH AND GENOMICS AND WILL PROVIDE GUIDANCE ON THE RESEARCH ACTIVITIES AND RECRUITMENT IN RESPONSE. SO AS I MENTIONED, OUR GOAL IS TO RECRUIT 10,000 AFRICAN-AMERICAN PROSTATE CANCER CASES ACROSS THE U.S. OVER A 5 5-YEAR PERIOD. WE PLAN TO CAPITALIZE ON THE INVESTMENT IN THE SEER AND NPCR CANCER REGISTRIES AND THE RESEARCHERS IN THESE REGISTRIES WHO HAVE EXPERIENCE WITH DOING POPULATION-BASED RECRUITMENT OF AFRICAN-AMERICAN PROSTATE AND MORE GENERALLY, CANCER CASES. SO THIS RECRUELTY WILL COVER SEVEN STATES, CALIFORNIA, TEXAS, LOUISIANA, GEORGIA, FLORIDA, NEW JERSEY AND MICHIGAN AND THESE SEVEN STATES REPRESENT 40% OF AFRICAN-AMERICAN MEN IN THE UNITED STATES. SO THIS IS A COITRATION IS BROADLY REPRESENTED. SO THERE ARE MANY CHALLENGES AND ONE OF THE MAJOR ONES WILL BE WITH RESPECT TO RECRUITMENT. AS DISTRESSED IN THE HEALTH CARE SYSTEM AND IN RESEARCH AMONG AFRICAN-AMERICAN MEN REMAINS A CRITICAL ISSUE. THIS IS RECENTLY IN THE NEWS AGAIN FOLLOWING THIS PUBLICATION JUST LAST MONTH AND MUCH DISCUSSION OF THIS ON NPR AND THIS IS SOMETHING THAT WE ARE ACUTELY AWARE OF AND WE RECENTLY HAD FOCUS GROUPS 6 AFRICAN-AMERICAN PROSTATE CANCER CASES AT EACH RECRUITMENT SALE TO GET THEIR VIEWS ON HOW TO BUILD TRUST AND CREDIBILITY WITH THE AFRICAN-AMERICAN COMMUNITY TO BE SUCCESSFUL IN OUR RECRUITMENT GOALS. AND THESE ARE JUST A FEW OF THE COMMENTS AND CONCERNS THAT WERE RAISED BY THESE MEN SUCH ADDS WHAT IS THE BENEFIT FOR ME AND MY FAMILY? THE NEED FOR TRANSPARENCY OF THE RESEARCH. CONFIDENTIALITY AND DATA AND RESULTS AND THEY PROVIDED SOME VALUABLE INPUT ABOUT HOW TO BUILD TRUST SUCH AS BUY IN FROM BLACK COMMUNITY LEADERS AND INSTITUTIONS. SO WE ARE CURRENTLY INTEGRATING ALL OF THIS VALUABLE INFORMATION INTO OUR RECRUITMENT MATERIALS AND OUR PLANS FOR PUBLICITY TO BEGIN TO ENROLL THE STUDY AND BEGIN RECRUITMENT EARLY NEXT YEAR. SO JUST TO END, I JUST WANTED TO COMMENT ABOUT HOW IMPORTANT THIS COMMITMENT IS FROM NCI AND NIMHD. IT TOOK OVER 25 YEARS TO BE ABLE TO RECRUIT AND ASSEMBLE 10,000 AFRICAN ANCESTRY PROSTATE CANCER CASES FOR GENETIC STUDIES, WHICH IS SOMETHING WE HOPE TO ACCOMPLISH NOW AND RESPOND IN FIVE YEARS. AND THROUGH COMBINING OUR EXISTING EFFORTS WITH THIS NEW INITIATIVE, WE'LL HAVE SUBSTANTIALLY GREATER POWER FOR IDENTIFYING LOCI THAT MAY BE IMPORTANT FOR OVERALL PROSTATE CANCER AND MORE IMPORTANTLY LOCI THAT MAY BE IMPORTANT FOR AGGRESSIVE DISEASE AND RESPONDING AND FUNDED TO EXOME SEQUENCE 20,000 CASES AND CONTROLS WHICH PUTS US ON PAR WITH THE CURRENCYQUENCING EFFORTS IN MEN OF EUROPEAN ANCESTRY WHICH I JUST DESCRIBED TODAY. SO PERSONALLY, I REALLY THINK THIS IS THE IMPORTANT INITIATIVE AND WILL HELP US REDUCE THIS MAJOR IMBALANCE IN THE NUMBER OF MINORITY CANCER PATIENTS THAT HAVE BEEN INCLUDED IN GENETIC STUDIES TO DATE. AND SO, JUST TO END, I WOULD LIKE TO ACKNOWLEDGE ALL THE COLLABORATORS AND MULTIETHNIC COHORT STUDY, THE PRACTICAL CONSORTIUM AND COLLABORATORS IN UGANDA AND OBVIOUSLY, I'D LIKE TO THANK ALL OF THE FUNDING MECHANISMS AND SOURCES HERE AND ESPECIALLY THE CANCER MOONSHOT INITIATIVE FOR THEIR COMMITMENT TO ACCELERATING THE SPEED IN WHICH WE HOPE TO MAKE IMPORTANT DISCOVERIES IN PROSTATE CANCER FOR MEN OF AFRICAN ANCESTRY. AND HAPPY TO ANSWER ANY QUESTIONS. [ APPLAUSE ] >> THANK YOU. GREAT PRESENTATION. QUESTIONS? >> THANK YOU. VERY INTERESTING PRESENTATION. I KNOW YOU TALKED ABOUT ASSOCIATIONS WITH METASTATIC DISEASE BUT DO YOU HAVE ANY HINTS OF TREATMENT RESPONSE? DAN SEPARATE ASCO JUST REPORTED ON A METANALYSIS OF ENERGY, RTOG DATA IN MEN TREATED WITH RADIATION THERAPY. DID A VERY SOPHISTICATED ANALYSIS, I DON'T KNOW THAT HE LOOKED AT ALL THE SAME MARKERS YOU'RE LOOKING AT. BUT WHEN THEY CONTROLLED FOR SOCIODEMOGRAPHICS, THE MARKERS THEMSELVES PRETTY MUCH FELL OUT AND IN FACT THERE WAS A TREND FOR AFRICAN-AMERICAN MEN WITH SPECIFIC MARKERS TO RESPOND BETTER TO RADIATION THERAPY. AND WE HAVE TONSE OF DATA THAT AFRICAN-AMERICAN MEN DO BETTER WITH RADIATION THERAPY. SO, I'M STILL NOT SURE WHAT THIS PORE ENDS IN. >> THAT'S AN INTERESTING QUESTION. AND I'M SLIGHTLY AWARE OF THE STUDY THAT YOU'RE TALKING ABOUT. I'D HAVE TO LOOK AT THE STUDY IN GREATER DETAIL TO UNDERSTAND AS TO ITS QUALITY. I BELIEVE IT WAS A METANALYSIS, WAS IT NOT? OF MULTIPLE STUDIES THAT ACCUMULATED DATA OVER TIME. SO IF THAT IS THE CASE, THEN I THINK OUR THINKING ON THIS ISSUE MIGHT CHANGE. BUT I THINK THAT STUDY FIRST NEEDS TO BE REPLICATED BEFORE WE CAN COME TO A CONCLUSION AS TO ITS VALUE. UNLESS MAYBE OTHER PEOPLE KNOW MORE ABOUT THE INDIVIDUAL STUDY. I HAVE NOT READ IT SPECIFICALLY. I BELIEVE IT WAS METANALYSIS. >> [ OFF MICROPHONE ] >> VERY FAMILIAR WITH THE DATA. IF YOU LOOK AT PATIENTS TREATED ON PROSPECTIVE PHASE III RANDOMIZED TRIALS, RACE FALLS OUT AS AN INDEPENDENT PROGNOSTIC FACTOR. IN FACT, THE MOST IMPORTANT PART OF YOUR RESEARCH IS THE ISSUE OF THE INCIDENCE OF PROSTATE CANCER. SO I THINK THERE IS TWO SEPARATE ISSUES. ONE IS WHY DOES PROSTATE CANCER COME ON AT A EARLIER AGE IN AFRICAN-AMERICAN MEN AND WHY IS IT MORE COMMON? THAT'S A SEPARATE QUESTION THAN, ONCE A PERSON WALKS IN WITH A CERTAIN PSA OR SCORE AND CERTAIN STAGE F THEY GET APPROPRIATE TREATMENT THEN WHAT HAPPENS? I THINK THE DATA THAT DEB IS REFERRING TO IS OUTCOMES DATA IN PATIENTS TREATED ON RANDOMIZED TRIALS. WHAT YOUR WORK IS REALLY LOOKING AT IS PERHAPS WHY IS PROSTATE CANCER MORE COMMON? ONE OTHER POINT IS THAT SOME YEARS AGO, AND THIS RELATES TO THE ISSUE OF CAUSE AND EFFECT. WE LOOKED AT CYP 3A4 AND POLYMORPHISMS, A MARKER FOR THE ANTIGEN RECEPTOR, AND WE SAW TREMENDOUSIC DIFFERENCES IN THE DISTRIBUTION BETWEEN AFRICAN MEN AND WHITES. 75% OF WHITE MEN HAD EITHER THE WILDTYPE OR A COMBINATION, AND 75% OF AFRICAN-AMERICAN MEN HAD SOME COMPONENT OF THE VARIANT TYPE. IT DID NOT AFFECT THEIR OUTCOME. SO THE FACT THAT YOU SEE DIFFERENCES IN THE DISTRIBUTION OF POLYMORPHISMS IN THE TWO POPULATIONS SOMETIMES CONFUSES PEOPLE INTO THINKING THAT THESE POLYMORPHISMS ARE NECESSARILY RELATED TO PROSTATE CANCER OUTCOME, PARTICULARLY IF THEY AFFECT THE ANTIGEN RECEPTOR BUT THEY MAY NOT. SO I THINK THE ISSUE OF INCIDENCE IS REALLY THE MOST KEY QUESTION IN PROSTATE CANCER FOR AFRICAN-AMERICAN MEN. >> I COULDN'T AGREE MORE. >> CHERYL? >> SO CHRIS, I REALLY ENJOYED YOUR PRESENTATION AND I HAVE TWO QUESTIONS ABOUT THE RESPOND PROJECT, MORE TECHNICAL APPROACH. SO REALLY INTRIGUES ME YOU MADE THE DECISION TO RECRUIT PATIENTS THROUGH SEER LARGELY, WHICH I THINK IS A REALLY INTERESTING STRATEGY AS MOST OF THOSE REGISTRIES ARE PRETTY DEEPLY EMBEDDED IN THEIR COMMUNITIES. SO THAT IMPLIES YOU'RE COMING AT PATIENTS AFTER THE DIAGNOSIS HAS BEEN MADE. SO HOW WILL YOU HANDLE THE TISSUE COLLECTION THEN? YOU'RE GOING TO DO MOSTLY F FBI AND BLOOD SAMPLES RETROSPECTIVE LEOR TRY TO GET FRESH TISSUE AFTER THE FACT? JUST OUT OF CURIOSITY. >> THE FOCUS WE'LL COLLECT SAMPLES AND THEN WE'LL GO AFTER FFPE TISSUE. >> SO WITH TECHNOLOGIES TODAY YOU'RE NOT WORRIED ABOUT THAT? >> WE ARE NOT. WE HAD TO DO A LOT OF PRELIMINARY DATA TO DEMONSTRATE WE COULD DO THIS MUTATION PROFILING AND BIOPSY SAMPLES. BECAUSE WE ARE NOT ONLY -- SUBSTANTIAL BIOPSIES IN ADDITION TO RADICAL PROSPECT I WAS. >> JUST HEARD YOU MENTION YOU WERE GOING TO DO A LOT OF TRANSCRIPTOMICS SEQUENCING -- IN OUR EXPERIENCE CAN BE PROBLEMATIC WITH THOSE SAMPLES. OR AT LEAST LESS HIGH YIELD. I THINK THAT'S A GREAT STRATEGY. MY SECOND QUESTION RELATED TO THE BEHAVIORAL SURVEY DATA THAT YOU'RE GOING TO COLLECT, WHICH I THOUGHT WAS REALLY INTERESTING, RELATED TO SOCIAL AND LIFESTYLE FACTORS POTENTIAL EXPOSURES AND STRESS RESPONSES BUT COMMENT NOT FOR YOU BUT REALLY FOR ALL OF US IS, I THINK THE INCLUSION OF THE EPIDEMIOLOGIC BEHAVIORAL SURVEYS IS APPROPRIATELY BECOMING MORE COMMONPLACE TO ACCOMPANY OUR GENOMIC STUDIES OUR OUTCOME STUDIES AND I HAVE A COMMENT THAT MAYBE OTHERS WOULD WANT TO RESPOND. IT WOULD REALLY BE NICE FOR US TO COME AT SOME STANDARDIZATION OF THOSE SURVEYS SO WE WERE COLLECTING THE SAME DA DATA ELEMENTS BECAUSE JUST LIKE YOU SAY, SOME OF THE RISK ALLELES YOU TUNED ARE AS IMPORTANT IN BREAST CANCER AS PROSTATE. SO IF YOU COULD BEGIN TO EXPLORE LINKS IN YOUR STUDY AND OTHER DISEASES, IT WOULD BE INTERESTING. SO TALKING ABOUT US THINKING ABOUT STANDARDIZATION OF THESE SURVEY INSTRUMENTS AND MEASURES ACROSS SEVERAL NCI PROJECTS. >> THANK YOU. >> REALLY AN IMPRESSIVE BODY OF WORK. I NOTICED THAT YOU PRESENTED DATA STRATIFIED BY A GLEASON STORE OF 8 AND A GLEASON SCORE OF LESS THAN 7. LOOKING AT DOING PROSTATE CANCER RESEARCH, THE GREATEST CHALLENGE FOR CLINICIANS WAS HOW TO HANDLE PATIENTS WITH THE GLEASON SCORE OF 7 AND WHETHER THERE WAS 3-4 VERSUS 4-3. IT MIGHT BE A QUESTION OF NUMBERS BUT HAVE PEOPLE LOOKED AT THOSE TWO GROUPS OF GLEASON SCORE 7? THAT REALLY IS A CLINICAL CHALLENGE AND HARD TO HANDLE THOSE PATIENTS. >> SO WITH RESPECT TO OUR STUDIES OF GENETIC SUSCEPTIBILITY. WE HAVEN'T DIVED INTO THAT QUESTION. WE HAVE MORE BEEN FOCUSING ON THE EXTREMES OF AGGRESSIVENESS. SO GLEASON 8-10 PLUS STAGE 3 AND 4 VERSUS ACTUALLY GLEASON 6. AND REMOVING THAT 7 CATEGORY DEFINED MARKERS. IF WE IDENTIFIED MARKERS ASSOCIATED WITH AGGRESSIVENESS, THEN WE WOULD TAKE THEM BACK TO TRY TO SEPARATE OUT 3 PLUS 4 AND 4 PLUS 3 CATEGORY. >> CHRIS, VERY NICE PRESENTATION, AND VERY NICE WORK. WE TALKED AS A BOARD HERE A LOT ABOUT DISPARITIES AND THEY EXIST FOR MULTIPLE DIFFERENT GROUPS AND CANCERS. YOU AND YOUR TEAM HAVE BEEN SYSTEMATICALLY CHIPPING AWAY AT THEM FOR 12 YEARS AS WE JUST SAW. THE MOONSHOT IS TO ACCELERATE THE OF THESE THINGS AND HAVING DONE THIS NOW FOR THE LAST 15-20 YEARS, ARE THERE THINGS THAT THE NCI OR THAT THE RESEARCH COMMUNITY COULD BE DOING TO REPLICATE YOUR SUCCESS IN ACCELERATING THESE THINGS FOR OTHER DISPARITIES, FOR OTHER CANCERS? IDEALLY WE WOULDN'T WANT TO HAVE TO WAIT ANOTHER 12 YEARS TO HAVE A SIMILAR PRESENTATION ON CLOSING THE GAP BETWEEN GENETIC MARKERS THAT HAVE BEEN IDENTIFIED IN WHITE POPULATIONS AND DISEASES THAT DISPROPORTIONATELY AFFECT HISPANIC AMERICANS. SO HAVING BEEN IN THIS WORLD, ARE THERE THINGS WE CAN THINK ABOUT TO TRY TO REPLICATE YOUR SUCCESS? >> I THINK PROBABLY THE MOST COLLABORATIVE NETWORK. BECAUSE IT IS INCREDIBLY -- A LOT OF THE WORK THAT HAS BEEN FUNDED TO DATE HAS BEEN BY INDIVIDUAL INVESTIGATORS COLLECTING DATA IN ISOLATION TO ADDRESS A SINGLE QUESTION. AND I THINK THROUGH COLLABORATIVE NETWORKS SUCH AS THIS, YOU COLLECT THE SAME DATA ON ALL THE INDIVIDUALS, ALLOWS IT TO BE INTEGRATED TO ADDRESS MULTIPLE QUESTIONS. SO I THINK THAT IS AN IMPORTANT FRAMEWORK TO CONSIDER WHEN ADDRESSING DISPARITIES FOR CANCER AND MOVING ON TO OTHER CANCER SITES SUCH AS MULTIPLE MYELOMA WHERE THE SAME DISPARITY EXISTS, WHERE A NETWORK NEEDS TO BE FORMED. >> I'D LIKE TO GET BACK TO JUST ONE QUESTION ABOUT DISCRIMINATING BETWEEN AGGRESSIVE AND NON AGGRESSIVE FORMS. IS THERE WORK TO FUNCTIONALLY CHARACTERIZE SOME OF THESE VARIANTS IN THESE DIFFERENT SUBTYPES WITH GLEASON SCORES OR JUST LOOK AT THE FUNCTIONAL CHARACTERISTICS OF THE VARIANTS? >> SO YES, SO THE VARIANTS HAVE BEEN IDENTIFIED FOR ASSOCIATED WITH AGGRESSIVE DISEASE ARE DELETERIOUS. THE PROTEIN DRUNKATING MUTATIONS ARE THOSE THAT ARE TRULY PATHOGENIC. THERE IS A LOT OF VARIANTS THAT WE HAVE UNKNOWN SIGNIFICANTS AND SOME OF THESE DNA REPAIR PATHWAY GENES, WE DON'T KNOW HOW TO CLASSIFY THEM IN TERMS OF FUNCTIONALITY. SO GROUPING THEM INTO THESE BURDEN TESTS CAN BE VERY CHALLENGING. WITH RESPECT TO THE MARKETERS IDENTIFYING GENOME-WIDE, THERE IS ENORMOUS AMOUNT OF RESEARCH ONGOING TO UNDERSTAND THE BIOLOGICAL MECHANISMS IN WHICH THESE VARIANTS ALTER RISK. AQ24, THOUGH, STILL NEEDS SOME ATTENTION. THERE IS NO DOUBT ABOUT IT. ALL THE VARIANTS ARE NON CODING SEQUENCE, LONG CODING RNAs, ELEPHANT IN THE ROOM IS RIGHT NEARBY. LOANING IS GOING ON. THEY ALTER EXPRESSION -- LOOPING IS GOING ON. THEY ALT EREXPRESSION OF C-MYC. CRISPR METHODOLOGY IS BECOMING A COMMON TOOL TO EXPLORE FUNCTIONALITY. WE DON'T YET HAVE A VERY GOOD HANDLE ON THE VAST MAJORITY IN TERMS OF MECHANISMS. >> CAN I JUST ADD THAT I PERCEIVE THE BIGGEST CHALLENGE IS GOING TO BE WHEN YOU DEFINE AGGRESSIVE PHENOTYPE IN PROSTATE CANCER, WHICH HAS A LONG UNTIL HISTORY IN USING SEER DATA, YOU'RE FINDING THESE MEN BUT WHAT HAPPENS TO THEM IN TERMS OF TREATMENT AND HOW MUCH FOLLOW-UP YOU'RE GOING TO HAVE IN ORDER TO ANSWER THE QUESTION, IS THIS AN AGGRESSIVE PHENOTYPE OR NOT? SOMEHOW WHATEVER YOU FIND NEEDS TO BE VALIDATED IN THE CONTEXT OF PATIENTS THAT HAVE BEEN SYSTEMATICALLY DIAGNOSED AND TREATED. SO FOR EXAMPLE, I'M SURE THAT WE HAVE 10,000 AFRICAN-AMERICAN MEN IN THE RTOG, NRG DATABASE, WHO ARE DIAGNOSED IN THE 70s, 80s, 90s, THAT HAVE BEEN TREATED ON PROSPECTIVE PHASE III RANDOMIZED TRIALS AND WE HAVE TISSUE ON THOSE PEOPLE. AND THERE YOU CAN DEFINED WHICH ONES ARE AGGRESSIVE BECAUSE PEOPLE HAVE DIED OF PROSTATE CANCER. THEY HAVE DEVELOPED METASTATIC DISEASE. THEY HAVE BEEN TRACKED. AND SO FINDING PEOPLE AND LOOKING AT THEIR GENETIC MAKEUP WON'T TELL YOU HOW AGGRESSIVE 3 DISEASE IS UNLESS YOU KNOW HOW MANY OF THEM ARE DYING AT 10 YEARS OR 15 YEARS. >> SO I THINK THAT IS THE NEXT PHASE OF WHAT WE ARE PLANNING TO DO. WE TRIED TO BUILD SOME OF THIS DATA COLLECTION OF TREATMENT INFORMATION IN FOLLOW-UP INTO THE BUDGET BUT IT GOT A LITTLE BIT TOO LARGE. BUT THAT WILL BE THE NEXT PHASE WE ARE TRYING TO DO IN RESPOND. I DON'T KNOW HOW SUCCESSFUL IT WILL BE. HOPEFULLY IT WILL BE COMPARED TO CLINICAL STUDIES WHERE THIS INFORMATION IS VERY WELL ANNOTATED. LOOKING AT WHAT WE IDENTIFIED HERE AT MARKERS OF AGGRESSIVENESS, EVEN THOUGH IDENTIFIED IN MEN WHO MIGHT HAVE LOW-GRADE TUMORS, WHAT THEIR ASSOCIATION IS WITH MORTALITY IS THE IMPORTANT QUESTION LONG TERM. >> SO I WONDER ONE OF THE THINGS& THAT FEELS LIKE WILL FALL OUT OF THIS IS THE NEED FOR INCREASED HEREDITARY RISK TESTING. AND THE FIRST DEGREE FAMILY MEMBERS OF THESE PATIENTS AND THEIR PRIMARY STRATEGIES. I'M NOT SURE THAT WE HAVE EVEN THE CAPACITY IF WE SAID TODAY THAT MEN WITH METASTATIC PROSTATE CANCER WHO CARRIED GERMLINE ALLELES ALL NEED TO BE -- [ INAUDIBLE ] IT'S MOSTLY A COMMENT. >> UNDERSTANDING IF SOMEONE IN A FAMILY CARRIES ONE OF THESE MUTATIONS, IT WILL BE FORTUNATE INCREASE HOW FREQUENTLY THEY ARE SCREENED AND BIOPSIED TO IDENTIFY BEFORE IT IS METASTATIC DISEASE. >> THE LAST QUESTION. SORRY. >> CHRIS, I WANTED TO -- GOING BACK TO THE RESPOND STUDY. I'M THINKING ABOUT THE GENETIC AND SOCIOBEHAVIORAL RISK FACTORS ALSO INCLUSIVE OF ENVIRONMENTAL RISK FACTORS. SO THINKING ABOUT MAYBE SOME METRICS IN ALL OF US YOU MIGHT BE ABLE TO GET AT SOME OF THE EXPOSURE RISK FACTORS ALSO SOME OF THE PLATFORMS AT NIEHS AND OTHERS HAVE IN TERMS OF EVALUATION OF BIOSPECIMENS. YOU COULD TRY TO LOOK AT SOME OF THOSE EXPOSURES POTENTIALLY AS WELL. SO ALSO KEEP THAT ON THE RADAR SCREEN. >> THANK YOU. >> THANK YOU VERY MUCH. WE APPRECIATE YOUR TALK. SO OUR NEXT TALK, BOB YOU'RE GOING TO INTRODUCE A SPEAKER ON TOBACCO PRODUCTS. >> YES, SO WE'LL SHIFT GEARS TO AN ISSUE A LOT OF YOU HAVE BEEN SEEING IN THE MEDIA. IF YOU READ ABOUT ELECTRONIC CIGARETTES, JEWEL, WHAT IS HAPPENING IN TERMS OF YOUTH, TOBACCO USE AND USE OF ELECTRONIC CIGARETTES. SO WE HAVE A STRONG ONGOING PARTNERSHIP WITH THE CENTER FOR TOBACCO PRODUCTS AT THE FDA AND YOU'RE GOING TO HEAR AN UPDATE FROM THE DIRECTOR OF THE CENTER FOR TOBACCO PRODUCTS, MITCH ZELLER, ON FDA'S APPROACH ON EXERCISING THEIR AUTHORITY. SO I'M GOING TO INTRODUCE& BRIEFLY BRIEFLY FOUR SAKE OF TIME. THERE ARE USUALLY LOTS OF QUESTIONS AND LOTS OF DISCUSSION. SO MITCH ZELLER IS A GRADUATE OF DARTMOUTH AND WASHINGTON COLLEGE OF LAW WORKING AT FDA FOR MORE THAN 30 YEARS. HE BEGAN AS PUBLIC INTEREST ATTORNEY. HE SERVED AS COUNCIL ON THE UNITED STATES HOUSE OF REPRESENTATIVES ON THE GOVERNMENT OPERATIONS COMMITTEE WHERE HE CONDUCTED OVERSIGHT AND ENFORCEMENT AND INVESTIGATION ON A VARIETY OF HEALTH AND SAFETY HE JOINED THE STAFF AT FDA COMMISSIONER DAVID KESSLER BACK IN THE DAY AND THEN WHAT BEGAN AS A TWO WEEK ASSIGNMENT THEN MORPHED INTO BECOMING A SOCIODIRECT COMMISSIONER AND DIRECTOR FOR FDA'S FIRST OFFICE OF TOBACCO PROGRAMS. THERE IS A LONG STORY THERE BUT THAT WENT AWAY AND THEN CAME BACK WITH CONGRESS'S PASSAGE OF THE ACT TO GIVE FDA SPECIAL AUTHORITY. SO MITCH HAS A HUGE REMIT AT FDA AND ALSO WHILE HE IS HERE, I WANT TO THANK HIM BECAUSE DURING THESE PAST FEW YEARS, SINCE FDA HAS BEEN GRANTED REGULATORY AUTHORITY, THE FDA CENTER FOR TOBACCO PRODUCTS NOW FUNDED OVER 100NCI RESEARCH GRANTS. SO I'M SURE THAT THIS COMMUNITY HERE IS VERY APPRECIATIVE OF THAT AS WELL. SO WELCOME MITCH ZELLER. >> Mr. ZELLER: THANK YOU FOR THE VERY KIND INTRODUCTION, BOB. IT'S A PLEASURE TO BE HERE TO GIVE THE BOARD AN UPDATE ON WHAT IS GOING TO AT FDA AND OUR COMPREHENSIVE PLAN FOR TOBACCO AND NICOTINE REGULATION. I'LL START JUST TO LEVEL SET AND WALK YOU THROUGH A FAIRLY HIGH LEVEL, OUR STATUTORY AND REGULATORY AUTHORITIES BEFORE TAKING YOU INTO A DEEPER DIVE INTO THE COMPREHENSIVE PLAN. AND I'LL TALK ABOUT REGULATORY POLICIES, WHAT WE ARE DOING TO PROTECT KIDS, AND PRODUCT REVIEW. AND THEN CLOSE WITH JUST A BRIEF OVERVIEW OF OUR COLLABORATION WITH NCI AND NIH LEAVING TIME FOR QUESTIONS. BUT JUST BY WAY OF BACKGROUND SO YOU HAVE SOME FAMILIARITY, STATUTORILY AND PROGRAMMATICALLY WITH WHO WE ARE AND WHAT WE DO, YOU HEARD BOB SAY THAT -- IT IS A LONG STORY ABOUT HOW THE AGENCY'S FIRST ATTEMPT TO REGULATE TOBACCO PRODUCTS CAME TO A CRASHING HALT BUT IT DID WHEN THE SUPREME COURT IN 2000, OVERTURNED FDA'S ASSERTION OF JURISDICTION. AND THE LITTLE OFFICE THAT WE HAD BUILT, WE HAD TO SHUT DOWN. AND IN ESSENCE WHAT THE SUPREME COURT SAID IN THAT DECISION WAS, ONLY CONGRESS COULD DECIDE WHETHER FDA SHOULD BE IN THE BE BUSINESS OF REGULATEY TOBACCO PRODUCTS. IT TOOK CONGRESS 9 YEARS TO DO THAT. IN 2009, WITH OVERWHELMING BIPARTISAN SUPPORT IN THE HOUSE AND SENATE, CONGRESS PASSED THE FAMILY SMOKING PREVENTION AND TOBACCO CONTROL ACT. THERE HAS BEEN AND THERE REMAINS COMPREHENSIVE TOBACCO CONTROL EFFORTS AT THE FEDERAL, STATE AND LOCAL LEVEL. BUT SINCE 2009, NOW PRODUCT REGULATION AND THE POWERFUL TOOLS OF PRODUCT REGULATION HAVE A SEAT AT THE TABLE AS A COMPONENT OF COMPREHENSIVE TOBACCO CONTROL. THE INTENT HERE WAS TO REDUCE HARMS ACROSS-THE-BOARD WHEN IT COMES TO TOBACCO USE. THE ORIGINAL GRANT OF AUTHORITY WAS OVER CIGARETTE, ROLE YOUR OWN TOBACCO AND SMOKELESS TOBACCO. AND AN ODD WORD THAT CONGRESS WROTE INTO THE STATUTE, DEEM. CONGRESS SAID WE COULD DEEM OTHER CATEGORIES OF PRODUCTS TO BE WITHIN OUR REGULATORY REACH BY GOING THROUGH A RULEMAKING PROCESS. AND THAT IS WHAT WE DID STARTING IN 2014 AND CONCLUDING IN 2016, THE SO-CALLED DEEMING REGULATION. THE FIRST TALK I GAVE WHEN I WAS CENTER DIRECTOR WAS TO AN INDUSTRY GROUP AND THERE WERE FINANCIAL ANALYSTS IN THE ROOM AND I WAS REFERRING TO THE DEEMING REGULATION AND THERE WAS DR. DEVOR: LIFT WHO THOUGHT I WAS REFERRING TO DEMON REGULATION. -- IT'S THE DEEMING REGULATION. WITH THIS REGULATION WENT INTO EFFECT IN OFF OF 2016, WE HAVE REGULATORY OVER EVERY CATEGORY OF A PRODUCT THAT MEETS THE STATUTORY DEFINITION. AND IF YOU LOOK AT THE FIRST SUB BULLET, AND YOU SEE E-CIGARETTES THERES YOU MAY ASK YOURSELF WHY IS FDA REGULATING e-CIGARETTES AS A TOBACCO PRODUCT IF THERE IS NO TOBACCO? AND THERE IS NONE. THAT COMES DOWN TO THE TWO-PRONG STATUTORY DEFINITION OF WHAT A TOBACCO PRODUCT IS. IT'S ANYTHING THAT IS MADE OR DERIVED FROM TOBACCO AND INTENDED FOR HUMAN CONSUMPTION AND THE NICOTINE IN E-CIGARETTES IS DERIVED FROM TOBACCO AND THAT'S WHAT GIVES US THE REGULATORY REACH OVER THE ENTIRE CATEGORY OF ELECTRONIC NICOTINE DELIVERY SYSTEMS IN ANY FORM. FOR THE PRODUCTS THAT WE REGULATE, WE REGULATE THEM UNDER A STANDARD THAT IS QUITE DIFFERENT FROM THE STANDARD THAT YOU ALL ARE PROBABLY MORE FAMILIAR WITH, WHEN IT COMES TO THE MEDICAL PRODUCTS. IN ITS WISDOM, CONGRESS WROTE A POPULATION-LEVEL PUBLIC HEALTH STANDARD FOR THE REGULATION OF TOBACCO PRODUCTS. AND THERE ARE MANDATORY CONSIDERATIONS AS WE INTERPRET THE STRAYING AND GENERAL WORDS, APPROPRIATE FOR THE PROTECTION OF THE PUBLIC HEALTH. THAT'S WHAT THE STATUTE SAYS. THE MANDATORY CONSIDERATIONS ARE IMPACT ON INITIATION, IMPACT ON CESSATION AND REINITIATION AND IN ADDITION TO ANYTHING WE KNOW ABOUT THE PRODUCTS THEMSELVES. AND WHILE THE STATUTE DOESN'T SAY, THIS THE WAY WE HAVE INTERPRETED THAT IS THAT IT'S OUR JOB, AND THIS IS WHERE THE REGULATORY SCIENCE AND THE WONDERFUL PARTNERSHIP BETWEEN FDA AND NIH AND NCI COME IN, OUR JOB IS TO USE THE REGULATORY SCIENCE TO ASSESS AT A POPULATION LEVEL NET PUBLIC HEALTH IMPACTS. OUR JOB IS MESSY. THE POPULATION LEVEL IMPACTS ARE NEITHER EXCLUSIVELY POSITIVE NOR EEXCLUSIVELY NEGATIVE. THERE IS SOME COMBINATION OF POSITIVE POPULATION IMPACTS AND NEGATIVE. OUR JOB IS TO ASSESS THE NET OF ALL THAT WITH THE REGULATORY SCIENCE AS OUR GUIDE. THIS SLIDE IS JUST A VERY HIGH-LEVEL OVERVIEW OF THE KINDS OF AUTHORITIES THAT WE HAVE AND IF YOU'RE FAMILIAR WITH FDA'S WORK FOR DRUGS OR MEDICAL DEVICES OR BIOLOGICS, THESE KINDS OF AUTHORITIES LOOK FAMILIAR. AND THEY ARE. THE FUNDAMENTAL DIFFERENCE IS, THE MEDICAL PRODUCT CENTERS AT FDA REGULATE PRODUCTS THAT HAVE SOME BENEFIT TO SOCIETY. OUR JOB IS TO REDUCE THE HARMS ASSOCIATED WITH TOBACCO USE. THERE IS NO BENEFIT TO USING TOBACCO USE. IT'S A QUESTION OF RELATIVE RISK. SO IT'S SOME OF THE VERY SAME AUTHORITIES THAT OTHER CENTERS AT FDA HAVE HAD FOR MANY, MANY DECADES BUT WE ARE USING IT BASICALLY TO REDUCE THE HARMS ASSOCIATED WITH TOBACCO USE. AND WE USE THOSE TOOLS AND AGAIN THIS IS AT A VERY HIGH LEVEL AND WILL I'M HAPPY TO ANSWER ANY QUESTIONS TO GET INTO MORE DETAIL, TO BETTER UNDERSTAND THE PRODUCT POWERFUL TOOLS THAT CONGRESS HAS GIVEN US TO COMPEL INFORMATION FROM TOBACCO COMPANIES. THE FUNDAMENTAL CONSUMER PROTECTION NOTION OF PRE-MARKET REVIEW OF CONSUMER PRODUCTS, SOMETHING THAT THE PUBLIC TAKES FOR GRANTED WHEN IT COMES TO NEW DRUGS OR NEW FOOD ADDITIVES FOR THE FOOD SUPPLY. NOW THERE IS PRE-MARKET REVIEW FOR TOBACCO PRODUCTS FOR CLAIMS. HEALTH-RELATED CLAIMS. CLIMBS REDUCE EXPOSURE OR RISK. IT'S NOT UP TO THE COMPANIES AND THEIR PRODUCT DEVELOPERS AND MARKETERS. THEY SUBMIT APPLICATIONS TO US AND THE SCIENTISTS AT THE CENTER FOR TOBACCO PRODUCT REVIEW THE APPLICATIONS ON A PRE-MARKET BASIS AND WE MAKE THE DECISION UNDER THE PUBLIC HEALTH STANDARD WHETHER A NEW PRODUCT SHOULD COME TO MARKET OR A HEALTH-RELATED CLAIM SHOULD BE AUTHORIZED. ALSO POWERFUL TOOLS TO RESTRICT MARKET AND DISTRIBUTION. I'LL TALK A LITTLE BIT ABOUT THE POWER WE HAVE TO REGULATE THE ALLOWABLE LEVELS OF INGREDIENTS, COMPOUNDS, CONSTITUENTS, ADDITIVES AND FINISHED TOBACCO PRODUCTS TO INCREASE HARM. POWERFUL ENFORCEMENT TOOLS, AND AS PART OF UPDATE ON THE PLAN, I'LL TELL YOU WHERE WE HAVE BEEN WITH ENFORCEMENT. I'LL TALK ABOUT THE STEPS THAT WE TAKE TO EDUCATE THE PUBLIC AND THE FINAL WAY THAT WE USE THE AUTHORITIES THAT WE HAVE IS TO EXPAND SCIENCE BASE AND I'LL TALK A SECOND ABOUT THAT BECAUSE THAT GOT TO THE HEART OF THIS WONDERFUL COLLABORATION BETWEEN OUR AGENCIES. FDA COULD HAVE RE-CREATED THE NIH PROCESS SINCE WE DO PUT OUT IN ANY GIVEN YEAR, WELL OVER 100 MILLION DOLLARS A YEAR INTO RESEARCH. BUT INSTEAD, THE DECISION WAS MADE TO WORK WITH NIH AND THE EXISTING FUNDING MECHANISMS HERE WHERE WE ARE THE FUNDER. OUR COLLEAGUES AT NIH AND THE VARIOUS INSTITUTES HAVE AN UNDERSTANDING OF WHAT THE REGULATORY PROGRAMMATIC NEEDS AND PRIORITIES OF US AS REGULATORS AND THIS WHOLE FIELD OF REGULATORY SCIENCE AS THE DRIVER FOR INFORMING POLICY. AND THE TOBACCO REGULATORY SCIENCE PROGRAM IN THE OFFICE OF DISEASE PREVENTION AT NIH IS ONE OF THE MOST IMPORTANT FEDERAL PARTNERSHIPS THAT WE HAVE TO DRIVE THE SCIENCE. AND THIS SLIDE JUST LIST THE TYPE OF RESEARCH THAT WE FUND. I'LL CALL OUT TWO AND GO INTO MORE DETAIL LATER ON ONE OF THEM. AND THE TOBACCO CENTERS OF REGULATORY SCIENCE, MULTI-CENTER, MULTIDISCIPLINARY, UNBELIEVABLY IMPORTANT TO THE FUTURE AS WE SEE NEW AND NOVEL PRODUCTS COMING INTO MARKET TO BETTER UNDERSTAND WHO IS USING THESE PRODUCTS, HOW ARE THEY BEING USED? TO BETTER UNDERSTAND THE PRODUCTS THEMSELVES. AND THE POPULATION ASSESSMENT OF TOBACCO AND HEALTH ARE THE PATH STUDY AND THE LARGEST FUNDED LONGITUDINAL STUDY EVER BEEN DONE ON TOBACCO AND THIS IS DONE THROUGH NIDA, THROUGH A CONTRACT WITH WEST END AND A NUMBER OF PARTICIPATING ORGANIZATIONS. BUT THIS IS FOLLOWING 46,000 CHILDREN AND ADULTS LONGITUDINALLY. AND THIS IS GOING TO CONTINUE WELL INTO THE 2020s IF NOT BEYOND. AND IT'S A COMBINATION OF SURVEY WORK AND FROM CONSENTING ADULTS AND NOW FROM CONSENTING PARENTS ON BEHALF OF THEIR KIDS. IT ALSO INCLUDES THE COLLECTION OF BIOSPECIMENS. EITHER BLOOD, SALIVA OR URINE THAT GETS STORED AND SO IMAGINE THE ABILITY THAT WE WILL HAVE, ALTHOUGH BIOSPECIMEN ANALYSIS TAKES A LONG TIME TO BE DONE. TO COMPARE WHAT WE KNOW ABOUT PATTERNS OF USE LONGITUDINALLY TO WHAT THE EXPOSURE DATA IS TELLING US ABOUT EXPOSURE TO HARMFUL CONSTITUENTS IN BLOOD SALIVA OR URINE. AND THE LAST TWO BULLETS ARE JUST THE SUPPORT THAT WE PROVIDE FOR ONGOING NATIONAL SURVEYS AND FOR THE VERY IMPORTANT LABORATORY AND REGULATORY LABORATORY WORK THAT NEEDS TO INFORM THE DECISIONS THAT WE MAKE AS REGULATORS BECAUSE THERE IS ALSO A LAW ENFORCEMENT COMPONENT TO WHAT WE DO. SCOTT GOTLY BECAME COMMISSIONER OF FDA OVER A YEAR AND A HALF AGO AND WE SPENT A LOT OF TIME WITH HIM IN HIS FIRST MONTH AND A HALF TO TWO MONTHS ON THE JOB TO GET HIM UP TO SPEED AT HIS REQUEST, ON OUR AUTHORITIES, WHAT WE ARE DOING PROGRAMMATICALLY. AND WHEN WE WERE FINALLY FINISHED WITH THE EMERSION, THIS WAS THE QUESTION THAT HE ASKED WHEN WE PIVOTED IT OKAY, WHAT ARE THE POLICY OPPORTUNITIES HERE? HOW CAN WE USE THESE REALLY POWERFUL TOOLS OF PRODUCT REGULATION TO HAVE THE GREATEST IMPACT ON PUBLIC HEALTH USING THE TOOLS OF PRODUCT REGULATION? THE COMPREHENSIVE PLAN ANNOUNCED IN JULY OF LAST YEAR. ONE OF THE POINTS HE MADE IS THAT WE ALL, NO THE JUST FDA AS REGULATORS, WE ALL FIND OURSELVES AT CROSSROADS. AND THE CROSSROADS NOTION FOR ME EXISTS IN A COUPLE OF DIFFERENT REALMS BUT ONE OF THEM IS JUST BASIC EPIDEMIOLOGY. SO IF WE PAUSE AND WE LOOK BACK TO THE TIME OF THE FIRST SURGEON GENERAL'S REPORT ON SMOKING AND HEALTH IN 1964 WHEN THERE WAS AN ADULT SMOKING RATE OF 43-44%. WHEN I AS A KID, GROWING UP NOT IN NORTH CAROLINA, VIRGINIA OR KENTUCKY, BUT IN BROOKLYN, NEW YORK, I REMEMBER WE MADE ASHTRAYS FOR OUR PATIENTS IN ARTS AND CRAFT CLASS. AND I DON'T REMEMBER THE SURGEON GENERAL'S REPORT BUT I REMEMBER MAKING THE ASHTRAYS. MORE THAN ONCE. I REMEMBER IN ANY HOUSE YOU WENT TO, THERE WOULD BE A BOWL OF LOOSE CIGARETTES ON FOYER TABLES AS A WELCOMING GESTURE. THAT'S HOW NORMALIZED TOBACCO USE WAS WHEN THERE WAS A 44% SMOKING RATE. FAST FORWARD TO THE 50TH ANNIVERSARY, SURGEON GENERAL'S REPORT ABOUT 4 PLUS YEARS AGO, AND THE SMOKING RATE HAS GONE DOWN BY 68% AND EVEN MORE SINCE. SO, THE EPIDEMIOLOGICAL CROSSROADS NOTION IF YOU WILL, IS EXTRAORDINARY PROGRESS IN REDUCING BOTH PREVALENCE AND EVEN GREATER PROGRESS IN REDUCING PER CAPITA CONSUMPTION BUT NONETHELESS, WE ARE STILL TALKING ABOUT THE LEADING CAUSE OF TOTALLY PREVENTIBLE DISEASE AND DEATH IN THE UNITED STATES AND THE WORLD. AND THE IRONY AT THE TIME OF THE 50TH ANNIVERSARY REPORT IN 2014, WITH AN OPPORTUNITY TO PAUSE AND REFLECT ON THAT 50 YEARS WORTH OF PROGRESS, THE ACTUAL ANNUAL DEATH TOLL FROM TOBACCO USE WENT UP BECAUSE THE SURGEON GENERAL WAS ABLE TO ADD DISEASES TO THE LIST OF TOBACCO-RELATED DISEASES. SO NOW THE CONSERVATIVE ESTIMATE, THIS IS EXTREMELY CONSERVATIVE, IS 480,000 OF, AVOIDABLE DEATHS EVERY YEAR FROM TOBACCO USE. SO DO THE SAME MATH FROM THE TIME OF THE 50TH ANNIVERSARY REPORT IN 2014 JUST THROUGH MID CENTURY, THAT'S OVER 17 MILLION AMERICANS WHO WILL DIE PREMATURELY FROM TOBACCO USE. IMAGINE THE PEOPLE WHO DON'T DIE BUT LIVE WITH AWFUL TOBACCO-RELATED DISEASES. SO THAT IS THE CROSSROADS NOTION. WITH ALL THE PROGRESS THAT HAS BEEN MADE, IT REMAINS THE LEADING CAUSE OF PREVENTIBLE DISEASE AND DEATH. IN ANY DIRECTION WE LOOK, AND PARDON THE CHOPPED IMAGE HERE BUT IT'S TO TRY TO MAKE A POINT. THAT IS IN ANY DIRECTION WE LOOKED, IN THINKING ABOUT COMPREHENSIVE APPROACH TO TOBACCO AND NICOTINE REGULATION, ALL ROADS LED US BACK TO THE PRIMARY CAUSE OF ALL OF THAT DISEASE AND DEATH IS CIGARETTES. ITS FIRST HAND AND SECOND HAND EXPOSURE AND MAYBE EVEN THIRD HAND EXPOSURE. TO THE TOXINS IN TOBACCO AND CIGARETTE SMOKE. AND THE COMMISSIONER HAS TRIED TO FRAME AND I HAVE TRIED TO FRAME THIS IN A SOMEWHAT PROVOCATIVE AND CONTROVERSIAL WAY FOR A NUMBER OF PEOPLE IN TOBACCO CONTROL. THERE IS A CONTINUUM OF RISK OUT THERE. THERE ARE MORE HARMFUL WAYS TO GET NICOTINE AND LESS HARMFUL WAYS TO GET YOUR NICOTINE. NO DISPUTE ABOUT WHAT THE ANCHOR POINTS ARE. AT THE MOST HARMFUL END IS THE CIGARETTE AND AT THE OTHER END IS GUM, PATCH, LOZENGE. AND IT'S NOT THE NICOTINE THAT DIRECTLY CAUSES THE LUNG DISEASE, HEART DISEASE AND THE CANCER. THE NICOTINE GOT YOU HOOKED AND KEPT YOU SMOKING FOR DECADES BUT IT'S OTHER COMPOUNDS IN TOBACCO AND SMOKE THAT DIRECTLY CAUSE THOSE CHRONIC DISEASES. AND THIS IS A KIDS ISSUE BECAUSE 90% OF ALL SMOKERS STARTED SMOKING WHEN THEY WERE KIDS. HALF OF THEM BECAME REGULAR SMOKERS BEFORE THEY WERE LEGALLY OF AGE TO BUY A PACK OF CIGARETTES. WELL ON THE PATHWAY TO ADDICTION. SO WE HAVE CHALLENGED OUR COLLEAGUES IN PUBLIC HEALTH AND TOBACCO CONTROL TO FIGURE OUT HOW TO ACCOUNT FOR AND APPLY THIS NOTION OF THE RISK CONTINUUM AS WE LOOK AT NEW AND NOVEL PRODUCTS THAT HAVE COME ALONG. AND THE VISION THAT THE COMMISSIONER ARTICULATED AND IN SPITE OF EVERYTHING THAT HAPPENED MORE RECENTLY, WITH KIDS AND e-CIGARETTES, WHAT REMAINS FOR US AN ACHIEVABLE VISION IS, WE CAN'T MAKE A SAFE CIGARETTE. CIGARETTES ARE GOING TO REMAIN UNBELIEVABLY TOXIC, DEADLY AND DANGEROUS. BUT WHAT ABOUT A WORLD WHERE CIGARETTES CAN NO LONGER CREATE SUSTAINED ADDICTION? THEY STILL WOULD BE VERY, VERY DANGEROUS. THE TO LACKO INDUSTRY LONG AGO AID CHILDREN AND ADOLESCENTS AS THE REPLACEMENT CUSTOMERS FOR ADDICTED ADULT SMOKERS WHO DIE OR QUIT. REMEMBER THAT FACT. 90% OF ALL SMOKERS STARTED SMOKING BEFORE THE AGE OF 18. WHAT IF FUTURE GENERATIONS OF WHO'S WILL ENGAGE IN RISKY BEHAVIOR, WILL EXPERIMENT WITH CIGARETTES, BUT THROUGH THE TOOLS OF PRODUCT REGULATION, THAT EXPERIMENTATION COULD NOT LEAD TO REGULAR USE AND ADDICTION. BUT A WORLD WHERE ADULTS WHOSE BRAINS HAVE BEEN COMPLETELY REWIRED BY THE NICOTINE AND CIGARETTES AND WHO ARE STILL SEEKING NICOTINE CAN GET IT FROM ALTERNATIVE AND LESS HARMFUL SOURCES. IT'S AN ACHIEVABLE VISION THE PUBLIC HEALTH RETURN ON INVESTMENT IS GENERATIONAL AND I'LL TALK ABOUT THAT IN A SECOND. IF WE GET THIS RIGHT, THIS WILL DECREASE THE LIKELIHOOD THAT FUTURE GENERATIONS WILL EVER BECOME ADDICTED T WILL ALLOW MORE ADDICTED SMOKERS TO QUIT. ALONG THE WAY, WE WILL ENCOURAGE INNOVATION OF THESE LESS HARMFUL ALTERNATIVE PRODUCTS AND SINCE THIS IS AN AGENCY-WIDE NOTION NOT JUST HOW TO REGULATE TOBACCO PRODUCTS, IT'S HOW TO REGULATE NICOTINE. SINCE THERE ARE THERAPEUTIC NICOTINE PRODUCTS OUT THERE THAT ARE BEING VASTLY UNDER UTILIZED, THIS IS ALSO A CHALLENGE TO OUR COLLEAGUES IN THE CENTER FOR DRUGS TO TAKE A LOOK AT THE ROLE OF MEDICINAL NICOTINE AND OTHER THERAPEUTIC CESSATION AIDS. SO THE COMPREHENSIVE PLAN FALSE INTO THE 3 BUCKETS YOU SEE HERE. REGULATORY POLICY, PROTECTING KIDS, AND THE SCIENCE-BASED REVIEW OF SO-CALLED MODIFIED RISK TOBACCO PRODUCTS. I'LL WALK THROUGH EACH ONE FOR YOU. POLICY WAS EMBRACED IN ADVANCED NOTICES OF PROPOSED RULEMAKING, A MORE. PRMs ALL OF WHICH WERE ISSUED BETWEEN MID AND LATE MARCH OF THIS YEAR. THE FIRST WAS ON THIS IMAGINE A WORLD WHERE CIGARETTES COULD NO LONGER CREATE OR SUSTAIN ADDICTION. THERE IS A DEVELOPING BODY OF SCIENCE SUGGESTIVE THAT THERE COULD BE A LEVEL OF NICOTINE IN CIGARETTES BELOW WHICH EITHER PROT DUCT WOULD BE MINIMALLY OR NON ADDICTIVE. AND SO WE SHARED THE SCIENCE. WE ARTICULATED A SERIES OF ISSUES AND QUESTIONS IN THE MARCH 15 ADVANCED NOTICE OF PROPOSED RULEMAKING AND OTHER AMOUNT MPRMs ON THE FLAVORS AND NARROWER ISSUE OF WHAT SHOULD THE REGULATORY STATUS OF SO-CALLED PREMIUM CIGARS BE? WHEN WE PUBLISHED THE NICOTINE AMPRM, WE PUBLISHED A POPULATION-MODELING PAPER IN THE NEW ENGLAND JOURNAL AND TOOK INPUT FROM A NUMBER OF OUTSIDE EXPERTS TO DRIVE THE ASSUMPTIONS PUT INTO THE MODEL AND THEN WE PUBLISHED THE RESULTS OF THE MODEL WHERE WE TUBING ONE NICOTINE REDUCTION SCENARIO AND PROJECTED THROUGH THE END OF THE CENTURY AND THE NUMBERS ARE FROM ONE FDA RULEMAKING. THE NUMBERS ARE STAGGERING IF WE GET THIS RIGHT. MORE THAN 33 MILLION PEOPLE WHO WOULD OTHERWISE HAVE GONE ON TO BECOME REGULAR SMOKERS FROM THE TIME SUCH A RULE WENT INTO EFFECT THROUGH END OF CENTURY, WHO WON'T, WHICH WOULD RESULT IN A SMOKING RATE BELOW 1 1/2%. AND ALONG THE WAY, WOULD PREVENT MORE THAN 8 MILLION DEATHS FROM TOBACCO USE, PRIMARILY CIGARETTE USE, FIRSTHAND AND SECOND HAND EXPOSURE FROM EVER OCCURRING. FROM A SINGLE RULEMAKING TAKING NICOTINE LEVELS DOWN IN CIGARETTES TO A MINIMALLY OR NON ADDICTIVE LEVEL. PROTECTING KIDS. THIS IS WHAT IS GETTING THE LION'S SHARE OF THE ATTENTION FROM THE MEDIA, FROM THE CONGRESS AND RIGHTLY SO BECAUSE PRIMARILY WHAT IS GOING ON WITH KIDS AND e-CIGARETTES. IN APRIL THE COMMISSIONER ANNOUNCED OUR YOUTH TOBACCO PREVENTION PLAN AND HE TALKED ABOUT ALL THE PROGRESS THAT IS MADE FROM THE TIME I WAS A KID MAKING ASHTRAYS FOR MY PARENTS IN THE 1960S, TO WHERE WE ARE TODAY BECAUSE HUGE PROGRESS IN REDUCING THE NUMBER OF KIDS WHO SMOKE CIGARETTES. YES SOME DIFFERENCES AT A SUB POPULATION LEVEL BUT OVERALL, UNBELIEVABLE FOR EXAMPLE IN REDUCING THE NUMBER OF KIDS WHO SMOKE. BUT WHAT IS GOING ON WITH NEW AND NOVEL PRODUCTS? AND THE COMMISSIONER HAS PUTAISE SERIES OF MARKERS DOWN THAT WERE NOT GOING TO ALLOW A NEW GENERATION OF KIDS TO GET HOOKED TO THESE NEWER AND MORE NOVEL PRODUCTS. SO WE HAVE TAKEN A SERIES OF ENFORCEMENT AND PUBLIC EDUCATION ACTIONS SINCE APRIL AND I'M GOING TO WALK YOU THROUGH EACH ONE OF THEM RATHER QUICKLY. THE PLAN HAS THESE THREE MAIN COMPONENTS, PREVENTING ACCESS, CURBING MARKETING AND EDUCATION. EVERYBODY HEARD OF JEWEL. JEWEL IS A PRODUCT THAT RESEMBLES A USB FLASH DRIVE. IT'S NOT ALONE. THERE ARE A NUMBER OF JEWEL-LIKE PRODUCTS. THERE ARE THINGS THAT ARE PECULIAR ABOUT THEM. THE PRESENCE OF SOMETHING CALLED NICOTINE SALTS IN THE MANUFACTURER, WHICH LEADS TO VERY, VERY HIGH LEVELS OF NICOTINE IN THE POD THAT GETS ATTACHED TO THE DEVICE. THESE ARE CHARACTERISTICS THAT ARE VERY, VERY APPEALING TO KIDS. THE PRODUCT CAN BE USED VERY DISCRETELY, ANECDOTAL REPORTS ARE THAT KIDS ARE JEWELING AND YES, IT IS A VERB. KIDS ARE JEWELING IN CLASS IN FRONT OF TEACHERS. IT CAN BE USED THAT DISCRETELY. AND THIS LAST POINT I FIND AMAZING. THAT SOME KIDS WALKING AROUND NICOTINE IN THESE PRODUCTS. THAT PART I DON'T UNDERSTAND. I KNOW WE ARE GETTING REPORTS OF THAT. STUNNING AND DISTURBING IF TRUE. SO THE INITIAL ACTION THAT IS WE TOOK GOING BACK TO THE SPRING. WE DID AN UNDERCOVER ENFORCEMENT BLITZ. WE ENFORCED THE YOUTH ACCESS PROVISIONS OF THE LAW THROUGH CONTRACTS WITH STATES AND TERRITORIES. AND WHEN A RETAILER ILLEGALLY SELLS TO A MINOR IN OUR PROGRAM, THE FIRST VIOLATION IS A WARNING LETTER AND SECOND AND SUBSEQUENT VIOLATIONS ARE CALLED CIVIL MONEY PENALTY ACTIONS OR CMPs. WE DID A BLITZ TO SEE WHAT WAS GOING ON REQUEST JEWEL AND ANNOUNCED IN THE SPRING WE HAD TO SEND 56 WARNING LETTERS AND FILE 6 MONEY PENALTY ACTIONS FEDERAL ILLEGAL SALE OF THAT PRODUCT TO MINORS IN OUR PROGRAM BETWEEN MARCH AND JUNE. WE ANNOUNCED THAT WE WORKED WITH eBAY TO TAKE DOWN A WHOLE BUNCH OF JUUL LISTINGS AND EBAY VOLUNTARILY PUT OTHER THINGS IN PLACE BEHIND-THE-SCENES TO PREVENT THE WHACK A MOLE THING FROM HAPPENING WHERE YOU TAKE IT DOWN OVER HERE BUT IT POPS UP OVER THERE AND eBAY DESERVES A LOT OF CREDIT FOR TRYING VERY HARD THERE. AND WE SENT MANDATORY INFORMATIONAL REQUEST TO JUUL AND THE COMPANIES THAT MAKE PRODUCTS LIKE JUUL. SECTION 904B ALLOWS US TO COMPEL THE COMPANIES TO BASICALLY GIVE US EVERYTHING THAT THEY HAVE FOR THE SPECIFIC QUESTIONS THAT WE ARE ASKING ABOUT AND THE ISSUES ARE TICKED OFF HERE IN THESE FINAL SUBBULLETS. WHAT DO YOU HAVE ON YOUTH INITIATION AND USE? WHAT DO YOU HAVE ABOUT DESIGN FEATURES AND INGREDIENTS WHAT DO YOU KNOW ABOUT THE DIFFERENTIAL APPEAL BY AGE OF THESIS FEATURES? DO YOU HAVE ANY INFORMATION ABOUT ADVERSE EVENTS WHEN IT COMES TO KIDS USING YOUR PRODUCTS? IN MAY, WE ANNOUNCED ANOTHER SERIES OF ENFORCEMENT ACTIONS AND AS THESE IMAGES FLIP BY ON THE SCENE, ASK YOURSELF WHICH IS THE FOOD PRODUCT AND WHICH IS THE E-LIQUID CONTAINING NICOTINE? WHEN IS THE CANDY? WHICH ONE IS THE WHIPPED CREAM? AND WHICH ONE IS THE JUICE BOX? WHICH ONE IS THE E-LIQUID WITH NICOTINE IN IT? WE FOUND THESE PRODUCTS TO BE VIOLATIONS OF BOTH AGENCIES STATUTES AND WE SENT JOINT WARNING LETTERS TO 13 OF THE 17 MANUFACTURERS THAT WE FOUND SELLING THESE PRODUCTS AND FDA SENT FOUR ADDITIONAL. THE GOOD NEWS IS, ALL 17 COMPANIES COMPLETELY REFORMULATED THEIR PACKAGING, LABELING AND ADVERTISING SO THAT PRODUCTS LIKE THIS, THESE SPECIFIC PRODUCTS NO LONGER APPEAR. I HAVE AN UNFORTUNATE UPDATE FOR ENFORCEMENT ACTION WE HAD TO TAKE LAST WEEK. BUT WE WERE ABLE TO AT LEAST CLEAN THESE UP. SADLY, ABOUT HALF OF THE COMPANIES THAT RECEIVED THOSE FIRST WARNING LETTERS RECEIVED A SECOND PART OF THE WARNING LETTER WHERE THEY HAD ALSO ILLEGALLY SOLD THESE PRODUCTS TO MINORS ON LINE. MORE ACTIONS WERE ANNOUNCED IN SEPTEMBER. WE UNDERTOOK THE LARGEST COORDINATED ENFORCEMENT ACTION IN THE HISTORY OF FDA NOT JUST TO SEE WHETHER JUUL WAS BEING SOLD BUT TO SEE WHAT WAS GOING ON WITH E-CIGARETTE SALES TO MINORS. AND UNFORTUNATELY, IN SEPTEMBER, WE HAD TO ANNOUNCE WE ISSUED OVER 1100 WARNING LETTERS AND LAUNCHED OVER 130 CIVIL MONEY PENALTY ACTIONS FOR ILLEGAL SALE OF JUST e-CIGARETTES TO MINORS. UNFORTUNATELY, WHILE THOSE FIRST 17 COMPANIES CLEANED UP THEIR ACT, THERE WERE 12 ON LINE RETAILERS THAT HAD NEVER GOTTEN THE MESSAGE AND WERE CONTINUING TO SELL THOSE PRODUCTS AND SO WE ISSUED ADDITIONAL WARNING LETTERS TO THOSE ON LINE RETAILERS. WE ALSO SENT LETTERS TO THE FIVE COMPANIES THAT HAD THE LIONS SHARE OF THOSE WARNING LETTERS AND HAVE MORE THAN 97% OF THE CARTRIDGE-BASED COMPONENT OF THE E-CIGARETTE MARKET AND SAID WHAT ARE YOU GOING TO DO ABOUT THE KIDS PROBLEM HERE? WE ARE THINKING OF TAKING ACTION BUT WHAT ARE YOU GOING TO DO? AND WE CALLED THE COMPANIES IN AND HAD MEETINGS WITH EACH OF THEM BETWEEN SEPTEMBER AND EARLY NOVEMBER TO HEAR FROM THEM STEPS THAT THEY COULD TAKE VOLUNTARILY. WE MADE IT CLEAR THAT WE WERE RECONSIDERING ALL POLICY POSITIONS THAT THE AGENCY HAD TAKEN IN LIGHT OF WHAT WE WERE SEEING IN THE MARKETPLACE. UNFORTUNATELY, MORE ENFORCEMENT ACTION FOLLOWED. IN OCTOBER, THIS FIRST ONE IS STUNNING. THIS IS A COMPANY THAT WAS PUTTING UNAPPROVED DRUGS, POWERFUL DRUGS FOR ERECTILE DYSFUNCTION OR WEIGHT LOSS, INTO ELIQUIDS. AND WE HAD TO SPEND A WARNING LETTER TO TELL THEM TO STOP DOING THAT. AND WE ALSO HAD TO SEND WARNING LETTERS TO ALMOST TWO DOZEN COMPANIES BECAUSE WE COULDN'T TELL IF THEIR PRODUCTS WERE BEING LAWFULLY MARKETED OR NOT. WE GET COMPLAINTS ALL THE TIME FROM THE PUBLIC HEALTH AND TOBACCO CONTROL COMMUNITY, FROM COMPETITORS, ALLEGING THAT PARTICULAR PRODUCTS ARE NOT EVEN LAWFULLY ON THE MARKET. FOR THESE COMPANIES, WE HAVE DONE OUR DUE DILIGENCE, WE ARE UNABLE TO CONCLUDE THEY WERE HALFY MARKETED AND WE ARE GIVING THEM AN OPPORTUNITY TO EXPLAIN TO US. AND THEN THREE WEEKS AGO, WE RELEASED THE PRELIMINARY RESULTS FROM THE NATIONAL YOUTH TOBACCO SURVEY FOR 20INE. AND -- 2018. THERE IS MORE DATA TO COME WITH A FULLER PAPER PUBLISHES NEXT YEAR. BUT I'LL GIVE YOU THE THREE NUMBERS THAT CAUSED US TO RECONSIDER REALLY EVERYTHING THAT WE ARE DOING ON THE POLICY FRONT. e-CIGARETTES WERE ALREADY THE MOST POPULAR CATEGORY OF TOBACCO PRODUCTS WITH KIDS. BUT FROM 2017-2018, THERE WAS A 78% INCREASE IN CURRENT E-CIGARETTE USE BY HIGH SCHOOL-AGED KIDS AND ALMOST A 50% INCREASE AMONG MIDDLE SCHOOL-AGED KIDS IN ONE YEAR. AND THIS INCLUDED FOR KIDS WHO ARE CURRENT E-CIGARETTE USERS, ABOUT A 10% INCREASE IN THEIR USE OF FLAVORED PRODUCTS. SO ABOUT THREE WEEKS AGO THE COMMISSIONER MADE CLEAR THAT WE NEEDED TO RETHINK OUR APPROACH TO THIS. AND HE ANNOUNCED A SERIES OF POSITIONS THAT WE WERE GOING TO TAKE ACROSS-THE-BOARD ON FLAVORED TOBACCO PRODUCTS, WHETHER IT'S IN A COMBUSTIBLE OR NON COMBUSTIBLE PRODUCT. AND I'LL WALK YOU THROUGH THE SPECIFICS BECAUSE IT'S IMPORTANT TO UNDERSTAND THE DETAILS. WE HAD TO DO A PUBLIC HEALTH BALANCING ACT. NO QUESTION THAT e-CIG RELATES ARE HELPING SOME ADDICTED CIGARETTE SMOKERS SWITCH AND SWITCH COMPLETELY FROM MOST HARMFUL FORM OF NICOTINE DELIVERY TO A LES HARMFUL FORM OF NICOTINE DELIVERY. BUT WHERE DO YOU DRAW THE LINE WHEN IT COMES TO FLAVORS? SO WHERE WE CHOSE TO DRAW THE LINE FOR NOW IS MINT, MENTHOL, TOBACCO FLAVORING AND NON-FLAVORED e-CIGARETTES COULD CONTINUE TO BE SOLD AS THEY ARE CURRENTLY BEING SOLD. BUT FOR ALL OTHER FLAVORS, WHETHER IT IS CHERRY, GRAPE, COTTON CANDY OR BUBBLE GUM OR UNICORN PUKE, IF YOU CAN BELIEVE IT, THOSE CAN ONLY BE SOLD IN AGE-RESTRICTED LOCATIONS. IF A RETAILER REALLY WANTS TO SELL THOSE PRODUCTS, IT NEEDS TO BE AN ADULT-ONLY ESTABLISHMENT OR IF IT'S A GAS STATION, CONVENIENCE STORE, SOME PLACE WHERE A KID CAN GET ACCESS INTO, THERE NEEDS TO BE AN AGE RESTRICTIVE LOCATION INSIDE THE STORE. SAME THING WITH ON LINE. WE'LL LOOK AT MINT AND MENTHOL AND TOBACCO FLAVORING AND NON FLAVORING ONE WAY BUT FOR EVERYTHING ELSE THERE NEEDS TO BE AGE VERIFICATION PROCESSES AND WE'LL HAVE MORE INFORMATION TO SHARE WITH INDUSTRY IN THE WEEKS TO COME. WE ALSO SAW THE POPULARITY OF FLAVORED CIGARS WITH KIDS. SO, THOSE PRODUCTS UNLESS THEY ARE GRANDFATHERED AND THERE ARE GRANDFATHERED FLAVORED CIGAR PRODUCTS THAT CAN REMAIN ON THE MARKET BUT THOSE PRODUCTS HAVE TO BE REMOVED FROM THE MARKET. WE WILL ALSO GO AFTER PRODUCTS MARKETED TO KIDS AND THIS HAS RECEIVED A LOT OF ATTENTION IN THE MEDIA. WE ANNOUNCED OUR INTENTION TO LAUNCH A RULEMAKING PROCESS TO BAN MENTHOL IN CIGARETTES AND CIGARS. AND AS I SAID, MORE DETAILS TO COME ON THIS NOTION OF AGE RESTRICTED LOCATION OR HEIGHTENED AGE FAIRIFICATION PROCESS ON LINE. I SAID THAT MORE ENFORCEMENT ACTION HAD TO FOLLOW. HERE IS THE LATEST. AND THESE WERE LETTERS THAT WE JUST SENT OUT LAST WEEK. AGAIN, THESE PRODUCTS THAT RESEMBLE KID FRIENDLY FOODS THAT ARE ACTUALLY ELIQUIDS WITH NICOTINE IN THEM. AND THIS WAS A COMPANY THAT REALLY HAD A TRIFECTA OF VIOLATIONS BEYOND SELLING PRODUCTS LIKE THIS, SELLING TO MINORITIES MINORS, FAILING TO LIST THEIR PRODUCTS WITH US, AND SO A NUMBER OF VIOLATIONS THAT WE CALLED OUT IN A WARNING LETTER TO ELECTRIC LOTUS LLC. WE ARE VERY BUSY WITH PUBLIC EDUCATION. IN SEPTEMBER, WE LAUNCHED THE YOUTH E-CIGARETTE PREVENTION CAMPAIGN AS PART OF A BRANDED EFFORT WE HAD FOR OVER FOUR YEARS, CALLED THE REAL COST. THESE ARE RUNNING ON LINE ADS IN VERY TARGETED LOCATIONS AS YOU'LL SEE IN JUST A MOMENT. AND THE FOCUS, ONE OF THE THINGS WE LEARNED FROM THE FORMATIVE RESEARCH IS KIDS HAVE ALMOST A COST-FREE MENTALITY WHEN IT COMES TO THINKING ABOUT E-CIGARETTES. VERY DIFFERENT FROM THEIR THOUGHTS ABOUT CIGARETTES. KIDS KNOW THAT CIGARETTES ARE HARMFUL. TOO MANY KIDS ARE WALKING AROUND THINKING, e-CIG RITS ARE MUCH LESS HARMFUL SO IT'S OKAY FOR ME TO TRY OR EXPERIMENT WITH THEM. SO, WE HAD TO COMBINE A LOSS OF CONTROL MESSAGE, HOW YOU COMMUNICATE TO KIDS ABOUT NICOTINE AND ADDICTION, WITH MESSAGING ABOUT HEALTH CONSEQUENCES. AND THIS IS AIKIN TALL-BASED CAMPAIGN AND IN-SCHOOL CAMPAIGN. AND -- A DIGITAL-BASED CAMPAIGN -- I HOPE WE CAN GET AUDIO TO WORK. >> THERE IS AN EPIDEMIC SPREADING. SCIENTISTS SAY IT CAN CHANGE YOUR BRAIN. IT CAN RELEASE DANGEROUS KEL CALLSLY FORMALDEHYDE INTO YOUR BLOODSTREAM. IT CAN EXEXPLOS YOUR LUNGS TO THINGS THAT CAN CAUSE IRREVERSIBLE DAMAGE. IT'S NOT A PARASITE. NOT A VIRUS. NOT INFECTION. IT'S SHAPING. >> I SAID THAT WE HAVE A IN-SCHOOL PRESENCE HERE AND YES, THIS IS YOUR FOOD AND DRUG ADMINISTRATION THAT HAS POSTERS IN OVER 10,000 HIGH SCHOOLS WITH MESSAGES LIKE STRANGELY ENOUGH, SOME STUDENTS COME IN HERE TO POUT CRAP INTO THEIR BODIES. AND WE HAVE A PARTNERSHIP WITH STUDENTS AGAINST DESTRUCTIVE DECISIONS WHERE STUDENTS IN SAD CHAPTERS IN HIGH SCHOOLS THAT HAVEN'T GOTTEN THE POSTERS FROM US, THE KIDS ARE GOING TO BE PUTTING UP THE POSTERS THEMSELVES WITH THE PERMISSION OF SCHOOL AUTHORITIES. THIS IS HOW YOU HAVE TO COMMUNICATE TO KIDS TO BREAKTHROUGH, TO GET THEM TO HIT THE PAUSE BUTTON. WE HAVE HAD TREMENDOUS SUCCESS WITH OUR CIGARETTE EFFORTS AND IT'S INCREASINGLY HARDER TO FIND THE AT-RISK KID FOR CIGARETTE SMOKING. BUT WE HAVE DONE A LONGITUDINAL EVALUATION. THE FIRST TWO YEARS OF EXPOSURE TO OUR CIGARETTE ADS RESULTED IN 350,000 KIDS WHO WOULD OTHERWISE HAVE GONE ON TO EXPERIMENT WELL WITH CIGARETTES WHO JUST BECAUSE OF EXPOSURE TO AND AWARENESS OF OUR CAMPAIGN WON'T. AND EARLIER THIS YEAR, WE PUBLISHED A COST EFFECTIVENESS STUDY THAT SAID THAT TRANSLATES TO 31 BILLION DOLLARS TO SAVINGS TO SOCIETY OVER TIME JUST FROM THE FIRST TWO YEARS OF EXPOSURE TO OUR AD SYSTEM. WE KNOW HOW TO DO THIS. WE KNOW HOW TO BREAKTHROUGH. THE CHALLENGE WITH THE E-CIGARETTE SPOTS WAS, WE DON'T WANT ADULTS TO BE SEEING THESE ADS, NOT BECAUSE WE WILL EMBRACE e-CIGARETTES AS A HARM REDUCTION AGENT. BUT THE RESEARCH SHOWED THAT IF ADULTS WERE -- IF HEALTH CONCERNED ADULT CIGARETTE SMOKERS WERE EXPOSED TO THESE ADS IT COULD ALTER THEIR PERCEPTIONS OF e-CIGARETTES IN A WAY TO MAKE THEM LESS LIKELY TO TRY AN E-CIGARETTE AND WE DIDN'T WANT TO GO THERE. SO THESE ADS ARE NOT RUNNING ON T.V. THEY ARE DIGITAL ADS AND IN-SCHOOL ADS AND THERE IS SOME TECHNOLOGY IF A KID IS ON SCHOOL GROUNDS AND IS ON A BREAK ON LUNCH AND TURNS ON HIS OR HER SMARTPHONE, WE CAN SHOOT THESE ADS DEPENDING UPON WHAT WEBSITE THEY ARE GOING TO, LIKE YouTube OR OTHER THINGS. VERY QUICKLY I'LL GO THROUGH THE SCIENCE-BASED REVIEW OF MODIFIED RISK TOBACCO PRODUCTS TO JUST SAY COMPANIES ARE FILING ALL MANNER OF APPLICATIONS TO GET AUTHORIZATION TO MAKE CLAIMS TO REDUCE EXPOSURE OR TO REDUCE RISK AND THE APPLICATIONS CURRENTLY BEFORE US ARE LISTED HERE. REMEMBER THIS IS PRE-MARKET REVIEW OF A COMPANY'S SCIENCE. IT'S UNDER THAT POPULATION-LEVEL PUBLIC HEALTH STANDARD. AND BY LAW, WHEN WE ACCEPT ANY APPLICATIONS FOR SCIENTIFIC REVIEW, WE MAKE THE APPLICATION AVAILABLE IN ITS ENTIRETY JUST REDACTING COMMERCIALLY-CONFIDENTIAL INFORMATION FOR THE PUBLIC TO SEE AND COMMENT ON AND WE TAKE EACH OF THESE APPLICATIONS TO OUR ADVISORY COMMITTEE, THE TO TOBACCO PRODUCT SCIENTIFIC ADVISORY COMMITTEE. LET ME CLOSE TALKING ABOUT AMAZING COLLABORATION WE HAVE WITH NC I AND NIH. WITH NCI IT'S IN TWO REALMS. THE TOBACCO REGULATORY SCIENCE PROGRAM. AS YOU HEARD BOB TALK ABOUT IN HIS INTRODUCTION, WITH OVER 250 GRANTS FUNDED OVER THE YEARS WE COUNTED 97. IF IT'S OVER 100 WE'LL HAVE TO CORRECT THE SLIDE. BUT THE POINT IS THAT NCI PLAYED AN ENORMOUS ROLE IN GETTING THE FDA DOLLARS OUT INTO THE FIELD TO INFORM REGULATORY SCIENCE. AND BEYOND THAT AND MORE PROGRAMMATICALLY, ONE OF OUR PUBLIC EDUCATION CAMPAIGNS THAT LAUNCHED EARLIER THIS YEAR IS CALLED EVERY TRY COUNTS. AND THIS IS AIMED AT ADULT SMOKERS CONCERNED ABOUT THEIR HEALTH WHO MADE A QUIT ATTEMPT WITHIN THE PRIOR 12 MONTHS BUT DIDN'T SUCCEED. AND THE ROLE THAT NCI PLAYED HERE WAS CREATING UNBELIEVABLE CONTENT FOR THE WEBSITE, THE WHOLE IDEA BEHIND THIS CAMPAIGN IS A POINT-OF-SALE CAMPAIGN WHERE PAYING RETAILERS, GAS STATIONS, CONVENIENCE STORES, TO PUT THESE ADS BECAUSE 96% OF ALL CIGARETTES ARE PURCHASED IN GAS STATIONS AND CONVENIENCE STORES, SO WE WANT THIS KIND OF POSITIVE MESSAGE TO CELEBRATE THE QUIT ATTEMPT ITSELF TO BE IN THE PLACE WHERE PEOPLE ARE GOING TO BUY THEIR PACKS OF CIGARETTES AND TO DRIVE THEM TO THE WEBSITE WEBSITE. >> [ OFF MICROPHONE ] THIS HAS NOTHING TO DO WITH EVERY TRY COUNTS. AND SO NCI HAS PLAYED AN ENORMOUS ROLE IN CREATING THE CONTENT FOR THE WEBSITE WHETHER IT IS PUTTING IN TOUCH WITH COUNCILORS, OTHER DOWNLOADABLE APPS, JUST THE TREMENDOUS AMOUNT OF CONTENT THAT COULDN'T HAVE BEEN CREATED WITHOUT THE HELP OF NCI. AND THEN FOR THE SECOND ROUND OF GRANTS FOR THE TOBACCO CENTERS OF REGULATORY SCIENCE, AND THESE WERE JUST ANNOUNCED A COUPLE OF MONTHS AGO. SO NCI HAD ADMINISTERED FIVE OF THE FIRST 14 AND THEY ARE NOW ADMINISTERING FOUR OF THE NINE IN THE SECOND ROUND. THE ONES THAT ARE CIRCLED IN RED AND TO GIVE YOU A FEEL FOR THE KIND OF WORK THAT IS BEING DONE WITH THE MULTI-DISCIPLINARY AND MULTI-CENTER STUDIES, THIS IS TO RESEARCH FLAVORED TOBACCO PRODUCTS. THE INTERSECTION BETWEEN TOBACCO PRODUCT USE AND DIVERSE POPULATIONS, THE IMPACT OF EVERYTHING FROM ADVERTISING, LABELING, AND PACKAGING ON PERCEPTIONS AND USE AND EXPOSURE WHEN IT COMES TO COMBUSTIBLE TOBACCO PRODUCTS. THERE IS STILL MORE TO LEARN THERE. AND ALSO ASSESSING PUBLIC HEALTH IMPACTS OF FDA'S REGULATORY INTERVENTIONS. SO JUST A WONDERFUL ONGOING COLLABORATION BETWEEN FDA AND NIH AND FDA AND NCI FOR THE NCI PIECE OF THE PORTFOLIO AND I'M HAPPY TO ANSWER ANY QUESTIONS. THANK YOU. [ APPLAUSE ] >> OTIS: AN AFFORD EXTRAORDINARY PRESENTATION. CAN WE GET A HARD COPY OF THESE SLIDES? >> SURE. >> THANK YOU. >> PETER? >> CERTAINLY I ASSUME THIS IS A MULTI-BILLION DOLLAR INDUSTRY THAT YOU'RE GOING UP AGAINST RIGHT NOW. AND MY GUESS IS THAT WILL NOT MAKE THIS PROBLEM EASIER IN THE UPCOMING YEARS, PROBABLY HARDER. WHAT ARE OUR EFFORTS TO EDUCATE CONGRESS ON THE MAGNITUDE OF THIS PROBLEM? WHAT ARE FDA'S EFFORTS? HOW MUCH SUPPORT OR PUSHBACK DO YOU ENVISION? >> I NEED TO BE CAREFUL ABOUT MY POLITICAL COMMENTS BUT I CAN MAKE A COMMENT ON THE LITIGIOUSNESS OF THE INDUSTRY. WHEN WE ISSUED THE FINAL DEEMING RULE IN 2016, EIGHT DIFFERENT LAWSUITS WERE FILED AGAINST THE AGENCY. REALLY THIS TAKES US BACK TO THE REGULATORY SCIENCE AND THE COLLABORATION WITH NIH. WE CAN ONLY GO AS FAR -- FROM A POLICY PERSPECTIVE, KNOWING WHO WE REGULATE AND WHAT WE REGULATE TO, PICK UP ON WHAT IS CENTRAL TO YOUR QUESTION. WE CAN ONLY GO AS FAR AS THE SCIENCE WILL TAKE US. IF WE THINK THE SCIENCE IS IS THERE TO SUPPORT POLICY X, Y OR Z, THEN WE'LL DO IT. AND IF IT IS SOMETHING THAT IS THEN SUBJECT TO CIVIL AND EVEN CRIMINAL ENFORCEMENT BECAUSE WE HAVE DONE IT THROUGH THE RULEMAKING PROCESS, THEN THE LAW WOULD SAY RIGHTLY, FDA, YOU BETTER GET RIGHT. IF THERE IS CIVIL AND CRIMINAL LIABILITY FOR A POLICY CHANGE THAT THE AGENCY IS GOING TO MAKE, YOU BETTER GET RIGHT. AND THAT IS WHY ANY INTERESTED PARTY WHEN THE AGENCY COMPLETES A RULEMAKING PROCESS, CAN SUE US. WE HAVE BEEN SUED BY PUBLIC HEALTH AND TOBACCO CONTROL BECAUSE THEY DIDN'T LIKE THE CHANGES THAT WE MADE TO CERTAIN POLICIES IN THE FINAL DEEMING RULE. WE WELCOME ALL COMMERCE IN COURT. WE HAVE GOT TO GET IT RIGHT, THOUGH. AND IF WE GET THE SCIENCE RIGHT, THEN WE WILL DO WELL IN COURT AND THESE KINDS OF PROGRAMMATIC INTERVENTIONS WILL SURVIVE. WE SPEND A LOT OF OUR TIME ON THE HILL SIMPLY INFORMING AND EDUCATING CONGRESS AND THIS IS MEMBERS OF BOTH PARTIES, MEMBERS ON ALL SIDES OF THE SO-CALLED HARM REDUCTION DEBATE. AND I THINK THAT THE DIALOGUE THAT WE HAVE WITH MEMBERS ACROSS THE POLITICAL SPECTRUM AND ACROSS THE POLICY SPECTRUM IS OPEN AND CANDID AND MY JOB AS CENTER DIRECTOR IN SPEAKING TO A SENATOR OR CONGRESSMAN OR CONGRESSWOMAN OR STAFF, IF THERE IS SOMETHING WE ARE JUST GOING TO DISAGREE ON IS TO BE VERY CANDID ABOUT THERE IS SOME THINGS WE HAVE TO AGREE TO DIGS AGREE ON AND HOPE THE DIRE LOG CAN CONTINUE. SAME THING FOR OUR DIALOGUE WITH INDUSTRY. >> I AGREE THAT SEEING FDA TAKE THE STANDS YOU HAVE ON TOBACCO CONTROL ARE VERY HARD. SO CONGRATULATIONS. I HAVE TWO QUESTIONS. FIRST COULD YOU TALK MORE ABOUT THE REASONING ABOUT EXEMPTING OR LOOKING AT MENTHOL DIFFERENTLY IN CIGARETTES AND E-CIGARETTES? AND SECONDLY, COULD YOU TALK A LITTLE BIT ABOUT WHAT YOUR TIMING AND PLANS ARE FOR NICOTINE REDUCTION IN CIGARETTES AND EVEN VIRTUAL ELIMINATION? BECAUSE THAT WOULD BE THE ENDGAME. THE GAME CHANGER. THOSE TWO WOULD BE REALLY INTERESTING FOR US TO HEAR. >> SURE. I'LL TAKE THEM IN REVERSE BECAUSE THE NICOTINE ANSWER IS SHORTER. SO, THE COMMENT PERIOD FOR THAT ADVANCED NOTICE RULEMAKING CLOSED IN JULY. WE GOT AROUND 8 INTEND COMMENTS IN RESPONSE TO THE QUESTION -- 8000 -- WE HAVE BEEN VERY CAREFULLY REVIEWING THOSE COMMENTS BY LAW WE HAVE TO REVIEW EVERY SINGLE COMMENT BUT THE COMMENTS THAT MATTER THE MOST TO US, THAT CARRY THE MOST WEIGHT, ARE SUBSTANTIVE COMMENTS, ESPECIALLY THOSE ACCOMPANIED BY INFORMATION THAT WE WERE PREVIOUSLY UNAWARE OF. I DON'T WANT TO PRE-JUDGE ANYTHING RELATED TO TIMING OR NEXT STEPS ON THE OTHER HAND TO REPEAT WHAT THE COMMISSIONER HAS SAID, WHICH IS THAT HE LOOKS AT THE POTENTIAL FOR US TO USE WHAT IS CALLED THE PRODUCT STANDARD RULEMAKING AUTHORITY TO FIRST PROPOSE, AND THEN TO FINALIZE, MANDATORY REDUCTIONS IN THE NICOTINE CONTENT IN CIGARETTES TO A MINIMALLY OR NON ADDICTIVE LEVEL, AS ONE OF THE MOST IMPORTANT THINGS THAT FDA COULD POSSIBLY DO. YOU SAW THE MODELING RESULTS. IF WE GET IT RIGHT. IN THE AMPR, WE TALK ABOUT UNINTENDED CONSEQUENCES IF WE WERE TO GET IT WRONG. ALL I CAN SAY WITHOUT GETTING INTO TIMING IS THIS REMAINS EXTREMELY HIGH PRIORITY OF THE AGENCY AND SOMETHING THAT WE ARE WORKING VERY CLOSELY ON. THE FIRST SIGN THAT THE PUBLIC WOULD HAVE THAT A PROPOSED RULE IS MAKING ITS WAY THROUGH THE PROCESS, IS WHEN IT FORMERLY IS SUBMITTED BY THE DEPARTMENT OF HEALTH AND HUMAN SERVICES TO THE OFFICE OF MANAGEMENT AND BUDGET. AND THERE ARE PEOPLE IN PUBLIC HEALTH AND TOBACCO CONTROL WHO GO TO THIS WEBSITE TO LOOK TO SEE WHAT IS NEW. AND IT IS THAT WEBSITE THAT WOULD REVEAL IF AND WHEN IT HAPPENS, THAT A PARTICULAR PROPOSED RULE HAS BEEN SUBMITTED TO THE WHITE HOUSE FOR OM. AND INTERDEPARTMENTAL REVIEW. THEY'LL BE MUCH MORE WE CAN SAY PUBLICLY ABOUT THIS IF WE EVER GET TO THE POINT WHERE WE HAVE A PUBLISHED PROPOSED RULE, - I'LL JUST SAY IT REMAINS EXTREMELY HIGH PRIORITY OF THE AGENCIES. ON MENTHOL, HERE IS THE PUBLIC HEALTH BALANCING ACT, THAT WE WERE TRYING TO ADDRESS IN THE ANNOUNCEMENT THAT WAS MADE A FEW WEEKS AGO. WE SAW THE SURVEY DATA THAT WHILE MINT AND MENTHOL REMAIN POPULAR FLAVORS WITH KIDS, WHEN IT COMES TO e-CIGARETTES, MINT AND MENTHOL COMBINED ARE MORE POPULAR WITH ADULTS THAN THEY ARE WITH KIDS, WHICH IS NOT TO MINIMIZE THEIR POPULARITY WITH KIDS, BUT WE KNOW THAT THEY ARE VERY POPULAR WITH ADULTS. IF WE WERE TO USE THE AUTHORITY THAT WE HAVE TO ORDER MINT AND MENTHOL COMPLETELY OUT OF ENDS, ELECTRONIC NICOTINE DELIVERY SYSTEMS, THEN WE WERE CONCERNED THAT THE HEALTH-CONCERNED CIGARETTE SMOKER WHO MANAGED TO COMPLETELY SWITCH TO A MINT OR MENTHOL e-CIG, WOULD WALK INTO THE GAS STATION AND CONVENIENCE STORE AND THE ONLY MEANT LATED PRODUCT THAT WOULD BE THERE FOR THEM TO PURCHASE WOULD BE A CIGARETTE. SO, WE WERE TRYING TO AVOID A PURCHASE ENVIRONMENT WHERE THE ONLY MENTHOL OPTION WAS AT THE MOST HARMFUL END OF THE CONTINUUM OF RISK SPECTRUM. HAVING SAID THAT, WE HAVE ANNOUNCED OUR INTENTIONS TO BAN MENTHOL IN CIGARETTES AND CIGARS AND THAT IS A RULEMAKING THAT WE ARE WORKING ON. IT'S A BALANCING ACT. IF WE DON'T SEE THIS GOING IN THE RIGHT DIRECTION, WE'LL REVISIT THAT PART OF THE POLICY AS WELL. BUT THIS IS WHERE WE THOUGHT WE SHOULD DRAW THE LINE FOR NOW FOR THE REASONS I JUST STATED. >> I ALSO ADMIRE YOUR FERVOR IN DEALING WITH THIS ISSUE. SO NOW MULTIPLE STATES HAVE LEGALIZED MARIJUANA AND MARIJUANA CONTAINS IN ITS SMOKE, NOT NICOTINE BUT MANY OF THE SAME CHEMICALS THAT CIGARETTES DO, AND THE TOBACCO COMPANIES ARE CONSIDERING REPLACING TOBACCO LEAVES WITH DIFFERENT LEAVES. WHERE DOES THE FDA STAND IN THIS? ARE YOU IN THE WAIT AND SEE? YOU SEEM TO BE PRETTY ENERGETIC AND I SUSPECT THAT YOU HAVE A TEAM OF PEOPLE THINKING AND WORKING ON THIS? AND YOUNG PEOPLE IN PARTICULAR ARE VERY SUSCEPTIBLE TO THIS. AND IF YOU'RE GOING TO GO AFTER THE YOUTH WITH E-CIGARETTE LITTLE THING THEY STICK IN THEIR MOUTH, MAYBE AT THE SAME TIME YOU WANT TO TALK ABOUT ALTERNATIVE CIGARETTES TOO THAT ARE ALSO NOT GOOD. >> WELL, WE SHARE THE CONCERN THAT THERE ARE SO-CALLED TOBACCO DEVICES OUT THERE THAT CAN BE AND ARE BEING USED TO INHALE MARIJUANA. AS LONG AS IT REMAINS UNLAWFUL AS A RECREATIONAL PRODUCT, WE DON'T HAVE REGULATORY AUTHORITY. OBVIOUSLY WE ON THE DRUG SIDE, WE CAN REGULATE THE CHEMICAL AS A MEDICINAL OR THERAPEUTIC AGENT BUT FOR THE USES THAT YOU'RE TALKING ABOUT, IT REMAINS NATIONALLY, ILLEGAL. SO WE DON'T HAVE REGULATORY AUTHORITY. WE TAKE A POLITICAL ACT BY CONGRESS TO LEGALIZE THE PRODUCT AND THEN FIGURE OUT WHICH REGULATORY ENTITY SHOULD TAKE ON THE RESPONSIBILITY OF REGULATING WHAT WOULD BE A LAWFUL PRODUCT. AND I THINK THE CONVENTIONAL WISDOM IS, WERE CONGRESS TO LEGALIZE THAT PRODUCT THAT THE REGULATORY RESPONSIBILITY WOULD FALL TO FDA, BUT YOU'D HAVE TO HAVE THAT POLITICAL ACT FIRST. >> LAST QUESTION, MAX. >> REGARDING INDUSTRY'S STRATEGY THEMSELVES TO TRY TO INCREASE e-CIGARETTES, IT'S A VERY LONG HISTORY OF THE TOBACCO COMPANIES SUPPORTING SO-CALLED RESEARCH, THE TOBACCO INSTITUTES AND THINGS LIKE THAT WAS BOGUS RESEARCH THAT WOULD SUPPORT THEIR POINT OF VIEW. AND THAT WAS OF COURSE A VERY MUCH BALANCE BY GOVERNMENT-FUNDED OBJECTIVE RESEARCH. MY QUESTION IS, HAS A SIMILAR THING HAPPENED WITH E-CIGARETTES TOO? IS INDUSTRY GOING AFTER THIS BY TRYING TO PUT MONEY INTO UNIVERSITIES AND THINGS TO FUND RESEARCH THAT WOULD BE SUPPORTIVE OF THEIR VIEWS OF THE SAFETY OF THESE PRODUCTS? >> I THINK THE ANSWER IS, GENERALLY YES. THE INDUSTRY IS GOING WHERE ARE THEY CAN TO GET THE RESEARCH DONE THAT BY LAW, WOULD NEED TO BE DONE TO FULFILL THE STATUTORY OBLIGATIONS UNDER THE TO BACKO CHAPTER OF OUR LAW, TO EITHER BRING A NEW PRODUCT TO MARKET, OR TO MAKE A HEALTH-RELATEED CLAIM, TO REDUCE EXPOSURE AND RISK. MY NCI COLLEAGUES CAN ALSO TALK ABOUT HOW CONTROVERSIAL WITHIN THE RESEARCH WORLD IT REMAINS TO EITHER CONSULT WITH OR TAKE DIRECT RESEARCH FUNDING FROM ANY OF THESE COMPANIES, WHETHER THEY ARE IN THE COMBUSTIBLE BUSINESS OR NON COMBUSTIBLE BUSINESS. A NUMBER OF RESEARCHERS BELIEVE THAT THE RIGHT THING TO DO, GIVEN THAT THE LAW COMPELS THE COMPANIES TO PRODUCE CERTAIN SCIENCE TO SUPPORT ON A PRE-MARKET BASIS, THE SCIENTIFIC EVIDENCE TO SUPPORT A MARKETING AUTHORIZATION FOR A NEW PRODUCT OR A CLAIM. THERE ARE A NUMBER OF VERY WELL RESPECTED PEOPLE IN THE FIELD WHO THINK THE RIGHT THING TO DO IS TO WORK WITH THE COMPANIES TO TAKE THE MONEY TO DO THE RESEARCH THAT THE LAW REQUIRES. THERE ARE ALSO A LOT OF PEOPLE IN THE FIELD WHO FEEL CONFLICTED, WHO THINK IT IS NOT THE RIGHT THING TO DO. AND JOURNALS ARE STUCK IN THE MIDDLE. A NUMBER OF JOURNALS IN OUR FIELD ARE REFUSING TO PUBLISH PAPERS WHERE THERE IS A DOLLAR OF INDUSTRY FUNDING BEHIND IT AND THERE ARE OTHER JOURNALS THAT BELIEVE THAT WHILE THE SCIENCE IS THE SCIENCE AND THAT'S WHY YOU HAVE A PEER REVIEW PROCESS AND IF IT MAKES IT THROUGH THE PROCESS, IT DESERVES TO BE PUBLISHED. ONE OF THE ORGANIZATIONS THAT I AND A NUMBER OF MY NCI COLLEAGUES BELONG TO IS THE SOCIETY FOR RESEARCH ON NICOTINE AND TOBACCO. AND JUST THIS PAST WEEK, THE WHOLE ISSUE FLARE-UP AGAIN ON A LIST SERVE ABOUT IF YOU WORK FOR OR CONSULT TO AN E-CIGARETTE COMPANY, SHOULD YOU EVEN BE ALLOWED TO BE A MEMBER OF THE SOCIETY FOR RESEARCH ON NICOTINE AND TOBACCO? THIS IS AN AGE-OLD ISSUE GOING BACK TO FIRST REDUCTION DEBATE IN THE UNITED STATES WHICH WAS OVER SMOKE LESS TOBACCO 20 YEARS AGO. I DON'T THINK WE HAVE PROGRESSED ALL THAT MUCH IN TERMS OF HOW TO GRAPPLE WITH IT. I'LL TELL YOU THAT A PROJECT THAT I WORKED ON WITH JOANNA COHEN, WHO OVERSEES THE GLOBAL HEALTH INSTITUTE AT JOHNS HOPKINS FOR TOBACCO CONTROL, A PAPER THAT WE PUBLISHED IN 2009 WHICH I WOULD ENCOURAGE FOLKS TO READ IN THE JOURNAL OF TOBACCO CONTROL, TRIED TO ARTICULATE A SERIES OF CONSIDERATIONS OR FACTORS FOR ANY POTENTIAL FUNDING MODEL THAT WOULD INCLUDE A FINANCIAL SUPPORT FROM A TOBACCO COMPANY. WE WEREN'T THINKING ABOUT E-CIGARETTES AT THE TIME BECAUSE WHEN WE STARTED CONVENING ON THIS ISSUE, E-CIGARETTES DIDN'T EVEN EXIST. IT'S THE SAME QUESTION. WE HELD MEETINGS AND THE PAPER WE PUBLISHED IS FOR ANY FUNDING MODEL OUT THERE, HERE ARE THE CRITERIA WE THINK NEED TO BE CONSIDERED AS A PI CONTEMPLATES, SHOULD I SAY YES OR NO TO A DIRECTOR INDIRECT OFFER OF ASSISTANCE? AND I'D LIKE TO THINK THAT PAPER STANDS THE TEST OF TIME. WE DID NOT COME DOWN ONE WAY OR THE OTHER ON A PARTICULAR MODEL. IT WAS MORE FOR ANY MODEL. THESE ARE THE KINDS OF CONSIDERATIONS WHETHER IT IS GOVERNANCE, INDEPENDENCE FROM THE COMPANY, WHO CONTROLS ULTIMATELY HOW A STUDY IS DESIGNED. WHO CONTROLS PUBLICATION, ET CETERA. BUT IT REMAINS A CONTROVERSIAL ISSUE IN THE FIELD. >> THANK YOU VERY MUCH. >> THANK YOU. >> THAT WAS A WONDERFUL PRESENTATION. [ APPLAUSE ] SO WE HAVE ONE MORE ITEM BEFORE LUNCH AND FRANCIS IS GOING TO TELL US OR GIVE US AN UPDATE FROM THE SUBCOMMITTEE ON GLOBAL CANCER RESEARCH. >> THANK YOU. THE MEETING OF THE GLOBAL HEALTH SUBCOMMITTEE OF THE NCAB HELD LAST NIGHT WAS THE FIRST MEETING SINCE THE REPORT OF THE AD-HOC WORKING COMMITTEE ON GLOBAL HEALTH WAS PRESENTED AND ADOPTED BY THE NCAB. A COPY OF THE MEETING ALSO.EIVED SO WHAT I'M GOING TO DO, GIVEN TIME IS MOVING FAST HERE, IS TO JUST TOUCH ON A FEW HIGHLIGHTS ON THE MEETING YESTERDAY. I REFER TO THE DRAFT REPORT FOR MEDETAILS. THERE ARE THREE AREAS BEFORE THAT. FOR THOSE PARTICULARLY NEW BORROWED MEMBERS, LET ME JUST -- NEW BOARD MEMBERS -- A LITTLE BACKGROUND ON THE WORKING COMMITTEE. THE GLOBAL HEALTH WORKING COMMITTEE WAS SANCTIONS, WORKING GROUP, EXCUSE ME. SANCTIONED UPON THE REQUEST OF DR. SHARPLESS SOON AFTER HE ASSUMED OFFICE. THIS IS CONSISTENT WITH HIS INTEREST OF COMMITMENT TO STRONG AND VIBRANT GLOBAL ONCOLOGY PROGRAM AT THE NCI. THE CHARGE OF WORKING GROUP FOR REVIEW AND APPLIES TO NCAB AND& DIRECTOR UNDER MISSION, VISION, OPERATION AND SCIENTIFIC ACTIVITIES ON THE CENTER FOR GLOBAL HEALTH, PROVIDE INSIGHT INTO MAJOR CHALLENGES AND OPPORTUNITIES AND GLOBAL HEALTH CANCER RESEARCH FOR THE CDH TO FOCUS ON. THE REPORT OF THE WORKING GROUP IS A PUBLIC RECORD AND ACCESSIBLE ON THE NCI WEBSITE FOR THOSE WHO ARE INTERESTED. THE MEETING YESTERDAY FOCUSED ON THREE MAIN AREAS, IN ANY OF TIME, I WILL FOCUS MORE ON THE FIRST PART OF IT, WHICH IS AN UPDATE ON DEVELOPMENTS OF THE CENTER FOR GLOBAL HEALTH. IZ REFER YOU TO THE REPORT FOR DETAILS ON THE OTHER, WHICH WERE GLOBAL CANCER RESEARCH AND NCI-FUNDED CANCER CENTERS BY ELANA DUNCAN AND UPDATE ON THE DCH TECHNOLOGY INITIATIVES. WITH RESPECT TO THE DEVELOPMENTS OF THE -- SINCE THE RECOMMENDATIONS WERE APPROVED, DEVELOPING A NUMBER OF AREAS, THE MAJORITY OF WHICH HAVE BEEN INTERNAL AND HAVE BEEN GUIDED LIKELY BY THE WORKING GROUP ACCOMMODATIONS AND INTERNAL REVIEW BY THE NCI CONDUCTED. THE ACTIVITIES HAVE INCLUDED REVIEW OF ONGOING CDH PROGRAMS AND COMMITMENTS AND OPERATIONAL BUDGETARY -- DETAILS ARE IN THE REPORT. I REFER YOU TO THE REPORT. THE MAIN GOALS OF THESE EFFORTS WERE TO STREAMLINE THE ACTIVITIES OF THE CDH IN THESE AREAS AND BECAUSE OBVIOUS SOME OF THESE CAME INTO BEING AND BRING THEM IN LINE WITH NCR PROCESSES AND ALSO TO PROVIDE MORE EFFICIENCY EFFECTIVENESS AND TRANSPARENCY AND ACCOUNTABILITY. THE SECOND GOAL OF THESE ACTIVITIES HAVE BEEN TO POSITION THE CDH -- THE NEW DIRECTOR WILL BE IN A BETTER POSITION TO MORE QUICKLY FOCUS ON THE BIGGER ISSUES THAT CHALLENGE. SOME TIME WAS SPENT DISCUSSING THE NCI GLOBAL RESEARCH PORTFOLIO AND IN THESE DISCUSSIONS IT IS IMPORTANT TO REALIZE GLOBAL RESEARCH ACROSS THE NCI IS SUBSTANTIAL AND COMPLEX AND BOTH CEH AND NON-CEH. DISCUSSIONS ON GOING ON MECHANISMS AT THE NCI FOR SOME KIND OF COORDINATION OF THESE EFFORTS. -- WORKING GROUP REPORT TO FOCUS ON THE CEH GLOBAL RESEARCH ACTIVITIES SHOULD BE ON LOW TO MIDDLE-INCOME COUNTRIES BECAUSE THEY OFFER UNIQUE RESEARCH OPPORTUNITIES AND ALSO ALLUDED TO BY DR. RIMER IN HER PRESENTATION, THE BIGGEST BURDEN OF CANCER AND MORTALITY FROM CANCER IS IN THESE COUNTRIES. RELATED ISSUE THAT WAS DISCUSSED BY THE SUBCOMMITTEE WAS THE CDH IN HEALTH DIPLOMACY. IN THIS CONTENT, THEY DISCUSSED THE HEALTH DIPLOMACY IN GLOBAL ONCOLOGY RESEARCH AND THE OPPORTUNITIES THAT EXIST FOR PARTNERING WITH ORGANIZATIONS SUCH AS THE W.H.O., NATIONAL ORGANIZATIONS, GOVERNMENTS AND INSTITUTIONS SUCH AS THE U.S. STATE DEPARTMENT. THE NCI LEADERSHIP EMPHASIZED THAT IN THIS ACTIVITIES, IT'S IMPORTANT TO SEPARATE HEALTH DIPLOMACY THROUGH THE RESEARCH AND ACTIVITIES BY THE INSTITUTE AND TO ENSURE IS THAT STRUCTURES ARE IN PLACE TO ENSURE THIS IS ACCOMPLISHED. CONDUCTING INTERNATIONAL RESEARCH AS MANY BIG CHALLENGES NOT THE LEAST OF WHICH IS DIFFERENCES IN NATIONAL REGULATORY CONTROLS AND GOVERNANCE OF RESEARCH. CHALLENGES OF DATA COLLECTION, OWNERSHIP SHARING AND ACCESSIBILITY IN DIFFERENT COUNTRIES, AND NO TROUBLE EXAMPLES OF THIS IS THE GDTR, OR THE DATA PROTECTION REGULATIONS IN DIFFERENT COUNTRIES, EUROPE AND US. ADDITIONALLY, THE UNIQUE CHALLENGES THAT ARE POSED BY SPECIFIC COUNTRIES SUCH AS CHINA CHINA, ARE SUBSTANTIAL RESEARCH PORTFOLIO, THE SUBCOMMITTEE NOTED THE IMPORTANCE OF HAVING APPROPRIATE LEGAL AND POLICY EXPERTISE AND INFRASTRUCTURE TO GUIDE THE GLOBAL RESEARCH ACTIVITIES. DR. SHARPLESS SAYS THIS ISSUE HAS BEEN TACKLED BY THE NCI. TRAINING WHICH IS A MAJOR COMPONENT OF THE COMMISSION, THE ACTIVITIES ARE ONGOING AND EFFORTS TO DEFINE THE TYPES OF TREATMENTS PROGRAMS AND THE MOST EFFECTIVE MECHANISM AND STRATEGIES FOR TRAINING AS WELL AS FOR FUNDING OF THE ACTIVITIES -- ALSO IN PARTNERSHIPS SUCH AS WITH THE FOGARTY. LASTLY, THE ISSUE OF NEW CDR DIRECTOR STATED BY THE SHARPLESS IN HIS REPORT THIS MORNING, IS ACTIVE RECRUITMENT FOR CDS DIRECTOR AND WHICH IS EXPECTED TO BE CONCLUDED BY MIDDLE OF NEXT YEAR. UNTIL THEN, DR. CROYLE WILL REMAIN AS INTERIM DIRECTOR. I THINK I WILL END HERE AND REFER YOU. I WENT THROUGH THE JOBS REPORT AND I THINK IT'S FAIRLY DESCRIPTIVE AND WELL WRITTEN WITH RESPECT TO THE SURVEY THAT WAS CONDUCTED BY CDH. JUST TO MENTION THAT THE GOAL OF THE SURVEY WAS TO CREATE A CENTRALIZED RESOURCE OF NON-NIH FUNDED GLOBAL ONCOLOGY ACTIVITIES AT NCI DESIGNATED CANCER CENTERS AND FOLLOWS ACCOMMODATIONS FOR THE WORKING GROUP. AND THIS WILL BE USED TO INFORM THE NCI PROGRAM PLANNING IDENTIFY OPPORTUNITIES AND COLLABORATIONS AND TO DECREASE DUPLICATIONS WHICH IS QUITE FREQUENT AND THIS HELPS TO COORDINATE THE PROCESSES. SO I THINK WITH THAT, I WILL STOP AND TAKE ANY QUESTIONS AND REFER YOU TO THE JOBS REPORT OF THE MEETING. >> THANK YOU VERY MUCH. WE HAVE TIME FOR ONE OR TWO QUESTIONS IF ANYONE HAS ANY. OKAY. THANK YOU TO ALL THE COMMITTEE MEMBERS. WE NOW HAVE TO TAKE A VOTE TO ACCEPT THE REPORT. DO I HAVE A MOTION TO ACCEPT? THIS IS JUST THE NCAB. THANK YOU. SECOND? ALL THOSE IN FAVOR? ANYONE AGAINST? ANYONE ABSTAINING? OKAY. WE ACCEPT THE REPORT. AND SO, JUST TO MENTION THAT THE ANNUAL BSA CONCEPT REVIEW REPORT IS POSTED ON THE MEMBERS ONLY WEBSITE. AS REQUESTED, PRIOR YEARS HAVE BEEN ARCHIVED SO YOU CAN ACCESS THEM. ARE THERE ANY OTHER ISSUES THAT YOU THINK THE BOARD SHOULD BE ADDRESSING AND FOR THOSE WHO ARE NEW MEMBERS, IF YOU HAVE SUGGESTIONS FOR FUTURE AGENDAS, YOU CAN BRING IT UP NOW OR YOU CAN REFER FOR A JOINT BOARD TO ALL THREE OF US, PAULET, MICE AND DAV NA, OR IF IT'S FOR BSA TO, DAV NA AND PAULET OR FOR NCAB, TO MYSELF AND PAULET. SO ANY NEW ISSUES YOU WANT TO BRING UP NOW OR JUST REFER TO US IN THE FUTURE? SO I THINK WITH THAT, WE ARE GOING TO HAVE LUNCH WE ALL BEGIN THE AFTERNOON SESSION WITH PHYSICAL SCIENCE ONCOLOGY NETWORK PROGRAM. DR. ZAHIR, PROGRAM DIRECTOR SECTORAL BIOLOGY AND MOLECULAR APPLICATION BRANCH, DIVISION OF CANCER BIOLOGY, WILL PROVIDE AN OVERVIEW OF THE SESSION. AND INTROTUESDAY THE SPEAKERS, DR. CLAUDIA FISHBACH-TESCHL, DR. MICHOR AND DR. SARKARIA. >> THANK YOU, GOOD AFTERNOON, I'M GOING TO PROVIDE AN OVERVIEW ON THE PHYSICAL SCIENCES ONCOLOGY NETWORK PROGRAM AND INTRODUCE THE THREE PIs WHO ARE HERE TODAY WHO WILL PRESENT HIGHLIGHTS FROM THEIR RESPECTIVE RESEARCH PROGRAMS. TEN YEARS AGO THE NCI HELD SERIES OF COMMUNITY-DRIVEN THINK TANKS TO EXPLORE THE POTENTIAL FOR BRIDGING PERSPECTIVES AND APPROACHS FROM THE PHYSICAL SCIENCES ENGINEERING AND MA TICKS INTO CANCER RESEARCH. AT THE NCI THERE WERE PROGRAMS THAT EXISTED TO SUPPORT TECHNOLOGY DEVELOPMENT AND CANCER SYSTEMS BIOLOGY USING COMPUTATIONAL APPROACHES BUT WITH AID OF EXTRAMURAL INVESTIGATORS, THE NCI BEGAN AN INITIATIVE ON THE PHYSICAL SCIENCES AND ONCOLOGY CONVERGENCE IN 2009. SO THE GOAL OF THIS PROGRAM IS TO FOSTER TRANSDISCIPLINARY RESEARCH ENVIRONMENTS INTEGRATING PERSPECTIVES AND APPROACHES FROM PHYSICAL SCIENCES WITH CANCER RESEARCH. THE CURRENT SCIENTIFIC THEME ATTIC AREAS THAT ARE INCLUDED BUT NOT LIMITED TO THAT SUPPORT THIS PROGRAM ARE PHYSICAL DYNAMICS, LOOKING AT PHYSICAL PROPERTIES SUCH AS MECHANICAL QUEUES, TRANSPORT ELECTRONICS, THERMAL FLUCTUATIONS AND HOW THEY MODULATE THE BEHAVIOR OF CANCER CELLS AND THE TUMOR MICROENVIRONMENT. HOW APPROPRIATE SPATIAL AND TEMPORAL ORGANIZATION OF STRUCTURES ACROSS MANY BIOLOGICAL AND PHYSICAL LINK SCALES IS REQUIRED FOR MANAGING INFORMATION TRANSFER THAT'S CRITICAL FOR REGULATING CELL GROWTH AND EVOLUTIONARY DYNAMICS. EXAMINING KAREN IS A COMPLEX ADOPTED SYSTEM AND HOW THAT'S MODELED USING EVOLUTIONARY THEORY TO BETTER UNDERSTAND PREDICT AND CONTROL DISEASE PROGRESSION. SO THE PROGRAMS BEEN ONGOINGTOR NINE YEARS, WHEN IN 2009 PHYSICAL SCIENCES ONCOLOGY CENTER FUNDED AND AFTER SERIES OF ADDITIONAL COMMUNITY DRIVEN WORKSHOPS THE PROGRAM CONTINUED FOR A SECOND PHASE IN 2015. SO THIS CURRENT PHYSICAL SCIENCES ONCOLOGY NETWORK IS COMPRISED OF 10 U-54 CENTERS AND TEN UO 1 INDIVIDUAL RESEARCH PROJECTS. THIS IS COMPRISED OF OVER 60 INSTITUTIONS, 300 INVESTIGATORS, 180 TRAINEES, WE ARE ACTIVELY ENGAGING TEN PATIENT ADVOCATES IN THIS PROGRAM AND TO DATE IN THE SECOND PHASE THERE'S BEEN OVER 400 PUBLICATIONS. THIS NETWORK CONTINUES TO GROW THROUGH SET ASIDE FUNDING MECHANISMS FOR TRANSNETWORK COLLABORATIONS AS WELL AS COLLABORATIVE ADMINISTRATIVE SUPPLEMENT FUNDING, PILOT PROJECTS, AND UPCOMING REISSUANCE OF THE UO 1 PROGRAM ANNOUNCEMENT. SO TODAY THREE PIs JOIN ME WHO WILL PRESENT SCIENTFIC RESEARCH HIGHLIGHTS IN RESPECTIVE PHYSICAL SCIENCES ONCOLOGY CENTERS, CLAUDIA FISHBACH-TESCHL FROM CORNELL UNIVERSITY WHO IS PROFESSOR OF BIOMEDICAL ENGINEERING T FRAN SKIS CO-MICHOR FROM DANA FAIR AND JAN SARKARIA. AND TODAY WE'LL PRESENT IN THAT ORDER STARTING WITH CLAUDIA FISHBACH-TESCHL. >> THANK YOU FOR HAVING ME AND LET MEG INTRODUCE THE CENTER THAT I'M COLLATING TOGETHER WITH LOU CAN'TLY, DIRECTOR OF THE CANCER CENTER NEW YORK. OUR CENTER FOCUSES ON CANCER METABOLISM WHICH IS INCREASINGLY EXPLORED IN THE CLINIC AND THAT IS OFTEN CHARACTERIZED BY GLYCOLYSIS -- AEROBIC GLYCOLYSIS AND GLUTAMINE ADDICTION AND INSIGHTS GENERATED OVER THE PAST DECADES BY STUDYING CELLS IN CULTURE BUT OBVIOUSLY WE KNOW METABOLISM IS NOT ONLY REGULATED MOLECULAR LEVEL BUT ALSO BY MICROENVIRONMENT AND MACRO ENVIRONMENT THESE CELLS ARE LOCATED. SO WHAT OUR CENTER DOES IS WE USING ENGINEERING APPROACHES WHERE WE ARE ADAPTING TISSUE ENGINEERING STRATEGIES TO BASICALLY DEVELOP THREE DIMENSIONAL TUMOR MODELS THAT MIMIC TISSUE PROPERTIESING SYNTHETIC BIOMATERIALS AND COMBINED WITH VARIOUS MICROFLUIDIC APPROACHES TO BASICALLY COME UP WITH WHAT WE CALL TUBULE MICROENVIRONMENT WITH STUDIES OF CANCER IN VITRO. OUR STUDY HAS THREE PROJECTS THE FIRST FOCUSES ON EFFECT OF MICROENVIRONMENT OF METABOLISM ON HOW THESE CHANGES ARE MODULATING MICROVESICAL AND EXOSOME BIOGENESIS INVESTIGATED PROJECT TWO, FINALLY IN PROJECT THREE WE LOOK AT FUNCTIONAL CONSEQUENCES IN CONTEXT OF TUMOR MIGRATION AND INVASION. THE CENTER SUPPORTED BY TWO CORES ON TISSUE MICROFABRICATION CORE MET BOBBIC IMAGING CORE. I WILL TELL YOU ABOUT PROJECT ONE THAT FOCUSES ON THE MICROAND MACRO ENVIRONMENT IN THE CONTEXT OF OBESITY. WHICH WHICH OBVIOUSLY IS INCREASING EPIDEMIOLOGICAL CONCERN AND AS WE KNOW IT WILL BE CITIES NOT ONLY INCREASING THE RISK BUT WORSENING PROGNOSIS OF CANCER AND WE HEARD THIS MORNING THE NUMBER OF CANCERS THAT ARE ASSOCIATED WITH WORSE PROGNOSIS MAINLY IN CONTEXT OF OBESITY. SO WHAT WE FOUND A COUPLE OF YEARS AGO DURING THE FIRST ROUND OF THE PHYSICAL SCIENCE OF ONCOLOGY NETWORK FUNDING IS WITH OBESITY WE'RE GENERATING EXOSOMAL MATRIX MICROENVIRONMENTAL CONDITIONS INDEPENDENT OF CANCER MIMICKING WHAT CANCER WOULD BE DOING. SO MORE SPECIFIC HI WE ARE FINDING THAT OBESITY PROMOTES FIBROTIC REMODELING IN BREAST TISSUE BY INCREASING COLLAGEN DEPOSITION, STRUCTURAL CHANGES OF COLLAGEN MATRIX YOU CAN SEE HERE WITH SECOND HARMONIC IMAGING BUT ALSO MECHANICAL DIFFERENCES IN THE TISSUE, THAT IS OF IMPORTANCE BECAUSE IN CONTEXT OF CANCER THIS IS WHAT WE'RE DETECTING WITH MAMMOGRAPHY AND IMAGING MODALITIES BUT HE WOULDN'T PICK THOSE UP IN CONTEXT OF OBESITY, BECAUSE OBESE TISSUE IS CHARACTERIZED BY A LOSELY APPEARING TISSUE AT LEAST. WHAT WE FOUND USING ENGINEERED MODEL SYSTEMS THAT MIMIC LEAN OR OBESE MATRIX PROPERTIES IS THAT TUMOR CELLS RESPOND TO THESE PROPHYPOROTIC AND MECHANICAL CHANGES OF THE MATRIX INCREASING THEIR GROWTH AND INCREASING PATHWAYS ASSOCIATED WITH MECHANIC KNOW TRANSDUCTION AND TRANSCRIPTIONAL CHANGES ASSOCIATED WITH MALIGNANCY AND IF YOU INTERFERE WITH THAT MATRIX INDUCED SIGNALING YOU CAN REDUCE THOSE PROPERTIES SHOWING FUNCTIONALLY RELEVANT. WE VALIDATED THIS ALSO IN THE CONTEXT OF PATIENT SAMPLES WHERE WE FOUND INCREASE MECHANIC KNOW ASPECT OF MECHANIC KNOW SIGNALING AND PATIENT SAMPLES BUT ADDITIONALLY WHAT WE IDENTIFIED WAS ALSO THAT IN THIS THESE PATIENT SAMPLES WE HAVE WITH OBESITY OTHER MARKERS ASSOCIATED WITH CANCER STEM CELL PROPERTIES BE INCREASED INCLUDING NANOG. AS MANY OF YOU MAYBE FAMILIAR WITH WHEN THINKING ABOUT WORSE CLINICAL OUTCOMES SUCH AS METASTASIS, THIS IS ATTRIBUTED TO TUMOR INITIATING STEM CELLS AND THESE CELLS ARE THE ONES THAT NOT ONLY EXPRESS NANOG BUT ALSO SOX 2 ONC 4 INCREASE LEVELS OF ALDEHYDE DEHYDROGENASE. WE WERE WONDERING COULD OBESITY BE POTENTIALLY NOT ONLY VIA THE KNOWN METABOLIC HORMONAL CHANGES INCREASE INCIDENCE OF CANCER STEM CELLS BUT COULD ALSO BE MATRIX ENVIRONMENTS ARE MODULATING EMERGENCE OF STEM CELL PROPERTIES INDEPENDENTLY. WHAT WE DID IS WE USED A COMBINATION OF REPORTER CELL LINES AND ENGINEERS EXTRA CELLULAR MATRIX MODELS MIMICKING LEAN OBESE MATRIX PROPERTIES FOUND WITH A BOWS MATRIX YOU GET INCREASE IN CANCER STEM LIKE CELL BEHAVIOR NOT ONLY CHARACTERIZED BY INCREASE OF NANOG SUCH AS SOX 2 OR 4 EXPRESSION BUT ALSO INCREASED STABILITY OF CELLS TO PERFORM UNDERSERVED CONDITIONS AS SHOWN HERE. IMPORTANTLY ALSO WE HAVE VALIDATED THESE FINDINGS USING PATIENT DERIVED FROM PDX SO THOSE ARE NOT ORGANOIDS BUT SPHERICS GENERATED FROM PDX WE HAVE SEATED ON EITHER LEAN OR OBESE MATRIX. WHEN WE HEAR VALIDATED THE LEVELS OF ALL THE ALDEHYDE DEHYDROGENASE USING THE AILED 4 ASSAY WE SEE IN THESE HETEROGENEOUS CELL POPULATIONS WE SEE INCREASE IN BEHAVIOR ASSOCIATED WITH CANCER STEM CELL SUGGESTING CLINICAL RELEVANCE OF FINDINGS THAT WE HAVE MADE. SO THEN OF COURSE THERE'S BEEN IN OUR COMMUNITY A LOT OF EMPHASIS ON STUDYING HOW DO MECHANICS ACTUALLY GET TRANSLATED INTO ALTERED CELLULAR BEHAVIOR, THAT OBVIOUSLY HAPPENS THROUGH BIOCHEMICAL OR CELL SIGNALING CHANGES. SO WHAT WE THEN THOUGHT, OKAY, STIFFNESS IS THE DRIVER OF OBESE MATRIX INDUCE CHANGES IN CELL BEHAVIOR WE SHOULDN'T INTERFERE WITH SIGNALING PATHWAYS WITH MECHANIC KNOW TRANSDUCTION. THAT'S WHAT WE DID, WE WERE EXPECTING THIS WOULD ALLOW US TO REDUCE LEVELS OF CANCER STEM CELLS ON OBESE MATRIX DOWN TO CONTROL LEVELS WITH TREATMENT BUT INSTEAD WHAT WE FOUND IS THERE'S NO EFFECT ON OBESE MATRIX AND WHEN WE ADDED THESE INHIBITORS OF MECHANICO TRANSDUCTION WE FOUND INCREASE EVEN ON LEAN MATRIX SUGGESTING SOMETHING IS HAPPENING IN A DIFFERENT WAY IN CANCER THEM CELLS WITH REGARDS TO MATRIX INDUCED CHANGES IN MECHANICO TRANSDUCTION. SO WE HAVE THEN A TOOL SET OF MODELS WHERE WE CAN MORE DIRECTLY INTERFERE OR CONTROL MATRIX STIFFNESS HYDRA GELS ARE MODEL WHERE WE CAN ADJUST CROSS LINKING RATIOS AND THUS STIFFNESS OF MATRIX OF CELLS INTERACTING WITH AND WHAT WE EXPECT CONSISTENT WITH THIS IDEA THAT INCREASED TUMOR STIFFNESS THEN WE PALPATE OBVIOUSLY FOR DIAGNOSIS, IS DRIVING MALIGNANCY, YOU WOULD SEE THE MAJORITY OF CELLS ON STIFFER MATRICES INCREASE GROWTH AND INCREASE SPREADING. BUT THIS IS LOOKING AT WHOLE POPULATIONS OF CELLS AND OBVIOUSLY THERE'S HETEROGENEITY IN STEM CELL POPULATION EXCLUSIVELY, YOU SEE CELLS RESPOND IN AN OPPOSITE WAY MEANING THEIR NUMBERS DECREASE WITH INCREASE STIFFNESS. CONSISTENT WITH THAT CELLS EXPRESS HIGHER LEVELS OF STEM CELL MARKERS THAT WE'RE READING OUT SPECIFIC MODEL THEY WERE LESS ABLE TO TRACTION FORCES MEANING TO PULL ON THAT MATRIX AS IT IS STIFFER AND PULLING IS A REAL IMPORTANT MECHANISM FOR CELLS TO INDUCE MECHANICALLY INDUCED SIGNALS TO ALTERED CELL BEHAVIOR. SO WE WANTED TO THEN SEE WHETHER OR NOT THIS HAS RELEVANCE, SO WE DID CO-TRANSPLANTATION STUDIES WHERE WE PUT IN TUMOR CELLS INTO MICE WITH EITHER LEAN OR OBESE ADIPOSE STROMAL CELLS, ARE CELLS THAT MEDIAD MATRIX AND POST FIBROTIC REMODELING AND TUMORS DIDN'T VARY IN THEIR SITES SO HOWEVER OBESE STROMAL CELLS INCREASE THE LEVEL OF FIBROSIS THAT WE WOULD SEE IN THESE TUMORS. AND WHAT IS IMPORTANT IS THAT THE FIBROTIC REMODELING OF THESE TUMORS OCCUR PRIMARILY PERIPHERAL REGIONS, CONSISTENT WITH INCREASE INVASION OF THESE TUMORS. MORE IMPORTANTLY WHAT WE FOUND IS THAT THE MARKERS FOR CANCER STEM CELLS IN THIS CASE YOU SEE IN NANOG ARE NOT ONLY INCREASED IN CENTER OF TUMORS AS YOU EXPECT IN HYPOXIA BUT THEY ARE DIRECTLY ASSOCIATED WITH WHERE THE MATRIX REMODELING IS HAPPENING. THIS IS THAT NOTHING EXPRESSION SHOWN AND THIS IS CORRESPONDING REGION AN COLLAGEN STAINING THAT'S WITH IT SUGGESTING THERE MAYBE DIRECT INTERACTIONS. NA FACT WHEN WE USE ANOTHER IN VITRO MODEL WE COULD VALIDATE THESE ADIPOSE STROMAL CELLS NOT ONLY MODULATE OR INCREASE LEVELS OF STEMNESS IN THESE MICROMODELS OF TUMORS BUT ALSO PROMOTE INVASION. SUGGESTING THAT THESE DIFFERENCES IN FIBROSIS COULD POTENTIALLY BE LINKED TO INVASION, EVENTUALLY METASTASIS. SO WHAT IS REALLY IMPORTANT AS WE'RE STUDYING INVASION, THIS IS SOMETHING THAT PROJECT 3 DOES IN OUR CENTER, WE HAVE TO CONSIDER THAT AS TUMOR CELLS INVADE EXPERIENCING A LOT OF PHYSICAL STIMULI, FOR EXAMPLE, AS THEY ARE SQUEEZING IN THE EXTRA CELL MATRIX. AS THE MATRIX STIFFER THERE'S MECHANICAL RESISTANCE TO BRIDGE AND IN FACT IN AND OF ITSELF MIGHT EFFECT NUCLEAR DEFORMABILITY AND POTENTIAL CHANGES IN DNA DAMAGE OR CHROMOSOMAL INSTABILITY. SO -- PART OF OUR CENTER DEVELOPED MICROFLUIDIC DEVICES WHICH HE CAN BASICALLY MIMIC THE PORE SIZES TUMOR CELLS EXPERIENCE AS THEY INVADE AND CAN THEN STUDY MIGRATION OF CELLS AT NUCLEAR DEFORMABILITY AND POTENTIAL FUNCTIONAL CONSEQUENCES OF THESE CELLS AS THEY ARE MOVING IN VIVO FOR EXAMPLE OR WITHIN A MATRIX SYSTEM THROUGH TISSUE. INTERESTINGLY WHAT HE FOUND, AS CELLS WERE SQUEEZING THROUGH THE NARROW CONSTRICTION, THEY ARE LEAKING NUCLEAR CONTENT OR DNA INTO THE CYTOSOL. WHAT IS HAPPENING IS CYTOSOLIC DNA IS A ACTIVATOR OF PATHWAYS INCLUDING THE PATHWAY TO BASICALLY AS A DEFENSE MECHANISM TO GET RID OF THESE CELLS, IN FACT ACTUALLY THIS IS WHAT YANA OBSERVED IN IN TO THE CYTOSOL DETECTED ALONG WITH NUCLEUS AS IT IS SQUEEZED THROUGH THESE PORTS. THIS IS SOMETHING IMPORTANT AS CONSIDERING INVASION METASTASIS, A RECENT PAPER YAN WAS INVOLVED IN, WHERE THEY FOUND CHROMOSOMAL INSTABILITY IN TUMOR CELLS ARE NOT ONLY LEADS TO THE FORMATION OF MICRONUCLEI IN THESE CELLS BUT IN FACT ACTUALLY AS CELLS ARE SQUEEZING AGAIN THROUGH NARROW CONSTRICTIONS THROUGH THE MATRIX AND ALSO USING YAN MODEL SYSTEMS THAT THESE MICRONUCLEI WOULD BRING -- WOULD BREAK DOWN, THEY WOULD ACTIVATE THE CS PATHWAY INSTEAD OF BEING USED AS A DEFENSE MECHANISM, THAT C DECEMBERING PATHWAY PROMOTES METASTASIS AND INVASION, REACTIVATION OF NON-CANONICAL NF KAPPA B SIGNALING. WHEN WE BLOCK THE BREAKDOWN OF THE NUCLEUS. STABILIZING THE NUCLEI OR BLOCK STING LOU HAS FOUND THIS IS ACTUALLY THEN ALSO REDUCING ME THATSTASIS. WE ARE DOING WHAT FUTURE GOALS ARE, THAT WE ARE INTEGRATING THESE MICROFABRICATED MODEL SYSTEMS AND APPROACHES DEVELOPING IN THE CENTER DIRECTLY WITH PRECISION MEDICINE PIPELINE AT THE CANCER CENTER WHERE THEY ARE USING THE IMAGE GUIDED TUMOR BIOPSIES, TO NOT ONLY BIOBANK THE TISSUE OR GENERATE ORGANOIDS FOR DRUG TESTING. WE WILL USE THESE ORGANOIDS IN OUR MICROVESICLES OR USING THEM ALREADY BUT INTEGRATE THESE TWO PLATFORMS MORE DIRECTLY NOT JUST RELYING ON MATRIGEL CULTURES TO MOUSE MODEL PDX TO INFORM CLINICAL TRIALS AND EMPHASIZE THE CIRCLE HERE. OF COURSE WE WANT TO THANK THE SUPPORT OF NCI TO DO THESE STUDIES AND ALL THE INVESTIGATORS AND OUR CENTER WE HAVE MORE THAN TEN LABS THAT WORK ON THIS -- AND IN DIRECT CLOSELY WITH THE OTHER CENTERS. THANK YOU. >> HI. I RUN THE DANA-FARBER CANCER INSTITUTE FOR THE CONSENSUS ON CENTER WHICH IS ABOUT TEN THEATER, IT'S BEEN A GREAT RUN TO BE PART OF THIS AMAZING NETWORK THAT HAS ALLOWED US TO DO THINGS THAT WE OTHERWISE WOULDN'T HAVE BEEN ABLE TO DO. OUR CENTER IS ORGANIZED INTO THREE PROJECTS, IN THIS PHASE THAT FOCUSES ON BREAST CANCER ON LEUKEMIA AND ON BRAIN CANCER BUT OVER THE YEARS WE HAVE STARTED DIFFERENT CANCER TYPES INCLUDING LUNG CANCER. SO WHAT I WANT TO SHOW YOU TODAY IS JUST ONE EXAMPLE OF WHAT WE HAVE DONE TO COMBINE COMPUTATIONAL EVOLUTIONARY MODELING APPROACHES AS MOUSE MODELING OF GLEE BLASTOMA BRAIN CANCER WITH THE AIM OF UNDERSTANDING HOW HETEROGENEOUS POPULATIONS RESPOND TO TREATMENT, FORMULATE THIS AS MATHEMATICAL FRAMEWORK AND USE MATHEMATICS TO TRY TO UNDERSTAND WHAT THE GLOBALLY OPTIMUM TREATMENT ADMINISTRATION WOULD BE THAT ALLOW US TO OPTIMALLY PREVENT PROGRESSION OF DISEASE. WE HAVE DONE THIS IN COLLABORATION WITH ERIC COLLINS LAB, CO-PI OF THE PSSC AND THE IDEA CAME UP ABOUT TEN YEARS AGO WHEN WE ARE THINKING ABOUT OPTIMUM RADIATION AND OTHER DOSE ADMINISTRATION LUNG CANCER USING MA LOT ANYBODY AND REALIZING THE CURRENT FDA APPROVED TREATMENTS WEREN'T OPTIMIZED TO OPTIMALLY PREVENT OR SLOW DOWN THE EVOLUTION OF DISEASE BUT RATHER IS REACHED BY A THREE PLUS THREE DOSE ESCALATION SCHEME TO MAXIMUM TOLERATED DOSE THEN IMPLEMENTED MOST LIKELY ON CONTINUOUS DOSING SCHEDULE, IN THE CASE OF RADIATION THERAPY, THIS IS GIVEN IN TWO GRAY FRACTIONS FIVE DAYS A WEEK FOR NEWLY DIAGNOSED FOR SIX WEEKS FOR TOTAL OF 60 GRAY. SO THE QUESTION AROSE, WHAT DO WE NEED TO UNDERSTAND ABOUT THE MICROENVIRONMENTAL ARCHITECTURE OF GLEE GLIOBLASTOMA, THEIR SPACE LOCALIZATION, MAINTENANCE IN TERMS OF STEM CELL LIKE CHARACTER AND PROGRESSION OF DISEASE USING MORE TUMOR (INDISCERNIBLE) ACCUMULATING MUTATIONS AN RESISTANCE MECHANISMS OVER TIME. SO WE COLLABORATED WITH ERIC'S LAB IN PSSC MOUSE MODEL DEVELOPED IN HAROLD VARMUSOUS LAB WHERE WE CAN STUDY THE MICROENVIRONMENTAL POPULATION OF DIFFERENT CELL POPULATION AND RESPONSE TO DIFFERENT DOSE AND TIMING OF RADIATION, FRACTIONATION SCHEDULES. SO BASED ON THIS UNDERSTANDING OF INTRATUMOR HETEROGENEITY OF GLIOBLASTOMA SIZE, WE FORMED A MATHEMATICAL MODEL IN FIRST PART OF THE PHASE U 54 MODEL STEM BASE POPULATIONS AS RESPONSE FORGIVEN FRACTION OF THE DEGREE OF RADIATION AND ARE THE DETAILS WHAT WE CAN DO IS TO WRITE DOWN THE EQUATIONS THAT GOVERN HOW THE NUMBERS CHANGE OVER TIME AND HOW THIS DEPENDS HOW MUCH RADIATION WE HAD MINISTER AT WHAT TIME AND HOW LONG -- ADMINISTER AND HOW LONG TO WAIT UNTIL YOU ADMINISTER NEXT FRACTION OF RADIATION. SO BASED ON THIS FIRST MATT MATTCAL MODEL WHICH TAKES SPACE INTO CONSIDERATION, THIS WAS A WELL MIXED MODEL, WHERE ALL CELLS -- SPATIAL LOCALIZATION OF EACH CELL, DOESN'T MATTER AS LONG AS WE CONSIDER THEM IN THE STEM OF DIFFERENTIATED CELL POPULATIONS. WE SAW THE GLOBALIZATION PROBLEM, OF ASKING IF WE GIVE TEN GRAY OVER ONE WEEK, MONDAY THROUGH FRIDAY BETWEEN 8 AND 5 TO MIMIC RADIATION ONCOLOGY CONSTRAINT, WHAT IS THE BEST POSSIBLE WAY TO DO THAT SUCH THAT WE MAXIMIZE SURVIVOR IN MOUSE MODEL OF DISEASE AND WE FOUND A SCHEDULE THAT LOOKS PRETTY RANDOM BUT REALLY IS NOT. ADMINISTERS ONE GRAY EACH AT DOSE TIME SLOTS INDICATED DOWN HERE AND WHEN TESTED IN PERSPECTIVE MOUSE TRIAL WE FOUND THIS WHICH IS INDICATED IN GREEN HERE, VERY SIGNIFICANTLY IMPROVES SURVIVAL ADS COMPARED TO THE STANDARD FRACTIONATION WHICH IS THE SAME TOLD AMOUNT OF GRAY BUT GIVEN STANDARD FRACTIONATION OF TWO GRAY A DAY, FIVE DAYS A WEEK OR 10 GRAY AT ONCE, IT WAS NON-SIGNIFICANTLY TO TWO WEEKS OF THE STANDARD FRACTIONATION. SO 20 GRAY TOTAL COMPARED TO 10 GRAY IN THIS GREEN FRACTIONATION OVER HERE. SO LED TO US ASKING WHAT THE MOLECULAR MECHANISM IS THAT UNDERLIES THIS STANDARD SURVIVAL OF MOUSE POPULATION SO WE FOUND THAT THIS OPTIMAL SCHEDULE ENRICHES FOR SLOW PROLIFERATING LESS DIFFERENTIATED SIZE SO TUMOR STEM LIKE POPULATION. THIS IS ACHIEVED BY TIMING THIS FRAGS MAKES SCHEDULE SUCH THAT WE CAN -- FRACTIONATION SCHEDULE. THIS SEEMS TO BE WHAT'S DRIVING SURVIVAL TIMES IN HUMAN CASE SO THIS IS RETROSPECTIVE ANALYSIS OF CLINICAL TRIAL, WHERE PATIENTS RECEIVE 60 GRAY CHEMORADIATION WITH ADJUVANT CHEMO WHERE DOSE PATIENTS HAD LARGE MEDIAN ENRICHMENT IN STEM LIKE FRACTION, COMPARED TO THOSE WITH LESS HAD SIGNIFICANTLY LONGER SURVIVAL, THIS IS THE MECHANISM OPERATING IN HUMAN AND BASED ON THIS E CURRENTLY -- AT DANA-FARBER CANCER CENTER COMPARED TO CONTROL ARM, THIS IS REFRACTORY SO DOING 35 GRAY, STANDARD OF CARE FOR REFRACTORY TO BM AND DELIVERED IN TEN FRACTIONS, ONE FRACTION PER DAY FIVE DAYS A WEEK. WE COMPARED IN TWO ARM STUDY AGAINST IDENTIFIED SCHEDULE, BASED ON SCHEDULE BUT A LITTLE BIT FURTHER OPT MICE IN ORDER TO MAXIMIZE IMPLEMENTIBILITY. DOING 28 FRACTION IN TOTAL ONE FRACTION GRAY AND NINE GRAY IN NINE FRACTIONSES SO THREE FRACTIONS FOR THE LAST THREE DAYS. FROM THIS IS COMPUTATIONALLY TO BE WORSE THAN WHAT WE PREDICTED FORD THE FULL GLOBAL OPTIMUM BUT SHOULD BE SIGNIFICANTLY EASIER TO IMPLEMENT, SO THIS IS IRB APPROVED AND WE ARE INVOLVED NOW. THE NEXT QUESTION WE WANTED TO ASK MOVING TOWARD THE SECOND PHASE, WAS WHAT WOULD BE TO OPT MAXIMUM -- GIVEN THIS IS STANDARD OF CARE FOR NEWLY DIAGNOSED GLIOBLASTOMA PATIENT AND IT BECOMES A SPATIAL PROBLEM BECAUSE RADIATION IS -- AS LONG AS WE'RE IN THE CENTER OF THE BEAMS, THE CONCENTRATION AMOUNT OF GRADE IN EACH INDIVIDUAL AREA OF TUMOR SHOULD BE THE SAME. THIS IS NOT TRUE FOR -- SINCE TRAVELS THROUGH THE BLOODSTREAM AND DIFFUSES FROM THE BLOOD VESSEL. SO CELLS THAT SIT CLOSER TO THE BLOOD VESSEL RECEIVE A LARGER CONCENTRATION COMPARED TO FARTHER AWAY FROM THE BLOOD VESSEL. AND SO WE BUILT SPATIALLY EXPLICIT STOCHASTIC MODEL WITH DIFFERENT CELL TYPES THAT LINE BLOOD VESSELS TO TUMOR STEM LIKE CELLS IN BLUE HERE AND TUMOR BULK CELLS AND INCORPORATE STROMAL CELLS THAT DEFINE MICROENVIRONMENTAL ARCHITECTURE OF THE PERIVASCULAR NICHE AND THEN EXPLICIT MODEL, SO THIS IS JUST A TWO D CROSS SECTION FROM ONE SIMULATION RUN FOR VISUALIZATION. YOU CAN SEE OVER TIME THE SIZE EXPANDS, ACCORDING TO ROLE, EACH CENTER HAS A ROLE HOW QUICKLY IT ROLES AND DIFFERENTIATES. DEPENDING ON THE RULES OF THIS STOCHASTIC EVOLUTIONARY MODEL THE TUMOR IS COMPOSED OF TWO CELL POPULATIONSES, STEM LIKE RESISTANCE SIZE AND DIFFERENTIATED MORE RAID GROW SENSITIVE SIZE. IN RESPONSE TO RADIATION BOTH CELL TYPES UNDERGO APOP DECISION OR ARREST AND TRY TO REPAIR DNA DAMAGE IF THEY START CYCLING AGAIN THEY PROLIFERATE ACCORDING TO GROWTH RATE, DEDIFFERENTIATE DEPENDING ON AMOUNT OF RADIATION TO THESE CELL IN THE TIME FRAME, TIME VARYING RATE, PARAMETERIZED USING THESE MODELS AND THE SAME RULES HOLD SIMILAR RULES HOLD FOR CHEMOTHERAPY WHERE CELLS DIE AFTER ADMINISTRATION OF CHEMOTHERAPY AND DEPENDS HOW MUCH CONCENTRATION DELIVERED TO LOCALIZATION OF CELLS. WAY WE DID THIS IS IDENTIFIED A PRIOR SET OF PARAMETERS BASED ON MOUSE MODEL, AND WE CONSTRUCTED THIS MODEL OPTIMIZED TO PERFORM SURVIVAL ANALYSIS PARAMETERS HAVE SENSITIVITY ANALYSIS TO SEE HOW THEY DEPEND ON EXACT KNOWLEDGE OF WHICH EACH INDIVIDUAL PARAMETER, PARALYZED THIS AND THEN PROSPECTIVELY VALIDATED IN MOUSE MODEL. THIS COMPUTATION IS SO COMPLEX IT HAS TO BE RUN ON SUITER COMPUTER SO WE RAN THIS -- SUPER COMPUTER, SO WE RAN IT AND THE TIME ON NUMBER TWO SUPER COMPUTER AT LIVERMORE NATIONAL LABS. WE USED FOUR REVIEW YEARS, AT THIS POINT IT'S MORE LIKE 8,000 COMPUTE YEARS. WE IDENTIFIED OPTIMIZED POTENTIAL UP HERE. IT'S COMBINED WITH 50 MG PER KG AT 3 P.M. EF DAY TO LEAD TO SUPERIOR SURVIVAL COMPARED TO STANDARD SUBOPTIMUM WHICH LOOKS SIMILAR AND OPTIMIZATION TECHNIQUE THAT IS DIFFERENCE FROM STANDARD AND WHEN WE VALIDATED THIS IN THE MOUSE MODEL WE ALSO FOUND VERY SUPERIOR SURVIVAL IN THE PREDICTED OPTIMIZED RADIATION CONCURRENT NEWLY DIAGNOSED DISEASE. WE ARE WORKING ON IMPLEMENTING THIS AS THREE CLINICAL TRIALS MENTIONED BEFORE TO SHOW FEASIBLE OF NON-STANDARD RADIATION DELIVERY SCHEDULES IN MULTI-INSTITUTIONAL TRIAL IF SHOWS THIS IS DOABLE FOR EFFICACY OF RADIATION ALONE AND TRIAL FOR CHEMORADIATION COMBINATION WE HAVE OTHER STUDIES ONGOING COMBINATION TREATMENT RADIATION SENSITIZERS PARP INHIBITORS FOR IMMUNOTHERAPY, THIS IS MULTIPLE DIFFERENT LABS FOR DIDN'T SCENARIOS AND ANTI-ANGIOGENIC DRUGS IN COMBINATION WITH RADIATION. WE HAVE ALSO APPLIED METHODS TO OTHER CANCER TYPES WE WORKED ON LUNG BREAST AND -- TYPES AND DIFFERENT TREATMENT TYPES COMBINATION AS WELL AS SINGLE AGENT AND ALSO WE ARE VERY INTERESTED IN OTHER PHYSICAL SCIENCES BASED INVESTIGATIONS IN INTRATUMOR HETEROGENEITY RESISTANCE TREATMENT RESPONSE AND METASTASIS. SO I WOULD LIKE THE CLOSE WITH A SHOUT OUT TO THE PSSC, IT'S AN AMAZING RIDE AND NONE OF THE STORIES WOULD HAVE BEEN POSSIBLE BECAUSE OF THE SO INTERDISCIPLINARY WE NEED A TEAM THAT IS CURRENTLY FUNDED TO BE ABLE TO MATHEMATICALLY MODEL THINGS AND THEN VALIDATE MOUSE MODEL AND PROSPECTIVELY IMPLEMENT CLINICAL TRIALS SO THANK YOU. NCI AND NIST SPECIFICALLY. >> THERE WAS QUESTION. MAYBE WE CAN TAKE THEM AS THEY COME. >> THAT WAS A GREAT PRESENTATION. THANK YOU. I JUST HAVE A QUESTION ABOUT TOXICITY AND NEUROCOGNITION. THAT SCHEDULE. >> YES. IT'S BIOLOGICALLY -- IT'S BIOLOGICALLY EQUIVALENT DOSE TO STANDARD. SO PART OF THE OPTIMIZATION IS TO FIND SOMETHING NOT PREDICTED TO DO WORSE BASED ON CALCULATING FOR INDIVIDUAL SCHEDULES. WE ALSO HAVE SUBPART OF THE MODEL TO TAKES INTO ACCOUNT EARLY RESPONDING TO TISSUE TOXICITY, THIS SHOULD BE TOLERABLE. >> DID YOU CONFIRM THAT? WE HAVE SEEN IT BEFORE. >> WE CONFIRMED IN IN MOUSE MODEL BUT TO CONFIRM IN HUMAN CLINICAL TRIALS IS FORTHCOMING. >> I WAS CURIOUS THAT IN YOUR MODELS ENRICHMENT OF STEM LIKE CELLS IS ASSOCIATED WITH BETTER PROGNOSIS, WHERE CLEARLY FOR MOST CANCER WE THINK INDUCTION OF STEM CELL PHENOTYPE ASSOCIATED WITH WORST PROGNOSIS BECAUSE THOUGH THESE MAYBE SLOWER CYCLING BECAUSE OF THEIR RESISTANCE MECHANISMS THEY ULTIMATELY MEDIATE MORE TREATMENT RESISTANCE. HOW DO YOU EXPLAIN THAT? >> THIS IS BECAUSE THIS IS INCURABLE DISEASE. THE GOAL IS NOT CURE SUBSET, BECAUSE WE HAVE NO COMBINATION STRATEGY OF EVEN THREE DRUGS THAT CURES SUBSOCIETY. BUT DELAY THE REBOUND, DELAY PROGRESSION OF DISEASE BECAUSE TUMOR VOLUME INCREASES AGAIN, THAT IS ACHIEVED BECAUSE WE MAXIMIZE THE NUMBER >> BRINGS UP A VERY INTERESTING POINT BECAUSE WHAT YOU HAVE DONE THEN IS WHAT IS A TUMOR REGRESSION AND OTHER KINDS OF CANCER WHICH ARE NOT ASSOCIATED WITH PATIENTS UNFORTUNATELY SO I WOULD BE CAUTIOUS APPLYING THIS MODEL TO OTHER DISEASES WITH METASTATIC PHENOTYPES. >> LET ME MAKE SURE I MENTION EACH INDIVIDUAL CANCER TYPE AND TREATMENT TYPE HAS INDIVIDUALIZED MODEL. THE REASON WE PICK THIS MODEL IS BECAUSE IT'S REALLY SPECIFICALLY CHARACTERIZING THE MOUSE MODEL OF DISEASE THAT ERIC'S LAB DEVELOPED, WE HAD THE QUANTITATIVE UNDERSTANDING HOW MANY OF CELL POPULATIONS WE HAVE AND QUANTITATIVELY RESPOND TO DIFFERENT TREATMENT TYPES SO MODEL FOR LUNG CANCER LOOKS DIFFERENT AND I REALIZE THAT IN GENERAL ENRICHING FOR STEM CELL IS PROBABLY NOT A GOOD IDEA IN BRAIN CANCER OTHERWISE INCURABLE ANYWAY, MIGHT BE A GOOD IDEA TO PROLONG SURVIVAL BUT PROOF IS IN THE PUDDING. >> I SUGGEST DEFERRING ADDITIONAL QUESTIONS TO THE END AND FIGURE OUT IF WE HAVE TIME. NOW WE WANT TO HEAR JAN SARKARIA. >> APPRECIATE YOU INVITING ME THE SHARE OUR WORK AND DELIGHTED TO PRESENT ON THE BEHALF OF OUR MIT FOCUSED ON UNDERSTANDING DRUG DISTRIBUTION IMPACT ON GLIOBLASTOMA AND HOW TO BETTER LEVERAGE DRUG DELIVERY. SO THE GOAL OF OUR CENTER IS TO PERFORM A MULTI-MODAL MODELING OF DRUG DISTRIBUTION FROM THE LEVEL OF WHOLE ANIMAL OR WHOLE PATIENT TO THE SUB-- TISSUE LEVEL DISTRIBUTION OF DRUG TO THE SUBCELLULAR IMPACT OF DRUG DISTRIBUTION ON EFFICACY COUPLING THAT WITH ONGOING EFFORTS FOR PRECISION MEDICINE, CRITICAL TO SELECT APPROPRIATE DRUGS T. UNDERSTANDING THE MOLECULAR FEATURES OF CLINICAL CHEMICAL FEATURES OF THE DRUG WE MIGHT SAY THIS PATIENT BENEFIT FROM SMALL MOLECULE VERSUS ADC OR SOMETHING LIKE THAT, THAT'S THE OVERALL GOAL FOR CENTER. TRY TO INFORM DRUG COMPLEX IN GLIOBLASTOMA P. GLIOBLASTOMA IS INCURRABLE AND WE BELIEVE ONE OF THE MAJOR DRIVERS OF THIS REFRACTORYNESS OF THERAPY IS ROLE OF DRUG LIVER DELIVERLY. IF WE LOOK AT TYPICAL GBM CONTRASTING PORTION OF TUMOR, WHICH CORRESPONDS WITH HIGH CELL DENSITY BASED ON BIOPSY STUDIES AND WE HAVE A NUMBER IN THE EDEMA REGION OR T 2 WHICH HAS LOWER BUT SIGNIFICANTLY DETECTSABLE FRACTION OF TUMOR CELLS AND AS WE GET NORMAL BRAIN WE HAVE SOME TUMOR CELLS BUT MORE DIFFUSE. SO SUPER IMPOSING THAN TISSUE DISTRIBUTION WITH A DRUG DISTRIBUTION, VAST MAJORITY OF DRUGS ARE IMPENETRANT BECAUSE OF BLOOD BRAIN BARRIER WE MIGHT SEE LOW DRUG LEVELS IN NORMAL BRAIN AND REALLY ONLY APPRECIABLE DRUG LEVELS IN CONTRASTING ENHANCING REGION WITH THE MOST DISRUPTIVE BLOOD BRAIN BARRIER, WE MIGHT SEE FAIRLY LOW DRUG CONCENTRATION. FLIP SIDE HIGHLY BRAIN PENETRANT DRUG WE SEE HIGHER LEVELS IN NORMAL BRAIN BECAUSE OF THE RICH NETWORK IN REGIONS OF TUMOR MIGHT SEE LOWER BUT SIGNIFICANT DRUG LEVELS AS VASCULATURE IS MORE DISRUPTED SO TO TRY TO UNDERSTAND THIS PARADIGM WE USE PATIENT DERIVED MODELS IN FLANK AND BRAIN AND FOCUS ON EGFR INHIBITOR AS MODEL TEST CASE. INITIALLY NATALIE IN OUR GROUP CORRELATED MR IMAGING IN A MOUSE MODEL GBM 12 WITH MODEL MASS SPEC IMAGING TO IMAGE DRUG LEVELS THROUGH THE TUMOR AND USING MULTI-MASS SPEC IN THIS CASE ROLLOUT ANYBODY WITH BRIGHTER GREEN HIGHER EPISODE OF GREEN. WE RECONSTRUCT WITH MRI SCAN AND THE KEY IS THIS ROI MASS WHERE WE'RE SAYING THERE'S THREE REGIONS ON THE MR, THE NORMAL BRAIN, THE T-2 NUMBER OF REGION WHICH HAS ASSUME HAS INTERMEDIATE DRUG LEVEL DISTRIBUTION AND CONTRASTING COOR, THE FACT WE ANALYZE SIGNAL WE SEE THAT IN FACT ESSENTIAL FOR AND HAS HIGHEST LEVEL AND LOWER BRAIN HAS LOWEST LEVEL SO TRYING TO EXTEND ON THAT MODEL, USING THE DRUG DISTRIBUTION WE DETECTED IN THE NORMAL BRAIN, WE DESIGN THIS COMPARING MULTIPLE DIFFERENT MOLECULAR ANALYSES MICE DOSED WITH EITHER ULTRA LOW DOSE DRUG DESIGNED TO MIMIC WHAT NORMAL BRAIN SEE WITH HIGH DOSE DRUG INTRACRANIAL TUMOR AND VARYING INCREASING CONCENTRATIONS OF DRUG IN THE FLANK MODEL AND COMPARING TO WHAT WE SEE IN BRAIN MODEL WITH HIGH DOSE OF TREATMENT SO AS FIRST PARADIGM HERE, WE ARE COUPLING MULTI-MASS SPEC IMAGING WITH STIMULATED SCATTERING MICROSCOPY WHERE WE CAN DETECT VARIOUS MOLECULES IN THE BRAIN. SO IN THIS MOUSE MODEL THINGS YOU CAN SEE IN THIS BLOW UP PICTURE HERE IS THAT ROLOTNIB IN PINK IS HETEROGENEOUS IN THE TUMOR CORE AND IT DOESN'T DISTRICT IN REGIONS HIGH LIPID CONTENT BUT DOES DISTRIBUTE IN THIRD SENTCAL AREAS OF HIGH CSF. VERY HETERO GENERALIOUS DRUG DELIVERY IN THE BRAIN AND TUMOR. THEN WE CAN TAKE THE SAME IMAGE, MULTI-MASS SPEC IMAGE AND TAKE SERIAL SECTIONSES THAT ARE UNSTAINED AND DO LASER CAPTURE MICRODISSECTION TO LOOK AT GENE EXPRESSION PROFILING DIFFERENCES IN DIFFERENT REGIONS OF TUMOR BASED ON DRUG LEVELS AND COMPARE& THAT TO DOSING LEVELS IN FLANK TUMORS AND USING BY RNA SEQ AND DOING HIERARCHICAL CLUSTERING THE ULTRA LOW LEVELS IN THE FLANK ARE ONES THAT CORRELATE BEST WITH INTRACRANIAL TUMOR SIGNAL COMPARED TO HIGH LOW DOSE FLANK TUMOR WHICH CLUSTER BY THEMSELVES SO ILLUSTRATING THAT HETERO GENEITY OF DRUG DELIVERY CAN DRIVE BIOLOGY OF THESE TUMORS AND THAT TREATMENT OF TUMORS WITH DRUG FAIRLY IMPENETRANT COULD HAVE DIFFERENT EFFECTS OF SIGNALING THAN JUST NO TREATMENT. TO UNDERSTAND BETTER ON THE SIGNALING LEVEL PHOSPHOPROTEOMICS OUR FIRST STEP AT THIS WAS BASICALLY DOING ALL MODELS IN FLANK TUMORS THOUGH NOW MOVING ON TO DOING PROTEOMICS INTRACRANIAL TUMORS BUT AGAIN HERE LOOKING AT TOES TOE THYROSEEN RESIDUE, THERE'S A CLUSTER HERE WHICH IS EGFR TARGETS LISTED HERE, THIS IS KIND OF SHOWN WHEN WE USE HIGH DOSE OR LOW DOSE IN THE FLANK WE SEE UNIFORM AND ROBUST SUPPRESSION OF EGFR SIGNAL BUG COMPARED TO PLACEBO, LOW DOSE TUMORS WE SEE HETEROGENEOUS RESPONSES WITH IN SOME CASES INCREASED PHOSPHORYLATION SIGNALS WITHIN THE EGFR SET WHICH ARE EVEN ABOVE THOSE SEEN IN PLACEBO, REALLY ILLUSTRATING THAT POTENTIALLY SUBTHERAPEUTIC EXPOSURE OF DRUG IN THE CONTEXT OF BRAIN TUMOR WITH INTACT BLOOD BRAIN BARRIER COULD BE DETRIMENTAL. SO REALLY UNDERSTANDING THE IMPACT OF DRUG DELIVERY IS CRITICALLY IMPORTANT. THE NEXT STEP REALLY THAT WAS CASE EXAMPLE WHICH WE KNOW HAS FAILED IN CLINICAL TRIALS AND WE'RE NOT PARTICULARLY EXCITED ABOUT BUT THE IDEA IS NOW WE HAVE MANY OF THESE BRAIN PENETRANT EGFR INHIBITORS LIKE THE AZD COMPOUND, SO TRYING TO UNDERSTAND AS WE CHANGE PHYSICAL CHEMICAL CHARACTERISTICS OF THE DRUG, HOW DOES THAT IMPACT SIGNALING CHANGE THAT WE SEE. THEN ALSO EXTENDING OUR DATA TO LARGER THERAPEUTICS SUCH AS PEPTIDE ADC OR ANTIBODY DRUG CONJUGATES, THE ADME COMPOUND THAT TARGETS EGFR AND THE SAME PDX MODELS IN THE FLANK, THIS DRUG IS INCREDIBLY EFFECTIVE, IN THE FLANK WE SEE YEAR SURVIVAL PROLONGATION WITH DRUG TREATMENT BUT BRAIN IS DIFFERENT. GBM 6 WE SEE NO SURVIVAL BENEFIT WITH TREATMENT WITH 414. WE HAVE A YEAR SURVIVAL FOR LON DIVISION IN THESE MICE TREATED WITH CONSTRUCT. JUST TO ILLUSTRATE THE IMPACT OF DRUG DELIVERY, WE DOSE MICE THEN HARVEST THEM DAY LATER AND STAIN FOR IGG TO DETECT DRUG LEVELS AND GBM 6 DETECT LOW LEVELS OF DRUG COMPARED TO GBM 39 OR DECK NICE LEVELS OF DRUG, JUST A HUMAN MARKER TO DELINEATE THE TUMOR. WE ALSO DEMONSTRATE IF WE ARTIFICIALLY DISRUPT THE BLOOD BRAIN BARRIER OVERTHRUSTING VEGF WE SEE BETTER EFFICACY HERE IN BIOLUMINESCENCE SHOWING THAT WITHOUT DISRUPTION NATIVE TUMOR WE SEE MODEST BENEFIT BY BIOLUMINESCENCE BUT CONTINUED PROGRESSION OF TUMOR WITH ABT 4 AND 4 THERAPY. BUT IN THE DISRUPTED BLOOD BRAIN BARRIER TUMOR MODEL WE SEE NICE EFFICACY AND RESPONSIVE THERAPY SO KIND OF EXTENDING TREATMENTS FOR SOMETHING LIKE ADC THAT'S CAN BE HIDELY POTENT AND ACTIVE -- HIGHLY POTENT AND ACTIVE HOW WE CAN LEVERAGE UNDERSTANDING THE BLOOD BRAIN BARRIER TO DISRUPT AND LEVERAGE THE IDEA OF PHYSIC AND CHEMISTRY OF THE BLOOD BRAIN BARRIER AND DRUG TO ENHANCE DRUG DELIVERY. I WOULD LIKE THE WRAP WITH THIS SLIDE HERE WHICH IS NOT MANY IN THIS ROOM ARE INTERESTED IN CURING GBM IN MICE BUT WE ARE INTERESTED IN CURING IT IN HUMANS SO WE'RE LEVERAGING THE CLINICAL FACILITIES WITH COLLABORATOR AT MIT UNIVERSITY OF MINNESOTA AND HARVARD TO TRY TO UNDERSTAND IF WE DOSE PATIENTS WITH DRUG AND TAKE THEM FOR IMAGE GUIDED BIOPSY AND RESECTIONS FOLLOWING DOSE OF DRUG WE CAN BUILD OUT MODEL NOT ONLY OF TUMOR CELL DENSITY BUT DRUG DELIVERY IN DIFFERENT REGIONS OF THE TUMOR BASED ON MRI CHARACTERISTICS ANDS COUPLED WITH RADIOMIC PREDICTION OF GENETIC IN THE TUMOR BASED ON MR FEATURES WE CAN TRY TO UNDERSTAND HOW THESE TARGETED THERAPIES MIGHT INFLUENCE ULTIMATE PROGRESSION OF THESE TUMORS. FINALLY I WOULD LIKE TO ALSO GIVE SHOUT OUT TO FIDCAL SCIENCES ONCOLOGY CENTER. THIS WAS THE GLUE THAT HELD TOGETHER THIS HIGHLY COLLABORATIVE TEAM ACROSS THE COUNTRY. THANK YOU. >> THANK YOU VERY MUCH, THANKS TO YOU WILL THE SPEAKER FOR INTERESTING EXCITING PRESENTATIONS. WE WILL HAVE TIME TO TAKE MAYBE A COUPLE OF QUESTIONS. ANY QUESTIONS? >> IT'S INTERESTING WORK. HAVE YOU MADE ANY EFFORTS TO VALIDATE YOUR MODEL FOR PREDICTING RESPONSES USING CLINICAL MATERIAL? FOR EXAMPLE, THERE'S BEEN MANY -- I DIDN'T SEE RADIATION ONCOLOGIST OR RADIO BIOLOGIST I RECOGNIZE INVOLVED IN ANY WORK BUT THERE HAVE BEEN MANY TRIALS DONE FOR EXAMPLE IN PROSTATE CANCER ASSUMING DIFFERENT ALPHA BETA RATIOS, AND LOOKING AT DIFFERENT BEDs AND DIFFERENT FRACTIONATION WITH DIFFERENT DRUGS IN HUMANS, IN YOUR MODELS WORK SO WELL IN ANIMALS TAKE THE PLETHORA OF DATA AVAILABLE IN HUMANS AND BACK CALCULATE TO VALIDATE THEY WORK IN PEOPLE? >> >> FOR ME? >> WHOEVER. >> OKAY SO FIRST IT'S A VERY TYPE SPECIFIC MODEL SO PROSTATE CANCER WOULDN'T BE VALIDATED BECAUSE IT'S SPECIFIC TO BE ABLE TO -- WE TRY TO GET PATIENT SPECIFIC ACCESS, THE DATA TO PATIENT SPECIFIC ACCESS FROM SOME OF THE LARGE COUNTRY WIDE GROUPS, THIS IS HARDER THAN ONE THINKS. WE HAVEN'T GOTTEN ACCESS BY PARTIALLY VALIDATED WITH RETROSPECTIVE STUDIES. SO MUCH THERE WAS A STUDY IN FRANCE AT ULTRA FRACTIONATION SCHEDULE PREDICTED TO LEAD TO SUPERIOR SURVIVAL DEPENDING THE TIMING BETWEEN INDIVIDUAL FRACTIONATION AN THOUGH WE DIDN'T GET PATIENT LEVEL INDIVIDUALIZED DATA OVERALL THE PREDICTIONS WOULD BE SIMILAR FROM WHAT WE PREDICTED WAS THE M&A MATCAL MODEL. NOW WE TRY TO ACCESS RETROSPECTIVE DATA FROM -- STILL ONGOING BECAUSE THERE ARE NOT SO EASILY ACCESSIBLE MEDICAL RECORDS SO WE'RE WORKING ON IT. I THINK THAT LOB VALIDATION OF RESULTS. AS I WOULD HAVE THOUGHT. >> QUICK QUESTION ON CONSTRAINTS YOU PUT ON FOR YOUR MODELS. HOW MUCH DEBATE DID YOU HAVE RECOGNIZING THAT CANCER DOESN'T TAKE WEEKENDS OFF? >> YEAH. >> THAT YOU CONSTRAIN THE MODEL AT THE OUTSET, NOT TO LOOK BEYOND FIVE DAY WINDOW, GIVEN HOW VARIABLE AND UNEXPECTED YOUR ULTIMATE RESULTS WERE. >> RIGHT. INCLUDING THE WEEKEND WOULD MAKE A DIFFERENCE AND IT DIDN'T SIGNIFICANTLY CHANGE THE SITE SO RADIATION ONCOLOGISTS ARE OFF THE HOOK. >> GREAT AGAIN, THANK YOU VERY MUCH. AND GOING TO MOVE NOW TO THE NEXT PART OF THIS AFTERNOON, DR. EIGHT NEW CONCEPTS FOR THE BOARD'S CONSIDERATION TODAY. BSA MEMBERS HAVE BEEN ASSIGNED AS REVIEWERS, THE BOARD WILL VOTE, APPROVE, DISAPPROVE OR DEFER NEW CONCEPT. BOTH NCAB AND BSA MEMBERS MAY PARTICIPATE IN DISCUSSION BUT ONLY BSA MEMBERS WILL VOTE. FIRST CONCEPT, CELLULAR CANCER BIOLOGY IMAGING RESEARCH RESOURCE PROGRAM, THIS IS AN RFA, WILL BE PRESENTED BY MICHAEL IPSI, ASSOCIATE DIRECTOR CANCER CELL BIOLOGY BRANCH DIVISION OF CANCER BIOLOGY. MIKE. >> THANK YOU. WHILE WE WAIT FOR SLIDES, MY NAME IS MIC ESPEY, CANCER DIRECTOR FOR DIVISION OF CANCER BIOLOGY, U FOLLOW THE PIECE ON PROGRAM REVIEW BECAUSE I HELP LAUNCH INTEGRATIVE MULTI-DISCIPLINARY PROGRAMS WHICH WE WILL TALK ABOUT FOR THIS RFA CONCEPT TODAY. EACH ELEMENT, THE CANCER CELLULAR BIOLOGY IMAGING ARE ALL FEATURED WITHIN THE RFA AND WE TRIED TO BUNDLE THIS TOGETHER IN THE BEST WAY POSSIBLE WITH SO CALLED CBER PROGRAM. SO BEGINNING BACK IN APRIL 2018 NCI CONJUNCTION WITH AMERICAN SOCIETY FOR CELL BIOLOGY HELD STRATEGIC WORKSHOP. THE GOAL WAS TO EXAMINE STATE OF IMAGING SCIENCE THE SUBCELLULAR TO CELLULAR LINK CELL, TWO TO NETWORK CELL BIOLOGY AND CANCER BIOLOGY COMMUNITIES. THROUGH THIS STRATEGIC WORKSHOP T COUPLE OF CONCEPTS BUBBLED UP. THAT CANCER BIOLOGY GENERALLY LAGS BEHIND OTHER FIELDS IN LEVERAGING ADVANCE CELLULAR IMAGING TOOLS. ACCESS TO SMALLER OSCILLATED LABS CUTTING EDGE IMAGING INFRASTRUCTURE CAN BE LIMITING. THERE EXISTS INITIAL BARRIERS MOVING CELL BIOLOGY IMAGING TO CANCER RESEARCH. TWO THINGS THAT CAME OUT OF THE WORKSHOP WERE THAT CANCER BIOLOGY IMAGING REQUIRES SPECIALIZE MODIFICATION TO SYSTEMS THAT ARE DESIGNED TO STUDY NORMAL CELLULAR PHYSIOLOGY AND SECOND DISCOVERY BASED CELLULAR IMAGING OFTEN DOES NOT FAIR WELL IN CANCER PEER REVIEW. IN TERMS OF PORTFOLIO ANALYSIS, IT'S DIFFICULT TO USE IMAMMING AND CELL BIOLOGY AND YOU WILL FIND INDIVIDUAL APPLICATION ALSO HAVE SPECIFIC AIMS OR SUBSETS OF AIMS THAT LEVERAGE ONE OR MORE OF THESE, BUT WE ATTEMPTED TO DO HERE HIGHLIGHT NUMBER OF DIFFERENT PROGRAMS ACROSS THE NCI PORTFOLIO THAT ARE INVOLVED IN IF ADVANCE IMAGING AND PUT IN CONTEXT OF SPATIAL SCALE. SO GOING FOR MOLECULAR TO PATIENTS WE CAN BENEFITED THESE TO CANCER CELL PROCESSES OR HIGHER SCALE CANCER DIAGNOSIS AND TREATMENT. THE DIFFERENT PROGRAMS, BSA SUBCOMMITTEE ASKED ME TO HIGHLIGHT TWO IN PARTICULAR THIS I MAP PROGRAM FOR INSTANCE IS ALL TECHNOLOGY DEVELOPMENT BUT AS LINES SHOW IS THAT IT DOESN'T REALLY NECESSARILY FOCUS ON ONE PARTICULAR SCALE AND ALSO NOT IMAGING SPECIFIC. IN FACT LESS THAN 10% APPLICATIONS THAT ARE FUNDED TO THIS FALL INTO THE CATEGORY OF CELLULAR IMAGING. LIKEWISE WITH THE P SIGN WE HER ABOUT YOU SAW GREAT IMAGING APPLICATIONS BUT THEY'RE NOT REALLY DEDICATED TOWARDS TECHNOLOGY DEVELOPMENT PER SE AND CERTAINLY NOT IN THE MODEL THAT I'M GOING TO PRESENT FOR THIS CONCEPT. THE IDEA IS THE CBER PROGRAM WOULD FIT INTO THIS GAP AND UNIFY ACROSS SPECTRUM OF SCALE OF BASIC CANCER BIOLOGY PROCESSES AND ALSO DERIVE BEST ELEMENTS OF ADVANCE IMAGING, CANCER BIOLOGY AND TECHNOLOGY DEVELOPMENT. SO THE GOALS OF THE RFA, FIRST CREATE RESOURCE CENTERSNA SILL AT A TIME DEVELOPMENT AND USE OF ADVANCE IMAGING TECHNOLOGIES, AT THE SUBCELLULAR TO CELLULAR SCALE AND ADDRESS BASIC CANCER RESEARCH QUESTIONS. SECOND IS TO FOSTER SUSTAINABLE COLLABORATIVE COMMUNITY BETWEEN CELLULAR IMAGING TECHNOLOGY DEVELOPERS AND BASIC CANCER BIOLOGY RESEARCHERS ACROSS THE NCI PORTFOLIO. SO WE CAME UP WITH THIS UO 1 COOPERATIVE AGREEMENT MECHANISM, IT'S A FOREIGN MECHANISM TO MOST OF US, BASICALLY ALLOWS FLEXIBILITY TO BUILD IN UNIQUE FEATURES WE FEEL BEST SERVES THE NEEDS OF COMMUNITY IN THIS REGARD. NUMBER ONE ENABLES CYCLE OF PROBLEM SOLVING BETWEEN TECHNOLOGY DEVELOPERS AND THE END USER ADOPTERS DEFINED AREAS OF CANCER BIOLOGY RESEARCH THAT LEVERAGE CELLULAR IMAGING APPROACHES. THE PROGRAM U MECHANISM DOES IS MANAGE ON PROGRAMMATIC SIDE, PILOT PROJECT PROCESS, THAT INCLUDES WORK FORCE DEVELOPMENT AND ALSO STIMULATES BROADER IMPACT AND IMPLEMENTATION OF THESE TECHNOLOGIES TO DRIVE TOWARD CANCER BIOLOGY QUESTIONS THEY ARE ADDRESSING. SECOND, COORDINATE SYNERGY WITH EXISTING COMPLIMENTARY NCI PROGRAMS FEATURED PREVIOUS SLIDE. AND LASTLY SORT OF A READER PROGRAM WHERE SPIN OFFS OF PROJECTS COME FROM THESE CENTERS THAT THEN CAN STAND ALONE AND BE SUCCESSFULLY REVIEWED AS SEPARATE MECHANISMS UNTO THEMSELVES LIKE PO 1 OR U 1 RO1, SO FORTH. THIS IS A DUPLICATE SIDE. THERE IS A SUBCOMMITTEE INTERESTED IN THIS CONCEPT THAT TECHNOLOGY DEVELOPMENT IS BEST DRIVEN BY CONTEXT OF ADDRESSING FUNDAMENTAL CHALLENGES. THE IDEA IS YOU DON'T WANT TO DEVELOP TECH NOL FOR TECHNOLOGY SAKE, YOU WANT TO HAVE IT FOCUSED ON RESEARCH PROBLEM AT HAND. ADDRESSING FUNDAMENTAL CANCER BIOLOGY QUESTIONS. THESE ARE EXAMPLES OF CANCER BIOLOGY THEMATIC OR PRIORITY AREAS RESPONSIBLE TO THE RFA. BIOPHYSICAL IMAGING OF ONCOGENIC SIGNALING IN LIVE CANCER CELLS, ABILITY TO HAVE SPATIAL THEM ORAL ELUSION THEKINE OF THINGS CLAUDIA WAS TALKING ABOUT, SUBCELLULAR COMPARTMENTS, THE ANATOMY OF CANCER STEM CELLS TO AID LINEAGE TRACING AND FOLLOW EVOLUTION OF EXISTENCE. COUPLE SINGLE CELL OMICS WITH LONGITUDINAL IMAGING TO METASTASIS IN WHOLE ANIMALS. CIRCUMSTANCE CELLULAR TO CELLULAR IMAGINING WITH RESPECT TO SPACE AN TIME TUMOR MICROENVIRONMENT AND DYNAMIC IMAGING OF IMMUNE CANCER CELL INTERACTIONS. HERE IS A FEW EXAMPLES OF IMAGING MODALITIES THAT ONE WOULD USE TO DEVELOP IN THE TECHNOLOGY SECTOR, SUPER RESOLUTION MICROSCOPY HAS BEEN NOBEL PRIZES HAVE BEEN RECENTLY AWARDED IN THIS AREA, BUT WE'RE NOT NECESSARILY LEVERAGING TO LOOK AT CANCER CELLS PER SE, THIS IS A CONCEPT WE WOULD LIKE TO INVITE THE PEOPLE THAT HIGHLY TECHNICAL AND PROFICIENT USING SUPER RESOLUTION MICROSCOPY TO USE A VANCE TOOLS THE ANSWER BIOLOGY QUESTIONS, WITH DIFFERENT SPECTRA SCOPIC IMAGING TECHNIQUES, MASS SPEC IMAGING, THESE TWO IMAGE MODALITIES WOULD BE MORE IN LINE WITH LOOKING AT FIX SPECIMENS. LIVE CELLULAR DYNAMICS OR GENOMICS. OPT TOE GENETICS, THESE THINGS LEVERAGED IN TERMS OF LIVE CELL IMAGING. GENETICALLY ENGINEERED, DAVE WAS INTERESTED IN THIS SO CALLED TOUCH LIST, OR NON-INVASIVE IMAGING APPROACHES. THESE ARE THINGS DEVELOPED BY LOOKING AT CANCER THROUGH THIS TYPE OF LENS. I'M GOING TO SPEND TIME ON THIS, I HAVE THREE SLIDES TO GO, THIS IS BASICALLY THE OVERALL PROGRAM STRUCTURE THAT WE HAVE DEVELOPED FOR THIS RFA, THERE'S THREE EQUAL BALANCE COMPONENTS THAT ARE PART OF PROGRAM STRUCTURE. WHAT WE WOULD LIKE TO HAVE IS TECHNOLOGY UNIT THAT WOULD BE INVOLVED IN DEVELOPMENT AND INNOVATION OF THE CELLULAR SCALED IMAGING MODALITIES, SECOND WOULD BE THE RESEARCH TEST BED WHICH INVOLVES THE WET LAB DEMONSTRATION PROJECTS, THAT THE TECHNOLOGY FEEDS INTO AND LASTLY AND IMPORTANTLY IS A COMMUNITY ENGAGEMENT COMPONENT, I MENTION THIS REALLY STARTED FROM A GRASSROOTS EFFORT, THAT WAS ONE OF THE THINGS WE HEARD LOUD AND CLEAR FROM THE COMMUNITY, THAT WE WANTED TO HAVE INCLUSION FROM OTHER LABS THE ABILITY TO CONNECT WITH LARGER LABS TO INPUT THEIR SCIENCE AND HAVE THOSE OPPORTUNITIES AS WELL. SO LET'S TAKE EACH IN TURN, THE TECHNOLOGY UNIT THEY DEVELOP INSTRUMENTATION THAT IT'S NOT INSTRUMENTATION ONLY, IT'S WHOLE PACKAGE, PROBES, COMPUTATIONAL DATA SCIENCE ON BACK END, WHAT WE WANT PEOPLE TO DO IS DEVELOP INTEROPERABLE SYSTEMS THAT ACT AS A UNIT OR SUITE OF TECHNOLOGIES THAT AGAIN DRIVE TOWARDS CANCER BIOLOGY QUESTION, THAT THE CENTER INTERESTED IN. ON THE RESEARCH TECHNOLOGY TEST BED IS WET LAB CONTEXT, IT'S DEMONSTRATION AND REFINEMENT CYCLE OF THE TECHNOLOGY. IT'S MEANT TO BE ENTER AND OVER TIME WITH THE AWARD, THE IDEA IS YOU INCREASE LEVEL OF SOPHISTICATION AND YOU COME BACK INTO THE TECHNOLOGY PART TO ADDRESS PROBLEMS OR BETA TESTING THAT OCCURRED IN WET LAB AND AT THE END OF THE AWARD YOU HAVE A SYSTEM HOPEFULLY THAT CAN BE FULLY OPERABLE TO ADDRESS THE QUESTIONS AT HAND. AGAIN I WILL LIKE TO EMPHASIZE BREATH AND SCOPE OF THESE CENTERS WOULD BE DEFINED BY A THEME, HERE IS A MENU OF THEMES WE JUST TALKED ABOUT. SO I THINK THAT'S THE TRUE CHARACTER OF THIS IS THE OTHER TECHNOLOGY DEVELOPMENT PROGRAMS TEND TO BE A ONE OFF OR SINGLE USE. PEOPLE HERE TO FORM TEAMS THAT WORK TOGETHER ENTER INCENTIVIZE EACH OTHER OVER TIME TO DRILL DOWN ON THESE SPECIFIC TARGET AREAS. LASTLY COMMUNITY ENGAGEMENT PART IS RAY INTERESTING FEATURE OF THIS CONCEPT WE PUTTING TOGETHER, I WOULD HAVE CONSTANT INFLUX OF PILOT PROJECTS IN YEAR TWO AFTER CENTERS UNDERWAY, PILOT PROJECTS SERVE TWO PURPOSES. ONE IS TO ENGAGE COMMUNITY, OBVIOUSLY BUT THE OTHER IS TO REALLY INFUSE THE CENTER WITH NEW IDEAS OVER TIME BECAUSE TECHNOLOGY SECTOR DOES MOVE FAST AND YOU DON'T WANT TO HAVE STATIC CENTER THAT ONLY IS RESTRICTED TO THE THINGS THEY SAW AT OUTSET T RATHER THAN TO BE ABLE TO EVOLVE AND CHANGE OVER TIME, THE PILOT PROJECT IS AN AVENUE TO DO THAT. CANCER BIOLOGY RENTED OR TECHNOLOGY ORIENTED OR BOTH, THE OTHER FEATURE IS IT WOULDN'T BE INTERIOR TO THE CENTER OR EXCLUSIVE TO THE INSTITUTION THAT HOLDS THE AWARD, RATHER THEY SOLICIT PILOT PROJECTS FROM THE OUTSIDE COMMUNITY SO THEY CONTINUALLY BE ENGAGING THE COMMUNITY IN THIS PROCESS. SO THE PROPOSED INITIATIVE WHAT WE PROPOSE IS THIS UM 1 CBER PROGRAM AND RFA WITH SET ASIDE OF 12 MILLION OVER FIVE YEARS, UO 1 GRAND MECHANISM ALLOW PROGRAMMATIC GUIDANCE WE CAN INPUT TO NURTURE SUCCESS OF THIS PROGRAM. WE'RE STARTING OFF WITH CONCERNED BECAUSE IT IS NEW WAY DOING THINGS ESSENTIALLY PILOTING THIS WITH THREE TO FOUR CENTERS THAT WOULD BE ROUGHLY $3 MILLION TOTAL COST AND ONE RECEIPT DATA. THERE'S DISCUSSION WITH B SA SUBCOMMITTEE ONE RECEIPT DATE VERSUS TWO. YOU CAN TALK ABOUT THAT IN QUESTION AND ANSWER PERIOD. MY WAY TO THINK ABOUT IT IS ONE RECEIPT DATE LAUNCH IT IS PROGRAM TOGETHER WITH THREE AWARD, THREE TO FOUR CENTERS, I THINK SLICES TOO THINLY, WE HAVE 12 CENTERS, DATES WOULD MAKE BETTER SENSE, NONETHELESS, CBER CENTER WOULD BE SEPTEMBERERED ON BASIC RESEARCH PRIORITY AREAS. PROGRAM WOULD WORK WITH THEM TO COORDINATE ADS APPROPRIATE THE PILOT PROJECTS WORKSHOPS INTERFACING WITH OTHER NCI IMAGING PROGRAMS OR ACTIVITIES. OUR DEA SPECIAL EMPHASIS REVIEW PANEL COVERS BROAD INTERDISCIPLINARY EXPERTISE NECESSARILY TO CONNECT TECHNOLOGY AND BASIC CANCER RESEARCH QUESTIONS. LASTLY WE ANTICIPATE RECEIPT BEGINNING 2019, AWARDS MADE IN APRIL 2020. THERE'S ALSO DISCUSSION ABOUT HAVING A LONG RUNWAY OR ENOUGH LEAD TIME FOR APPLICANTS TO UNDERSTAND MECHANISM AND PREPARE THE BEST APPLICATION FORWARD. WHAT WE PLAN TO DO IS SIGNIFICANT OUTREACH, WE ENGAGE THE COMMUNITY, LET THEM KNOW ABOUT THE OPPORTUNITY COMING FORWARD AND HELP GROOM THEM IN PROCESS TO PUT THE BEST APPLICATIONS FORWARD. SOME OF THE INITIAL QUESTIONS FROM BSA SUBCOMMITTEE BASICALLY IS IT ALLY CANCER BIOLOGY OR MOLECULAR ONCOLOGY, WHERE IS THE BALANCE? MY COMMENT ON THIS, IT'S BOTH. WE WANT TO HAVE THREE WAY COMMUNICATION BETWEEN TECHNOLOGY, CANCER BIOLOGY TEAM AND COMMUNITY OUTREACH COMPONENTS. THESE WORK TOGETHER IN AN ITERATIVE WAY, THE SYNERGY BETWEEN THOSE ELEMENTS IS WHAT WE WANT APPLICANTS TO PREPARE IN THEIR APPLICATION TO MAKE SURE THERE'S A GOOD BALANCE BETWEEN THAT. SO A END OF THE THEY WE DON'T WANT -- WE WANT BOTH SIDES INTEGRATED TOGETHER. ANOTHER QUESTION WHY NOT USE U2 1 AND U2 4 SIMILAR TO THE PI SUN PROGRAM. THE ANSWER TO THAT IS THROUGH THE U 1 MECHANISM, WE HAVE TO STITCHING TO ELEMENTSMENT AND BY HAVING UO 1 AND U 24, SEPARATE OWNERSHIP OF DIFFERENT COMPONENTS SO BY COMBINING WITHIN APPLICANT AWARD YOU FORCE THAT TEAM TO COME TOGETHER AND LEVERAGE COMPONENTS WITHIN CENTERS THEMSELVES AN OVERALL, THERE WOULD BE PROGRAMMATIC GUIDANCE BECAUSE OF UO 1 PROGRAM OR UO 1 STRUCTURE. LASTLY THIS IS ALWAYS QUESTION, WHAT IS YOUR MEASURE OF SUCCESS, I SEE IT MEASURE OF SUCCESS HERE WOULD BE HAVING TECHNOLOGIES AND CONCEPTUAL ADVANCES, OPEN UP NEW AREAS CANCER RESEARCH, THERE'S ADVANCES IN CELLULAR SCALE IMMA'AMING BUT IT'S NOT APPLIED ADS VIGOROUS AS IT COULD INTO THE CANCER BIOLOGY SPACE SO TEMPORAL SPATIAL DYNAMICS OF ONCOGENIC SIGNALING RATHER THAN JUST HERO ON A DIAGRAM, YOU SEE IT, OR SUBCELLULAR LINK SCALE THAT INFORMS EFFICACY OR DEVELOPMENT OF RESISTANCE. SECOND PERMEATION OF THESE ADVANCES INTO THE BROADER RESEARCH COMMUNITY IS ONE MEASURE OF SUCCESS. AND WE QUANTIFY THAT BEYOND BIBLIOMETRICS WOULD BE TO SEE SPIN OFF AWARDS OCCURRING IN OUTGROWTH OF THE CENTURY ITSELF. LASTLY DID CBER STIMULATE DISSEMINATION OF SCALABLE IMAGING TECHNOLOGIES AND I WORK WITH THE SBIR PROGRAM THROUGH NCI TO CONNECT IMAGING DEVELOPERS AND THE OMIC DEVELOPERS BE SURE WE CAN ROLL THAT OUT. I'M ALMOST DONE. I AM DONE. I'LL BE HAPPY TO HAND OVER TO CHRIS OR IF THERE'S QUESTIONS FIRST, HAPPY TO FIELD THOSE. >> STARTING NOW TO THE SUBCOMMITTEE, CHRIS, MAYBE YOU CAN START. MEMBERS OF THE COMMITTEE WHERE CHRIS, -- >> YOU'LL KEEP IT SHORT BECAUSE WE HAVE TO GET THROUGH 8. IN MY MIND IT'S AN INTERESTING APPROACH TO TRY THE UM 1 MECHANISM TO FILL THIS GAP IN THIS CONTINUUM OF IMAGING FROM SUBCELLULAR TO PATIENT BUT AS WE DISCUSSED THERE REMAINS THREE ISSUES TO REITERATE HERE. FIRST I ASK THAT CANCER BE CENTRAL THEME OF THE RFA AND BE SWORE DRIVENING REVIEW. 'S STILL IN MY MIND VERY HEAVY IMAGING CENTRIC AND SO I ONLY ASK THAT CANCER BUBBLE UP TO BE CENTRAL THEME. ADS YOU MENTIONED THE COMMITTEE THOUGHT THAT WE REALLY NEED ENOUGH LEAD TIME BETWEEN THE CALL AND SUBMISSION, SOMETHING LIKE SIX MONTHS AND TO HAVE TWO CALLS TO GET MOST NUMBER OF PEOPLE CHANCE TO APPLY AND SECOND CHANCE TO IMPROVE UPON ORBNAL SUBMISSION. THE THOUGHT WAS TO INSTEAD OF AWARD PEOPLE WHO HAVE SOMETHING SHOVEL READY, TO GIVE PEOPLE A CHANCE TO PUT INNOVATIVE IDEAS TOGETHER AND A LITTLE MORE LEAD TIME TO GET THE WORD OUT. BIG FAN OF TWO CALLS. THEN LAST ONE ALL OF US BROUGHT UP IN ONE LAYER OR ANOTHER IS WHETHER THIS IS THE RIGHT WAY TO SUPPORT CELLULAR IMAGING AND CANCER, THOUGH WE ARE SUPPORTIVE OF IT. I DON'T KNOW WE CAME TO CONSENSUS, THIS IS BETTER THAN SOME OF THE IDEAS WE HAD, THE TOTAL BUDGET FOR THIS PROGRAM IS 60 MILLION BY IS EQUIVALENT TO 50 FIVE YEAR MAXIMUM MODULAR RO1 GRANTS WITH 19% HAIRCUT PUSH IT UP TO 60 GRANTS SO SIGNIFICANT POOL OF RO1s BEING CONSOLIDATED IN THREE CENTERS. SO BECAUSE OF THAT, WE THOUGHT IT WOULD BE REALLY IMPORTANT TO HAVE MORE FIRM METRICS OF SUCCESS SO WHEN IT COMES UP FOR RENEWAL, YOU HAVE A GOOD IDEA WHAT SUCCESS LOOKS LIKE FROM CONSOLIDATING THIS MONEY IN THREE CENTERS AS OPPOSED TO IF YOU FUNDED 60 GRANTS, WHAT WOULD THAT LOOK LIKE. THE IDEA FOR THE CENTERS IT SHOULD BE MORE. SO I APPRECIATE THE METRICS UP THERE BUT NICE TO HAVE -- CODIFY THOSE FURTHER. PASS IT ON TO MY COLLEAGUES. >> THANK YOU, CHRIS. MARY. >> SO THE COMMITTEE FOUND PROPOSAL TO BE INNOVATIVE AND RELEVANT UNDERSTANDING FUNDAMENTAL PRINCIPLES OF CANCER CELLS AND CELLS NEXT TO THEM. WE DID DISCUSS THAT UNDERSTANDING THE PHENOTYPES OF THE CELLS AND TUMOR BE THEY NEOPLASTIC CELLS OR NON-NEOPLASTIC CELLS AS WELL AS PHENOTYPES OF ACELLULAR MATERIAL WHICH HEARD COUPLE OF EXAMPLES OF IN THE PRESENTATION BEFORE. WILL HELP DOCTORS DESIGN METHODS FOR KNOWING WHETHER PATIENTS ARE RESPONDING TO DRUGS. THAT'S WHY HAVING NON-INVASIVE IMAGING COUNT PARTS TO THIS WOULD BE SALIENT FOR THE FIELD WHERE YOU COULD SEE TUMOR BREATHING SO YOU CAN DETERMINE WHETHER MEDICINE IMMUNOTHERAPY HAS IMPACT. WE ALL AGREE HAVING MORE FOLKS INVOLVED IN THE ENGINEERING SIDE, PHYSICS SIDE, IMAGING SIDE, NUCLEAR MEDICINE SIDE ET CETERA WITH CANCER BIOLOGIST WOULD BE TERRIFIC. WE WERE STUCK ON GRANT MECHANISM AS CHRIS WAS SAYING. NEW CONCEPT FOR US, WHAT THAT MEANS, THE UM 1 IS A CATCH ALL, THE GRANT THAT DOESN'T FIT ANYWHERE ELSE. YOUR EXPLANATION HERE HELPS ME UNDERSTAND THIS BETTER, MIC. -- MIKE. OFALL, TEAM, WE WERE SUPPORTIVE OF IT, WANTED CLARIFICATION PROVIDED SOME OF IT HERE TODAY. MARY WILL HAVE MUCH BETTER QUESTIONS THAN ME. >> TO SUM RIDE AGAIN, I THINK WE WERE AS A GROUP I THINK FOUND COMPELLING THE NCI CELL BIOLOGY WORKSHOP FOR IDENTIFYING CLEAR GAP AND CLEAR OPPORTUNITY IN TERMS OF BRINGING DEEP CELL BUY LOGICAL CANCER QUESTIONS TOGETHER WITH THE REMARKABLE NEW IMAGING TECHNOLOGIES THAT ARE BECOMING AVAILABLE AND THAT ARE NOT INTEGRATE IN AN ORGANIC WAY IN TO THE CANCER COMMUNITY THOUGH THERE'S CERTAINLY GREAT EXAMPLES. I THINK MIKE POINTED OUT ADS WELL, THIS GAP THAT WE IDENTIFY OR THIS OPPORTUNITY ALIGNS WELL WITH THE GAP IN THE CURRENT NCI FUNDING PORTFOLIO, SO THERE IS ALIGNMENT THERE, THE THINGS WE DISCUSSED THAT ARE MOST IMPORTANT ARE FIRST OF ALL IT SHOULD BE A COMPELLING CANCER QUESTION THAT IS THE DRIVER HERE, YOU DON'T WANT TECHNOLOGY TO BE TAILED TO BE WAGGING THE DOG AS IT WERE. SO THAT'S VERY IMPORTANT AND SOMETHING CHRIS MENTIONED ALREADY. WE ALSO -- IT WAS POINTED OUT BY MIKE, ONE OF THE BIGGEST CHALLENGE IS THESE HIGH END IMAGING CENTERS THAT HAVE THESE EXCEPTIONAL TECHNOLOGY IT IS ARE GEOGRAPHICALLY ISOLATED IN VARIOUS POCKETS ACROSS THE COUNTRY AND A LOT OF CANCER INVESTIGATORS DON'T HAVE ACCESS IS COMMUNITY ENGAGEMENT CORE PROVIDES MECHANISM WHEREBY CANCER COMMUNITY AT LARGE COULD GAIN ACCESS TO BOTH THE TECHNICALK PER TEASE, THE TECHNOLOGY AND ALSO POTENTIAL COLLABORATORS SO WE LIKED THAT CONCEPT ADS WELL. THE THING I'M THINKING OF NOW IS GIVEN WHAT WE HEARD THIS IMPORTANTING ABOUT THE CHALLENGE WITH THE RPG POOL, IT'S A TIMING ISSUE, IT'S NOT A QUESTION IN MY MIND ABOUT WHETHER IT'S JUSTIFIED, JUST A QUESTION OF WHETHER THE TIMING IS RIGHT FOR A NEW MECHANISM OF THIS TYPE GIVEN CONSTRAINTS WE ARE FACE MORE BROADLY. CHRIS, WOULD YOU LIKE TO MAKE A MOTION? >> ALL WE NO ED NOW IS A MOTION TO ACCEPT. (OFF MIC) (OFF MIC) >> MAKE YOUR MOTION AND INCLUDE WHATEVER YOU WANT TO PUT IN IN THE AMENDMENT IN YOUR MOTION. >> I MAKE A MOTION TO APPROVE WITH THE REQUEST THAT TWO CALLS. IS THERE ANYTHING ELSE YOU WANTED TO INCLUDE? >> YOU HAVE THE SPECIFIC CANCER FOCUS AND THE CANCER BIOLOGY BE THE DRIVER. >> IN GOOD FAITH THOUGH? >> THAT'S OUR INTENTION, >> SO NOW I WOULD LIKE TO HAVE A SECOND. I NEED A SECOND. >> I WILL SECOND. NOW DISCUSSION. I WAS A LITTLE SURPRISED BY THE MOTION GIVEN THE NATURE OF THE COMMENTS AND AGAIN, I HAVE READ THE MATERIALS BUT DIDN'T PARTICIPATE IN THE QUESTIONS. SO SIT ON THE FREDERICK BOARD IS ALSO VERY INTERESTING. BECAUSE WE WATCH A LOT OF PHENOMENAL TICKNOLOGIES BE DEVELOPED -- TECHNOLOGIES DEVELOPED AND THE THING TO DECRY THERE IS HOW TO MAKE THEM MORE WIDELY AVAILABLE THE WIDE CANCER COMMUNITY, CRYO-EM IS ONE EXAMPLE OF MANY NEW IMAGING TECHNOLOGIES COMING DOWN, FOR MOST CANCER CENTERS INSTITUTIONS ARE NOT GOING TO BUILD THAT DEPTH OF IMAMMING CENTER SO WHEN I LISTEN TO PROPOSAL OR READ, WHAT I WONDER IS WOULD WE DO BETTER TO CREATE REGIONAL SUPER MASSIVE IMAGING CORE FACILITIES, IF YOU WILL. AND MAKE THEM AVAILABLE TO THE BROADER CANCER RESEARCH COMMUNITY. IN THE CONSTRAINTS OF THE MECHANISM YOU HAVE CHOSEN YOU'RE GOING TO ASK THE SAME GROUP OF HIGH-TECH ENGINEERING DEVELOPERS TO ALSO HOPEFULLY BE ALIGNED WITH GREAT CANCER BIOLOGISTS TO ASK A QUESTION, MY EXPERIENCE THAT ALIGNMENT DOESN'T EXIST VERY MUCH IN OUR FIELD. YOU MAY GET A FEW INSTITUTIONS WHERE YOU HAVE A GREAT TEAM OF CLINICAL TRANSLATIONAL SCIENTISTS THAT CAN COME UP WITH THE GREAT QUESTIONS FOR THAT CENTERS CORE THEN IT'S LIMITING TO THAT INSTITUTION. SO WONDER IF A BETTER MODEL IS TO CREATE PHENOMENAL SUPER CORE FACILITIES THAT ARE BROADLY SHARED ACROSS THE NCI COMMUNITY AND OPEN THEM UP TO EVERYONE. SO I WOULD LIKE TO HEAR YOUR COMMENT ON THAT. >> WITH REGARD TO SUPER CORE, THIS IS SORT OF LIKE THAT IN ESSENCE, THAT IS THE CONCEPT EXCEPT THAT A CORE CAN NOTES A SERVICE -- DA NOTES A SERVICE COMPOUND, PEOPLE DELIVER A SAMPLE AND PICK UP THE DATA, THAT'S NOT WHAT WE WANT HERE. WE WANT THE CANCER BIOLOGY TEAMS TO WORK LOCK STEP OVERTIME AND DECIDE ITERATIVE CYCLE OF INCREASING SOPHISTICATION IS KEY. THE OTHER POINT ON THE COMMUNITY ENGAGEMENT PART I THINK WITHOUT THAT, AS CHRIS NOTED HAVING A LARGE COLLECTION OF RO1s DOESN'T SUBSERVE PILOT PROJECT CONCEPT WHERE PEOPLE COME IN WITH NASCENT IDEAS, THAT CAN BE VETTED AND PERHAPS DEVELOP INTO SOMETHING GREATER, WHAT THEY ENVISION ONCE THEY GET TYPE THIS CIRCLE OF PEOPLE. WE CAPTURE THE HIGHEST LEVEL OF INNOVATION BUT WE HAVE A WIDE NET BECAUSE DIFFERENT PEOPLE CAN COME TO THE DOOR. >> EVERY FUNDED CENTER WOULD DO ENGAGEMENT THAT INCLUDES BROADLY ACROSS ALL THE NCI INITIATIVES AND CENTERS? >> YES, BUILT INTO THE FOA AND IT WOULD BE A SPECIAL -- >> NOT SOMETHING STATIC. I TAKE GREAT CORES CONTINUALLY INNOVATION THEIR SIGNS AND INFRASTRUCTURE. I AGREE WITH YOU, I ACCEPT EXPECT THAT THAT WOULD BE THE EXPECTATION. I JUST STILL WORRY THAT THIS MODEL CONSTRAINED. >> WE'LL BUILD IN THE FLEXIBILITY OR ENSURE APPLICANTS UP FRONT HONOR THAT PILOT PROJECT PROCESS AS A CRUCIAL COMPONENT THAT'S A REVIEWABLE ITEM THAT WILL GET THEM HOPEFULLY AWARDED. AGAIN, WE ARE NOT TALKING ABOUT DOZENS AND DOZENS O THESE AWARDS, WE ARE TRYING TO PILOT THIS AS THREE OR FOUR SO I THINK THIS CONCEPT BECAUSE IT IS DIFFERENT AND DOES HONOR THIS IDEA OF BRINGING IN THE COMMUNITY, IS SOMETHING WE SHOULD TRY OUT. THE ALTERNATIVE IS CONTINUE TO DO WHAT WE DO AND WHAT WE HAVE IS THIS LARGE GAP. >> NICE PRESENTATION, TWO WORDS I KEPT COMING BACK TO. ONE IS COMMUNITY ENGAGEMENT, I WONDER IF THAT MEANS DIFFERENT THINGS ACROSS DIFFERENT SECTORS. THERE'S A CLEAR THEME IS THAT THE CANCER COMMUNITY SHOULD BE ENGAGED IN SETTING RESEARCH PRIORITIES FOR THIS PILOT AMONG THAT GOOD LIST YOU MENTIONED. SECOND COMPONENT OF ENGAGEMENT IS TECHNOLOGY DEVELOPMENT. THAT'S JUST GOOD OLD FASHIONED PRODUCT DEVELOPMENT. THERE'S COMMUNITY AND THINGS, I THINK IT YOU HAVE BEEN NICE TO SEE SOME OF THAT RECOGNIZED IN THE CONCEPT. THE THIRD COMPONENT OF COMMUNITY ENGAGEMENT IS MAKING RESOURCES AVAILABLE. THAT IS WHERE I KEPT WONDERING WHEN THE NCI CANCER IMAGING DATA COMMONS WAS GOING TO POP UPMENT MANY WAYS THAT MEETS SOME OF THESE NEEDS. RATHER THAN BUILDING ISOLATE #-D CENTERS WHAT WE TOLD IMAGING DATA COMMONS IS GOING TO PROVIDE IS SCALED UNIVERSAL RESOURCE. IMAGINE THIS COULD EVOLVE TO A POINT WHERE IMAGING DATA COMMONS INCORPORATES KEY CANCER BIOLOGY COMPONENTS DRIVEN BY A CONSENSUS AMONG COMMUNITY HIGHEST RESEARCH NEEDS ARE. I THINK THIS THERE'S AN OPPORTUNITY IF THAT COULD MATERIALIZE REALLY FILL THE GAPS Y'ALL TALKED ABOUT. >> THANK YOU FOR YOUR COMMENT. WE HAD DISCUSSION ALONG WAY ANT THIS THINK OF IT Z THE BACK END OF THE DATA SIDE OF THIS. AFTER YOU DEVELOPED THE IMAGING INSTRUMENTATION SYSTEMS HOW DO YOU HAND THE DATA. CERTAINLY WE ARE INTERESTED IN INTERFACING WITH OTHER NCI EFFORTS IN DATA SIDE OF IT. MY COLLEAGUES SHANNON OVER HEREND I TALKED ABOUT IN PARTICULAR THE HUMAN TUMOR ATLAS NETWORK. AND THE TYPE OF THINGS THEY'RE DOING WITH DATA TO INTEGRATE THIS RFA CONCEPT WITH THAT IN TERMS OF HANDLING THE COMPUTATIONAL AND DATA SCIENCE THAT'S NECESSARY >> VERY BRIEF, WE ARE REALLY BEHIND. >> WHEN I HEARD THE WORD COMMENT, MY QUESTION IS HOW DO YOU ENTER FAIRNESS, WE TALK NEW INVESTIGATORS OR INVESTIGATORS IN SMALL INSTITUTIONS. HOW DO YOU MAKE SURE THIS COMMONS AND THIS ENGAGEMENT IS EQUITABLE AND IS OPEN TO EVERYBODY? >> THANK YOU FOR YOUR QUESTION. THE ARC TECH CHU ALLOWS US TO HAVE A STEERING COMMITTEE SO AWARDEES SERVE ON STEERING COMMITTEE SO NO ONE PERSON WOULD DOMINATE. ALSO PROGRAMMATICALLY WE CAN SERVE COMMITTEE TO MAKE SURE IT'S DEMOCK ADVERTISED AND HAVE EXTERNAL ADVISORY BOARD THAT WOULD BE SEPARATED FROM THE STAKEHOLDERS WHO CAN ALSO HELP ADVISE AND GUIDE IN THE SELECTION PROCESS. SO THOSE ARE CRITICAL FEATURES, THAT WOULDN'T BE POSSIBLE THROUGH NORMAL UR MECHANISMS THAT WE HAVE. >> OKAY. JUST ONE LAST COMMENT. I THINK ONE OF THE THINGS SUBCOMMITTEE TALKED ABOUT QUITE A BIT IS THIS ISSUE OF HOW BROAD CANCER CELL BIOLOGY OR CANCER BIOLOGY COMMUNITY CAN GAIN ACCESS TO THESE EXCEPTIONALLY HIGH-TECH AND SPECIALIZED IMAGING RESOURCES THAT WE TALKED ABOUT TODAY. AND WE I THINK ALL AGREED THIS MECHANISM WHICH CREATES A HUB THAT BRINGS TOGETHER THE PLACE WHERE TECHNOLOGY EXIST WITH REAL CANCER BIOLOGIST WITH MEANINGFUL QUESTIONS AS FOUNDATION BUT LAYERING ON TOP OF THIS, THIS COMMUNITY ENGAGEMENT MECHANISM THAT ALLOWS HUB TO REACH OUT BROADLY ACROSS THE CANCER COMMUNITY IN THE COUNTRY, WAS A VERY CREATIVE APPROACH. AND ONE THAT REALLY HELPS TO ADDRESS THE AIR OF GAP AND OPPORTUNITY -- AREA OF GAP AND OPPORTUNITY. >> RESPONSE TO CHERYL AND FOLLOWING UP MARY, THIS WILL BE THE LAST COMMENT. WE DID TALK ABOUT THE NATIONAL LAB, CHERYL, AS BEING POTENTIAL PARTNERS IN THIS PROGRAM. AMEND THAT IS TOTALLY POSSIBLE. SO COULD BE THE NATIONAL LABS LOCATED NEAR YOU ENTERACT WITH ACADEMIC GROUP SOMEWHERE TO DO THIS. AND THEN THAT WOULD PROVIDE ACCESS THAT PEOPLE HAVE TALKED ABOUT, TO MANY INVESTIGATORS. JUST LIKE -- >> WE CAN PROBABLY CONTINUE DISCUSSIONS OFFLINE UNLESS -- >> LIVING IN THE NATIONAL LAB WORLD IS WHAT MARY SAID OFTEN, THERE'S THE TAIL WAGGING THE DOG. SOMEBODY DEVELOPS A GREAT TECHNOLOGY THEN HUNT AROUND FOR APPLICATION. SOME THE KEY SUCCESS HERE IS THAT INTEGRATION BETWEEN BIOLOGIC CLINICAL COMMUNITY AND -- I LIKE THIS CONCEPT, I JUST THINK THE KEY AND SUCK OASES OF THIS PROGRAM SUCCESS OF THIS PROGRAM WILL BE ENGAGEMENT PIECE HOW YOU DO IT. NOT SURE WHAT IS POSED IS NOT GOING TO WORK, THINK ABOUT THAT MORE AND IT WOULD BE MORE COMFORTABLE. >> SO WE NEED TO -- WE HAD A MOTION TO APPROVE AND WE NEED TO GET A VOTE NOW. SO ALL IN FAVOR. AGAINST. EILEEN AGAIN. >> EILEEN YOU VOTE TO DISAPPROVE? >> YES. >> YOU VOTE TO APPROVE OR DISAPPROVE? >> OKAY. >> ALL RIGHT. >> THANK YOU. >> WHILE CHANGING I'LL MAKE A REMARK. WE'RE GOING TO BE REALLY LATE IF WE DON'T TIGHTEN UP. YOU HAVE THREE OPTION, KILL IT NEVER HAVE IT COME BACK, ALMOST NEVER HAPPENS BUT YOU CAN DO THAT. WE LIKE IT BUT NOT SO MUCH TO APPROVE IT TODAY, SUGGEST SIGNIFICANT REVISION AND HAVE IT COME BACK. WE LOVE IT AND WANT SMALL TWEAKS. IF YOU'RE ADVOCATING, LET'S DO THOSE COMMENTS BY EMAIL. LAUDABLE DISCUSSION THAT WE WILL NOT BECAUSE TO OUR COMPRESSED SCHEDULE. IF YOU HAVE OBJECTIONS PLEASE LET THEM BE KNOWN. >> INTRODUCE YOU TO NED'S CONCEPT, CONSENT PRESENTERS, PRESENTATIONS IN TEN OR 15 MINUTES. >> NCI STAFF TIGHTEN YOUR PRESENTATIONS TOO. >> YES. YES. >> SO WE'LL MOVE NOW TO THE SECOND NEW CONCEPT, MOLECULAR AND BIOLOGICAL EFFECT OF HIGH LINEAR ENERGY TRANSFER HIGH LET RADIATION EXPOSURE. WE IT WILL BE PRESENTEDDED BY JEFFREY BUCHSBAUM, MEDICAL OFFICER, CLINICAL RADIATION ONOLOGY BRANCH, DIVISION CANCER TREATMENT DIAGNOSIS WHO WILL PRESENT THE CONCEPT. JEFF. >> TRY TO KEEP THIS TIGHT. COUPLE OF THINGS TO GET ON THE TABLE BEFORE I FORGET TO GET THEM ON THE TAUGHT, THE MOST IMPORTANT PART OF -- OPT TABLE THE MOST -- ON THE TABLE, THE MOST IMPORTANT PART IS SIT ESTEEM PRESENTATION, A PRESENTATION BETWEEN DCTD AND DCB, DIVISION OF CANCER TREATMENT AND PIOLOGY AND DIVISION OF CANCER BIOLOGY THAT'S CRITICAL, LEADERSHIP AT BOTH DIVISIONS HAS BEEN HIGHLY SUPPORTIVE. INDIVIDUALS INVOLVED IN THIS ARE NOT JUST MYSELF, ERIC BURNHART RETIRED AS BRANCH CHIEF AND THAT GROUP RRB RATIO RESEARCH PROGRAM DID HEAVY LIFTING. (INDISCERNIBLE) ONE OF MY COLLEAGUES IS A CHEMIST AND PHYSICIST IS EXPERT AND RICHARD IS A DNA EXPERIMENT AND LARGE GROUP OF PEOPLE NO ON THIS SHEET HELPED US. THE I A DRESS SOME OF THE ISSUES BROUGHT UP, SO I DON'T AVOID OR FORGET. THIS IS A -- THE PURPOSE OF THIS PRESENTATION IS RADIATION BIOLOGY, DATA AND NEW SPACE BEFORE WE START EMPLOYING THAT RADIATION ON PATIENTS. TO UNDERSTAND BIOLOGY FUNDAMENTALLY IS SURVIVORSHIP ISSUE, IF YOU USE TREATMENT ON THE RIGHT PATIENT AND AVOID RIGHT PATIENT TO AVOID, YOU HAVE A VERY DIFFERENT SURVIVORSHIP MODEL THAN YOU DO IF IGNORANT OF BIOLOGY GOING FORWARD. SECONDLY, THIS IMPACTS MOST OF THE NCI SPACE, BIOLOGY IMPACTS IMAGING WE HAVE SBIR RFA LOOKING AT RADIATION BIO SENSORS ALLOWING US WE HOPE TO GET REAL TIME DATA ABOUT THE BIOLOGY OF TREATMENT DURING TREATMENT USING NANOPARTICLES. THIS CAN IMPACT RADIATION EPIDEMIOLOGY, AND FUNDAMENTALLY THE DEVELOPMENT OF NEW DRUGS TO ESSENTIALLY FACILITATE USE OF THESE NEW BIOLOGICAL PATHWAYS AND DATA TO OPTIMIZE RADIATION AND CANCER TREATMENT FOR OUR PATIENTS SO WHAT IS HIGH LINEAR ENERGY TRANSFER RADIATION THERAPY? GENERALLY MORE BIOLOGICALLY EFECTIVE MEANING THE SAME QUOTE DOSE KILLS MORE CELLS. HAVE TO BE MORE EFFECTIVE IN SOME CASES SOME TYPES OF CANCER MORE DAMAGING TO DNA. LESS THAN ACTIVE HYPOXIA, THE AREA RADIATION ONCOLOGIST CONSIDERS MIDDLE TUMOR, THE DEPICTION OPT RIGHT IS A CARTOON. LOW LET RATIO THERAPY THOUGH YOU CAN HAVE A VERY FAST PARTICLE BEGINNING OF A PARTICLE BEAM CONSIDERED LOW LET IN PERFORMED PROTONS AS SLOWS DOWN OR IN THE CASE OF CARBON IONS YOU GET HIGH LET RADIATION. AS THE PARTICLE SLOWS DOWN IT'S MORE EFFICIENT DELIVERING DAMAGING ENERGY TO THE DNA SUBSTRATE SO MORE EFFICIENT. GIVING THE ENERGY TO THE TARGET AS IT SLOWS DOWN THE CASE OF PARTICLE THERAPY. ADDITIONALLY, THIS IS NOT SOMETHING YOU IMMEDIATELY THINK IS ONLY FOR GIGANTIC MONSTER CENTERS WHICH IS A SLIDE FOLLOWING THIS, I O LESS SOMETHING USED FOR ALPHA PARTICLE THERAPY AND RADIO PHARMACEUTICALS SO THE SYSTEM DEMOCRATIZED IN THE SENSE DELIVERED IN THE COUNTRY THAT HAS NUCLEAR MEDICINE DEPARTMENT. JUSTIFICATION FOR THIS PROPOSAL, INTEREST IS HIGH, AND HIGH NO PUN INTENDED, HIGH LET RADIATION FOR THERAPY, THE INFRASTRUCTURE FOR PARTICLE THERAPY CENTERS COSTLY, SO UNDERSTANDING HOW BIOLOGY WORKS PRIOR TO CONSTRUCTION OF CENTERS AND EMPLOYMENT OF THOSE CENTERS IN INITIATION OF TREATMENT TRIALS FOR THOSE CENTERS WOULD BE COST EFFECTIVE IN THE OVERALL NATIONAL PICTURE. THERE'S SIGNIFICANT UNANSWERED QUESTIONS ABOUT THE BASIC CHARACTERISTICS OF THE MOLECULAR DAMAGE CAUSED BY HIGH LET THERAPY, REPAIR AND CELLULAR RESPONSE NOT ONLY IN THE TUMOR BUT IN THE NORMAL TISSUE. BETTER UNDERSTANDING OF THE BASIC BIOLOGY OF HIGH LET RADIATION IS ESSENTIAL TO INFORM FUTURE DECISION REGARDING APPLICATION CANCER TREATMENT OF NOTE EDGES AND ENDS OF PROTON BEAMS ARE HIGH LET SO WE'RE DOING THIS TO PARENT POPULATION RECEIVING PROTON THERAPY. BARRIER NUMBER ONE, SPECIALIZED CENTERS. THIS IS SOMETHING TO AVOID GIANT CENTERS ALL OVER THE COUNTRY AND NOT UNDERSTANDING WHAT WE'RE DOING TO OUR PATIENTS. THERE ARE CURRENTLY 11 CLINICAL SITES IN THE WORLD, FOUR IN EUROPE, NINE IN ASIA, NONE IN THE UNITED STATES. BARRIER TWO, LACK OF UNDERSTANDING OF HOW HUMAN CANCER CELLS RESPOND TO THERAPEUTIC LEVELS OF HIGH LET RADIATION. HOW DO TISSUES CELLS AND ORGANELLES AND MACRO MOLECULES RESPOND. AS INTERESTING SIDE LIGHT AFTER WE HEARD PHYSICAL MEDICINE THINGS, FROM PRIOR TWO SPEAKERS AGO THOSE MODELS EMPLOYED IN THESE STUDIES. ARE THERE DIFFERENCES IN TUMOR VERSUS NORMAL TISSUE, SURVIVORSHIP QUESTIONS ARE DNA PATHWAYS UNDER HIGH -- HOW ARE CELLS STRESSED DEATH AND SURVIVAL PATHWAYS IMPACTED. WHAT IS THE IMPACT ON INNATE IMMUNITY, WE DON'T KNOW THAT. WHAT IS THE EFFECT ON TUMOR IMMUNE MICROENVIRONMENT, WE DON'T KNOW THAT WITH HIGH LET RADIATION THERAPY. IS THERE A DIFFERENT NEOANTIGEN SPECTRUM? HOW CAN HIGH LET AND EFFECTS BE EXPLOITED IN CANCER THERAPY THIS IS AN EXAMPLE OF DNA DAMAGE AFTER HIGH LET RADIOTHERAPY. THIS IS TRANSITION ELECTRON MICROSCOPY, THIS COMES FROM GERMANY, LEFT SIDE IS LOW THERAPY AND EQUIVALENT DOSE TO RIGHT SIDE, THE RIGHT SIDE IS HIGH LET RADIOTHERAPY, THE GREEN DOTS ARE PARTICLES THAT ARE BOUND, GOLD PARTICLES BOUND TO 53 BP 1 AND RED PARTICLES ARE -- THEY ARE GIGANTIC CLUSTERS SOME GO UP TO 60, 50 TO # 0 PARTICLES 53 BP TO #, DIFFERENT BIOLOGY OF REPAIR, COMPLEXITY OF REPAIR AND DAMAGE. YOU GET HETERO CHROMATIN AFTER TREATMENT BY SIX TO 12 HOURS, IT RETAINS HETERO CHROMATIN BIAS COMPARED TO OTHER CELLS. THERE IS A HIGH T SIGNATURE EVIDENCE FOR BUY PHASIC REPAIR, CONFERENCE REPAIR PATHWAYS ARE ACTIVATED THERE'S A LINK TO THE CHECK POINT AND MITOTIC REFULLYCATION. WE HAVE HAD WORKSHOPS WITHIN THE RADIATION RESEARCH PROGRAM AND SOME OTHER PROGRAMS OCCASIONALLY, WORKSHOPS ARE FOLLOWS, FIRST THERE WAS AN RFI. THE INPUT OF PARTICLE INPUT ON PARTICLE BEAM FACILITY FOR RADIO RELATED CANCER THERAPY RESEARCH TWO WERE AWARDED. PLANNING GRANTS TO DESIGN POSSIBLE CANCER CENTERS, POST PLANNING GRANTS REPORTS SUGGEST SIGNIFICANT BIOLOGICAL NEED. WORKSHOPS WORKSHOPS ON CHARGE RADIO BIOLOGY APRIL 16, MECHANISTIC LINKS BETWEEN DNA DAMAGE RESPONSE NETWORK AND IMMUNOGENIC TOXICITY AND TRANSFORM CELLS AUGUST 17 UTILIZING CONSEQUENCES OF RADIOTHERAPY AND DEVELOPMENT OF NEW TREATMENT APPROACHES SEPTEMBER 17. IMMUNOBIOLOGY RADIOTHERAPY 17 WORKSHOPS AND TARGETED RAY OWE KNEW COLLIE TIDE THERAPY NOVEMBER 16 AND APRIL 18. RESEARCH TOPICS OF INTEREST TO PROGRAM, CHEMISTRY OF HIGH LET DAMAGE TO DNA, PROTEINS AND LIPIDS. MACRO MOLECULAR DAMAGE, SIMULATION OF DAMAGE PROPAGATION, MATHEMATICAL COMPUTATIONAL, ET CETERA. BIOLOGY OF HIGH LET DNA DAMAGE REPAIR RESPONSE RECOGNITION AND PROCESSING OF DNA DAMAGE INDUCED BY HIGH LET RADIATION. TARGETING DNA REPAIR PATHWAYS AFTER HIGH LET RADIATION IMPACT ON CELL INNATE IMMUNITY. IN OTHER WORDS, WHAT DO WE DO IN TERMS OF PORTFOLIO WITH HIGH RADIOTHERAPY, NOT ASSUMABLE, NOT KNOWN THE SAME DRUGS OPERATE THE SAME FASHION IN THIS CONTEXT. IMPACT OF HIGH LET RADIATION THERAPY ON TUMOR VERSUS NORMAL TISSUE, IE SURVIVORSHIP, AS A RADIATION ONCOLOGIST WHEN I TREAT WITH PROTON THERAPY EVERY PATIENT IS SURVIVORSHIP PROBLEM. IF I CURE THAT PATIENT I'M LEFT WITH A PATIENT WITHOUT AS MUCH BIOLOGICAL DATA WHAT THAT TREATMENT DID TO THAT PATIENT AS WITH PHOTON THERAPY. CANCER -- THIS IS EXACERBATED IN HIGH LET CONTEXT. CANCER CELLS STRESS RESPONSES INTRACELLULAR DAMAGE SIGNALING PATHWAYS MITOCHONDRIAL EFFECTS, CELL DEATH PATHWAYS. IMPACT OF HIGH LET RATIO THERAPY ON IMMUNE RESPONSE, YOU DON'T KNOW MUCH ABOUT THIS, WE'RE CURIOUS ABOUT THE NEOANTIGEN SHIFT IN IMMUNE MICROENVIRONMENTS. THERE ARE SOME DATA WE DON'T HAVE A LOT OF DATA. THE PROPOSALS MUST SHOW RELEVANCE TO CANCER THERAPY THAT INCLUDES STUDY OF PARTICLES FROM HELIUM TO CARBON. THIS IS NOT MEANT TO STUDY PROTONS. THE PROTON ARM IS CONTROL ARM, ONE CONTROL ARM ON EXPERIMENTAL THERAPY, NOT JUST PROTON THERAPY, OTHER THINGS INCLUDING ALPHA THERAPY PHARMACEUTICALS. ANYONE CAN PRODUCE THIS IN THEIR LAB THEORETICALLY. NIH PORTFOLIO, THERE'S 80 APPLICATIONS UNRELATED TO THIS TOPIC ACROSS THE ENTIRE NIH, MAJORITY STUDYING TARGETED RADIONUCLIDE THERAPY, THERE'S TREMENDOUS WORK IN TARGETED RADIONUCLIDE THERAPY, SIGNIFICANT WORK 12 WERE FUNDED. 59. 14 APPLICATIONS -- INCLUDING PARTICLE B MODELING AND DNA DAMAGE REPAIR, THESE THREE WERE FUNDED. AS NOTED EARLIER. ADDITIONALLY HAVE A CONTRACT AT PANCREATIC CANCER, PHASE 1 RUN IN TRIALS CLOSING SOON, DATA ARE SOON TO BE PUBLISHED AN ANTICIPATED PHASE 3 TRIAL LOOKING AT DIFFERENT FRACTIONATION SCHEDULES, I DON'T KNOW THE DETAILS OF PHASE 3, IT'S STILL BEING DRAFTED. NONE OF THE FUNDED APPLICATIONS DEALT WITH THE UNDERLYING MECHANISMS OF HIGH LET INDUCE CELL DEATH OR MECHANISM OF RESISTANCE OF THESE CELLS TO CELL DEATH. CONCEPT PROPOSAL FOA. REQUEST FOR APPLICATION. EXPERTISE IN REVIEW PANEL FOR PARTICLE BEAM RADIATION, DNA DAMAGE REPAIR AND CELL PIOLOGY, WE NEED SCIENTIFIC REVIEW OFFICER AND PROGRAM COORDINATING REVIEW ORIENTATION TO THE GOALS DURING THAT SESSION OF THE REVIEW. THERE HAS TO BE REVIEW CRITERIA. WE WILL INCLUDE RO1, WE REQUEST RO1 AND R21. MULTI-PI REQUIREMENT WITH CLINICIAN OR CLINICAL PHYSICIST AND SCIENTIST COLLABORATION TOO COMPLICATED FOR ONLY INDIVIDUAL. PHARMA COMPONENTS ARE ENCOURAGED. ON THAT NOTE AS I NOTED NO U.S. FACILITY, ALL THE CURRENT CLINICAL CENTERS ARE FOREIGN. YOU'RE INVESTING IN DCTD LEADERSHIP, IN A TRIP THE DA ARM GERMAN NATIONAL CENTER BASE IN HEIDELBERG TEAMS OF INDIVIDUALS WITH EXPERTISE TO STAY BROOK HEIGHTH BEAM IN NEW YORK IN APPROXIMATELY FROM 17th THROUGH # 1st OF DECEMBER LED BY ONE OF MY COLLEAGUES IN RRP. TO EVALUATE WHETHER OR NOT THAT BEAM TOLERATE FOR USE OF THESE PURPOSES FOR THIS RFA IF BROOK HAVEN U.S. BEAM IS OF QUALITY OF A QUALITY TO ALLOW QUALITY RESEARCH. TIME LINE, WE OPENED IN 19 RUNNING THROUGH 2021, THREE YEARS, ANTICIPATE FIRST APPLICATIONS, 2020, ENDING IN 2022. WE WANT FIVE RO1 AND 2 R # 1EST PER YEAR. STANDARD RECEIPT DATES. USING THE RO1 MECHANISM BECAUSE DATA ARE SPARSE THAT WE DON'T FEEL IT'S APPROPRIATE YET TO USE UO 1 MECHANISM. ONCE WE HAVE A LARGER DATA SET, WHEN WE SEE HOLES AND GAPS WE THINK AT THAT POINT WE MIGHT BE ABLE TO LOOK AT A UO 1 MECHANISM IN FUTURE. THAT'S IT. THANK YOU VERY MUCH. >> THANK YOU VERY MUCH. SO IN THE INTEREST OF PUTTING US BACK ON TRACK WHAT I SUGGEST IS HEAR NOW FROM THE MEMBERS OF THE SUBCOMMITTEE THE CHAIR WILL SUMMARIZE IT AND THE OTHER MEMBERS ONLY IF YOU HAVE ANYTHING SIGNIFICANT TO ADD PLEASE CHIME IN. BUT WE NEED TO FAST FORWARD. SYLVIA. >> COMMITTEE WITH KEVIN WHITE AND KEITH AND I CAN SAY THAT AFTER OUR REVIEW, I BELIEVE THAT WE ALL FELT THERE WAS NOVEMBER SUBSTANTIVE ISSUES WITH THE CONCEPT, MY OPINION IS I FIND THE CONCEPT COMPELLING FOR REASONS, ERADICATE CANCER IN A DIFFERENT FORM RADIATION MER PI THAT IS CURRENTLY PRACTICED. RFA IS FOCUSED ON BIOLOGY OF HIGH LEG. FOR ITS MORE INFORMED CLINICAL USE, IT PROVIDES AN OPPORTUNITY FOR INTERNATIONAL COLLABORATION WHICH IS APPEALING AND I THINK THE FUNDING MODEL SEEMS VERY REASONABLE, I WELCOME ANY OTHER COMMENTS. >> KEITH, KEVIN >> KEVIN. I'LL MAKE A COUPLE OF BRIEF COMMENTS. AS SYLVIA SAID, I THINK THE COMMITTEE WAS CONVINCED THAT THERE'S A NEED TO MORE DEEPLY UNDERSTAND HOW LET WORKS WHEN IT WORKS AND WITH WHAT CHEMO COMBINATIONS IT WORKS. THERE'S A COUPLE OF ISSUESES THAT CAME UP IN THECAL. ONE POSITIVE -- THING WE FOUND VERY POSITIVE ABOUT WHO ARE CONCEPT ON THE CALL DIDN'T MENTION HERE IS IDEA OF BUILDING OUT BIOMARKERS FOR IMAGING MOLECULAR BASE THAT MIGHT BE USED TO ENHANCE DOSING SCHEDULES. SO THAT WAS VERY INTERESTING PART OF THE PROPOSAL WORTH MENTIONING. THE ONE BIGGEST CONCERN I HAD HAS TO DO WITH AVAILABILITY OF THE FACILITIES. NEEDED TO COMPLETE THE WORK. I KNOW HAVING DISCUSSIONS WITH BROOK HAVEN, SO FORTH BUT THIS IS SOMETHING THAT OBVIOUSLY NEEDS TO BE IN PLACE BEFORE YOU DO BASIC SCIENCE PART OF THIS. THE FLIP SIDE OF THAT IS YOU DO HAVE 11 SITES AROUND THE WORLD, ENCOURAGING THE COLLABORATION WITH ENTITIES. I BELIEVE THAT WE MAKE APPLICATION POOL MUCH STRONGER OR THINKING YOU COULD MAKE OVERALL PROGRAM MORE EXCITING. AND APPROXIMATELY CABLE IF YOU ENCOURAGE NOT ONLY -- APPLICABLE IF YOU ENCOURAGE THE USE OF SYNTHETIC, GOING TO BROOK HAVEN AND IRRADIATING YOUR BIOMATERIALS FROM YOUR PDX MODEL BUT GETTING PATIENTS MATERIALS TO EXTENT YOU CAN GET BIOPSIES FROM PATIENTS BEING TREATED THAT ARE ON CLINICAL TRIALS, IN THESE FOREIGN SITES. SO THOSE ARE MY MAJOR QUESTIONS. >> TWO QUICK HIGH LEVEL COMMENTS. CONSENSUS BIG UNMET NEED ON THE KNOWLEDGE SIDE AND THIS IS A RELATIVELY SMALL ASK. THEN I GUESS THE OTHER POINT THIS IS NOT ABOUT PROTON BEING RADIOTHERAPY, THAT'S RELEVANT PRECEDENT FOR COMMITTEE TO BE MINDFUL OF, PROTON RADIOTHERAPY CLINICALLY AND ARGUABLY COMMERCIALLY GOT AHEAD IN TERMS OF APPLICATION, AND CONSUMPTION OF RESOURCES IN ADVANCE OF REALLY A DEEP SCIENTIFIC UNDERSTANDING. SO I SEE THIS PROPOSAL IS BEING ONE TO TRY TO WALK AWAY, IT RATING THAT MISTAKE WITH OTHER FORMS OF RADIATION. >> THANK YOU. SYLVIA, MAKE A MOTION. >> MOTION TO APPROVE. >> SECOND. >> SECOND. >> DISCUSSION. COULD WE HAVE QUICK CLARIFICATION, I HAVE THE ISSUE, I DON'T HEAR THE CLEAR COMMITMENT OF THE SITES TO THE PROJECT, IS THAT SOMETHING YOU NEGOTIATE, YOU DON'T THINK IT'S A PROBLEM, CAN YOU CLARIFY THAT FOR US? >> YOU MEAN INTERNATIONAL SITES? >> I MEAN YOU TALK ABOUT A BROOK HAVEN DISCUSSION, DOESN'T SOUND LIKE A COMMITMENT TO ME AND I DON'T KNOW THAT THE INTERNATIONAL SIDES ARE WILLING& TO PARTS PIT IN RESEARCH, CAN YOU SPEAK TO THAT? >> I CAN ACTUALLY CHIME IN ON THAT. FOR THOSE OF US WHO WORK IN THIS SPACE, THIS IS EXTREMELY IMPORTANT AREA FOR RESEARCH, THE TECHNOLOGY WAS INVENTED AT UC BERKELEY. THEN DISSEMINATED TO THE REST OF THE WORLD SO YOU CAN GET IN CHINA, YOU CAN GET IT IN JAPAN GERMANY AND IT ITALY BUT NOT IN THE i. ALL THOSE INVESTIGATORS LOVE TO COLLABORATE WITH US IN RESEARCH ON THIS SPACE. SO THERE'S NO QUESTION THERE'S SOME OF US THAT ARE WORKING IN THIS AREA, WAIF JOINT ENTERNATIONALITY MEETINGS. ALL THE SITES COMMITTED TO THIS AREA. >> DO WE HAVE A MECHANISM TO FUND THE JOINT COLLABORATION? 'S WHAT I'M ASKING. >> WE HAVE -- THERE ARE MECHANISMS. THERE COULD BE MORE. >> STANDARD RO1 ALLOWS INTERNATIONAL COLLABORATION IN STANDARD MECHANISM AND HAVE VIEW PANELS ARE IN MY EXPERIENCE EXCELLENT AT FILTERING THROUGH THE GOOD AN BAD AND I HAVE SET FOOT IN MAYBE 80% CENTERS OF NOTE. ALL BIOLOGIST WILL BE WILLING COLLABORATORS BUT I CAN'T INITIALLY SPEAK TO THAT IN IN A CONTRACTUAL FASHION BUT I THINK THAT THERE IS A HUNGER TO DO THE SCIENCE. >> ONE MORE POINT ABOUT THE AVAILABILITY OF THE TECHNOLOGY, CATCH 22 SITUATION. THERE'S NO RESEARCH INFRASTRUCTURE SO NOBODY WANTS TO SPEND $300 MILLION TO BUILD FACILITY FOR WHICH THERE'S NO FUNDING TO SUPPORT RESEARCH. IF YOU BUILD IT THEY WILL COME, IF YOU FUND RESEARCH AND HIGH LET RADIATION, THAT WILL HELP ENCOURAGE OTHER PEOPLE TO PUT UP THE MONEY NECESSARY TO BUILD FACILITIES. >> ANY FURTHER DISCUSSION? IF NOT, MOTION WAS TO APPROVE. I WILL TAKE A VOTE. ALL IN FAVOR. DISAPPROVALS? DEFER? OKAY. UNANIMOUS. WE'LL MOVE NOW TO THE THIRD NEW CONCEPT. INFORMATIC TECHNOLOGY FOR CANCER RESEARCH, IPCR. IT WILL BE PRESENTED BY JULIE KLEMM, ACTING DIRECTOR CANCER INFORMATIC BRANCH CENTER FOR BIOMEDICAL INFORMATICS AN INFORMATION TECHNOLOGY. JULIE. >> GOOD AFTERNOON. TODAY I WILL TALK MOTIVATION AND ACCOMPLISHMENTS OF THE INFORMATICS TECHNOLOGY FOR CANCER RESEARCH PROGRAM AS FUNDED THROUGH PROGRAM ANNOUNCEMENTS. THEN TALK PROPOSAL TO CONTINUE AND EXPAND THE PROGRAM THROUGH RFAs. THE ITCR PROGRAM IS A TRANSNCI PROGRAM THAT SUPPORTS INVESTIGATOR INITIATED INFORMATICS TECHNOLOGY DEVELOPMENT, THAT'S DRIVEN BY CRITICAL NEEDS IN CANCER RESEARCH. AND PROGRAM IS PLAYED AN IMPORTANT ROLE OF CONNECTING INFORMATICS TECHNOLOGY DEVELOPMENT WITH CANCER RESEARCH ACROSS NCI PROGRAMS. THE PORTFOLIO TODAY SPANS SEVERAL SCIENTIFIC DOMAINS INCLUDING GENOMIC VISUALIZATION AND ANALYSIS MEDICAL IMAGING ANALYSIS PATHWAY DATA EXCHANGE MINING THE EHR SO FORTH. ALL THE TOOLS DEVELOPED THROUGH ITCR ARE OPEN SOURCE AND ALL FREELY AVAILABLE TO ACADEMIC AND OTHER NON-PROFITED RESEARCHERS. THE PROGRAM PLAYS IMPORTANT EMPHASIS ON BROAD DISSEMINATION ON RESOURCES GENERATED THROUGH THE PROGRAM. IPCR PLANNING FOR PROGRAM ORIGINATED IN 2011 AND THE INITIAL PROGRAM ANNOUNCEMENTS RELEASED IN SEPTEMBER 2012. THE PROGRAM WAS THEN RENEW IN 2015 AND NEW PROGRAM ANNOUNCE MENTS RELEASED IN AUGUST 25015. IN 2012 AT THIS TIME THERE WAS NO NCI WIDE PROGRAM TO SUPPORT INVESTIGATOR INITIATED INFORMATICS TECHNOLOGY THOUGH THERE'S DISCONNECTED INITIATIVES FOR SUPPORTING INFORMATICS TECHNOLOGY SO I TCR WAS INITIATED TO FILL THAT GAP. SINCE INCEPTION THE PROGRAM HAS HAD SEVERAL IMPORTANT IMPACTS AND ACCOMPLISHMENTS. FIRST AND FOREMOST THE PROGRAM HAS SUPPORTED THE BROAD DEVELOPMENT INFORMTICS TECHNOLOGY RESOURCES, ACROSS THE CANCER RESEARCH CONTINUUM. THE RESOURCES DEVELOPED ARE SOME OF THE MOST WIDELY USED SOFTWARE TOOLS IN CANCER RESEARCH. THE TABLE ON THIS PAGE SHOWS TON OF HIGHLY USED RESOURCES SUPPORTED THROUGH PROGRAM. IN ADDITION, WE HAVE ALSO PLAYED PARTICULAR EMPHASIS ON INTEROPERABLE TOOL DEVELOPMENT, PROVIDING TRAINING FOR NCI INTRAMURAL SCIENTIST, SUPPORTING INFORMATICS NEEDS OF SPECIFIC SCIENTIFIC PROGRAMS AND ALSO SUPPORT THROUGH ITCR LED TO IMPROVE ADOPTION AND CITATION OF THESE TOOLS AND ALSO THROUGH EMPHASIS ON OUTREACH AND TRAINING BY INVESTIGATORS. AS I HAVE SAID, WE PLACE A HIGH EMPHASIS ON COLLABORATION AND OUTREACH, COLLABORATION AMONG IPCR INVESTIGATORS ARE SUPPORTED THROUGH BUDGET SET ASIDES AS WELL AS ADMINISTRATIVE SUPPLEMENTS. GRAPH ON THE SLIDE DEPICTS THE CONNECTIVITY AMONG TOOLS IN THE ITCR PROGRAM WHERE TOOLS ARE REPRESENTED AS GRAY OVULES EXISTING CONNECTIONS DEPICTD WITH THE ORIGIN LINES, THOSE UNDER DEVELOPMENT IN BLUE AN THOSE PLANNED ARE DEPICTED BY DOTTED LINES. WE MAINTAIN A CATALOG OF TOOLS THROUGH THE PROGRAM ALONG WITH SHORT INTRODUCTORY VIDEOS ON THE ITCR WEBSITE. WE ENGAGE IN SEVERAL OUTREACH OPPORTUNITIES FOR EXAMPLE, LAST YEAR WE PARTNERED WITH AACR CANCER JOURNAL RESEARCH TO PUBLISH SPECIAL ISSUE ON CANCER INFORMAICS THAT FEATURE 27 ITCR TOOLS. SO I TALKED ABOUT THE PROGRAM HIGH LEVEL BUT NOW TALK THREE SPECIFIC EXAMPLES TOOLS DEVELOPED THROUGH THE PROGRAM AND THE IMPACT THEY HAVE HAD. BUT FIRST I WILL TALK ABOUT THE CLINICAL INTERPRETATION OF VARIANT IN CANCER OR CIVIC, THAT'S A TOOL DEVELOPED THROUGH A GROUP AT WASU. THIS IS A CURATED BASE OF CANCER GENOME ALTERATIONS. THERE ARE MANY CONTRIBUTORS OUTSIDE THE PROGRAM TEAM CONTRIBUTING TO KNOWLEDGE FACE AND FOR EXAMPLE, IMPORTANT DONATIONS DATA DONATIONS HAVE BEEN MADE BY ALUMINA AND ASCO. THIS DR. GRIFFITH GROUP COLLABORATED WITH MANY GROUPS WITHIN AND BEYOND ITCR TO PROMOTE ADOPTION AND INTEGRATION OF KNOWLEDGE BASE SO ANNOTATIONS FROM THIS KNOWLEDGE BASE ARE AVAILABLE THROUGH OTHER ANALYTICAL TOOLS. ALSO MENTION THROUGH ADMINISTRATIVE SUPPLEMENT THAT WAS AWARDED THROUGH THE CANCER MOON SHOT, SPECIFIC TEAM IS COLLABORATING WITH INVESTIGATOR TO I ADAPT THIS TOOL TO INFORM DEVELOPMENT OF NEW ULTRA SENSITIVE PLATFORM FOR DETECTION OF CANCER MUTATION. ITCR SUPPORTED SEVERAL TOOLS IN THE AREA OF MEDICAL AND PATHOLOGY. AMONG THOSE IS THE WORK OF JILL'S GROUP AT STONY BROOK. SO DR. SALT'S GROUP DEVELOPED QUANTITATIVE IMAGING PATHOLOGY TOOLS USED TO SUPPORT SEVERAL RESEARCH COLLABORATIONS. THIS GROUP HAS LED THE TCGA ATLAS IMMUNE GROUP SLIDE IMAGING ANALYSIS EFFORT TO IDENTIFY TUMOR INFILTRATING LYMPHOCYTES IN THE SLIDES FROM TCGA TISSUES. ALSO COLLABORATED WITH SEVERAL ITCR GROUPS, FOR EXAMPLE COLLABORATED WITH THE 3-D SLICER PLATFORM INTO CORP RATE TOOLS INTO THIS HIGHLY USED IMAGING PLATFORM TO DISSEMINATE THESE IT CANNOLOGIES. -- THESE TECHNOLOGIES. FINALLY, THIS GROUP WAS ALSO AWARDED MOON SHOT SUPPLEMENT TO COLLABORATE WITH I MAT INVESTIGATOR TO ADAPT THESE TOOLS TO MAP TUMOR ASSOCIATED COLLAGEN. IPCR HAS A STRONG PORTFOLIO OF GENOMICS TOOLS. ONE IS THE TRINITY CANCER TRANSCRIPTOME ANALYSIS TOOL KIT OR C AT THAT TIME THAT SUPPORTED DEVELOPED AND SUPPORTED BY GROUP AT THE BROAD INSTITUTE. SO TRINITY ITSELF SUPPORTS DE NOVO TRANSCRIPTOME ASSEMBLY AND THE EXTENSION SUPPORTED THROUGH ITCR. SPECIFICALLY FOCUSED ON CANCER APPLICATIONS. TRINITY AND TRINITY C PAT HAVE BEEN USED IN SEVERAL HIGH PROFILE CANCERVATION AIMED AT STUDYING TUMOR HETEROGENEITY AND TUMOR MICROENVIRONMENT. THE TOOL IS AVAILABLE BRAND HOSTED BY INDIANA CYBER COMPUTING RESOURCE AND IT'S USE CONTINUES TO INCREASE OVER TIME AS SHOWN IN GRAPHIC ON THE LOWER RIGHT AND THEY GET OVER 2000 USERS PER MONTH. LIKE THE OTHER TWO TOOLS I MENTIONED, THE TRINITY TEAM COLLABORATED WITH SEVERAL INVESTIGATORS WITHIN AND OUTSIDE OF ITCR. TO INTEGRATE THEIR TOOL WITH OTHER ANALYSIS EFFORTS. IN PREPARATION FOR REQUESTING THESE RFAs WE ENGAGE THE IDA SCIENCE AND TECHNOLOGY POLICY INSTITUTED TO CONDUCT EVALUATION OF THE ITCR PROGRAM, AND A KEY COMPONENT OF THAT EVALUATION WAS REVIEW OF THE PROGRAM BY EXPERT PANEL. CONCLUSIONS DRAWN BY PANEL HAVE BEEN IMPORTANT INPUT TO OUR FUTURE PLANS THAT I WILL PRESENT TODAY. THEIR CONCLUSIONS ARE AS FOLLOWS. FIRST INFORMATICS TECHNOLOGY DEVELOPMENT REMAINS A PRESSING NEED IN CANCER RESEARCH. BUT ENHANCEMENTS ARE NEEDED TO FURTHER PROGRAM IMPACT AND INFLUENCE. ADDITIONAL OUTREACH IS NEEDED FOR TOOLS TO BE FULLY INTEGRATED TO THE CANCER RESEARCH COMMUNITY. THEY SUGGESTED THAT NEW FUND MECHANISMS ARE NEEDED TO FOSTER COLLABORATION BETWEEN ITCR TOOL DEVELOPERS AND CANCER RESEARCHERS. AND FINALLY, THEY NOTED THE SUCCESSFUL TOOLS WILL REQUIRE SUSTAINMENT TO REMAIN BOLDER CLASS. SO AS I MENTIONED THESE RECOMMENDATIONS HAVE BEEN FOUNDATIONAL FOR PLANNING FOR THE FUTURE STRUCTURE OF THE PROGRAM I WILL TALK ABOUT ON THE NEXT SLIDE. FIRST WE PROPOSE TO CONTINUE TO SUPPORT TECHNOLOGY DEVELOPMENT THROUGH MECHANISMS THAT HAVE BEEN SUPPORTED THROUGH PROGRAM ANNOUNCEMENTS. THESE ARE R-21 THAT SUPPORTS EARLY STAGE COMPUTATIONAL RESEARCH AND ALGORITHM DEVELOPMENT. UO 1 TO SUPPORT EARLY STAGE SOFTWARE DEVELOPMENT, U 24 TO SUPPORT ADVANCE STAGE SOFTWARE DEVELOPMENT AND SECOND U 24 THAT SUPPORT SUSTAINMENT OF HIGHLY INVOLVED ACCESS TOOLS. IN ADDITION TO TECHNOLOGY DEVELOPMENT ASPECT. WE PROPOSE TO ADD A TRAINING AND OUTREACH COORDINATION CENTER. THIS IS TO ADDRESS THE FEEDBACK THAT ADDITIONAL OUTREACH IS NEEDED FOR ITCR DEVELOPED TOOLS TO BE FULLY INTEGRATED INTO THE CANCER RESEARCH COMMUNITY. WE ALSO PROPOSED TO ADD SET OF COMPETITIVE REVISION APPLICATION S TO RESPOND TO SUGGESTION THAT NEW FUNDING MECHANISMS MAY BE NEEDED TO FOSTER COLLABORATION BETWEEN ITCR TOOL DEVELOPERS AND CANCER RESEARCHERS. AS REMINDER COMPETITIVE REVISIONS ARE SUPPLEMENTS TO ACTIVE GRANTS BUT UNLIKE ADMINISTRATIVE SUPPLEMENTS THESE ARE COMPETITIVELY REVIEWED. SO THE NEXT TWO SLIDES I WANT TO GO INTO MORE DETAIL ABOUT THE TWO NEW COMPONENTS WE ARE PROPOSING. WE ENVISION THE TRAINING AND OUTREACH COORDINATION CENTER, THE MISSION OF THE CENTER WILL BE TO CONDUCT ACTIVITIES THAT ENGAGE RESEARCH AND INFORMATICS COMMUNITIES TO USE AND TO EXTEND ITCR TECHNOLOGIES. ONE OF THE KEY ACTIVITIES OF THE CENTER WILL BE TO PROVIDE IN DEPTH COURSES AND WORKSHOPS ON TOPICS IN CANCER INFORMATICS, INCORPORATING THE ITCR TOOLS AS EXAMPLES OF THOSE TOPICS. SECOND, WE ENVISION THE CENTER WILL ORGANIZE INFORMATICS CHALLENGES AND HACK ON THISES THAT WILL PROVIDE OPPORTUNITIES FOR -- TO EVALUATE OR ADAPT ITCR TECHNOLOGIES TO SPECIFIC RESEARCH NEEDS. AND FINALLY THE CENTER WILL COORDINATE PROGRAM PRESENCE AT CONFERENCES AND TO PROVIDE OUTREACH AT THOSE VENUES AS WELL AS TO COORDINATE ONLINE OUTREACH ACTIVITIES. REVISION TO SUPPORT APPLICATION OF INFORMATICS TECHNOLOGY TO CANCER RESEARCH WOULD BE INTENDED TO ADDRESS CHALLENGES AND APPLYING INFORMATICS TECHNOLOGY DEVELOPED THROUGH ITC R IN SUPPORT OF NCI SUPPORTED RESEARCH. THE KINDS OF ACTIVITIES WE ANTICIPATE THROUGH THESE REVISION ARE ADAPTATION OF ONE OR MORE EXISTING TOOLS TO MEET THE UNIQUE RESEARCH NEEDS OF THAT GRANT. OR GENERATION OF DATA TO SUPPORT APPROPRIATE APPLICATION OF THE INFORMATICS TECHNOLOGY. THESE SUPPLEMENTS COULD SUPPORT INTEGRATION OF INFORMATICS TOOLS TO SUPPORT RESEARCH GOALS OR IN SOME CASES TO SUPPORT SYSTEM INSTALLATION AN CONFIGURATION OF TOOL ADOPTING INSTITUTION. WE REQUEST PROGRAM BE FUNDED THROUGH RFA SO PROGRAM HAS SET ASIDE BUDGET WE ANTICIPATE, WILL PROMOTE CONTINUITY OF THE PROGRAM AND SIGNIFY ONGOING COMMITMENT TO NCI TO INFORMATICS TECHNOLOGY DEVELOPMENT. WE ALSO BELIEVE RFAs WILL INCENTIVIZE APPLICATIONS? CANCER RESEARCH DOMAINS NOT CURRENTLY REPRESENTED IN THE PORTFOLIO. AS WELL AS TO INCENTIVIZE APPLICATIONS FOR THE PROPOSED TRAINING AND OUTREACH CENTER AND TO THE COMPETITIVE REVISION. IN ADDITION, HAVING RFAs WILL SUPPORT THE CONTINUED PEER REVIEW THROUGH NCI DEA AND CREATION OF APPROPRIATE SPECIAL EMPHASIS PANELS TO REVIEW THESE PROPOSALS AND SUPPORT REGULAR ENGAGEMENT AND REVIEW THIS PROGRAM BY BSA. IF APPROVED, WE EVALUATE ON THE FOLLOWING CRITERIA. FIRST DEVELOP TOOLS AN RESOURCES BY RESEARCH COMMUNITY AND CLINICIANS. AS MEASURED THROUGH CITATION OF PUBLICATIONS AND THROUGH TOOL USAGE METRICS. WE MEASURE APPROACHING METHODS COMMUNITY ENGAGEMENT AND DISSEMINATION AND LEVEL OF PARTICIPATION IN THESE SESSION. WE ALSO MEASURE THE LEVEL OF COLLABORATION AMONG TEAMS FUNDED THROUGH ITCR AND/OR PARTICIPATING IN ITCR PROGRAMMATIC ACTIVITIES. FINALLY VERY IMPORTANTLY WE MEASURE IMPACT OF ITCR PRODUCT ON SINING DISCOVERY IN TRANSLATIONAL SCIENCE IN CANCER MANAGEMENT CAPABILITIES. OUR PROPOSED BUDGET FOR THE FIRST YEAR OF THIS PROGRAM WOULD BE 11 MILLION AND THAT WOULD INCLUDE 9.34 MILLION FOR TECHNOLOGY DEVELOPMENT ASPECTS, 600K FOR COMPETITIVE REVISION, AND THE FIRST AWARD OF THE TRAINING OUTREACH COORDINATION CENTER OF 1.05 MILLION. WE REQUEST TWO REISSUANCES AND THOSE WOULD BE APPROXIMATELY 9.94 MILLION BECAUSE TRAINING OUTREACH WOULD BE ONE TIME AWARD. FINALLY I WOULD LIKE TO MENTION NCI BEING TRANS-NIH PROGRAM SUPPORTED THROUGH A VERY DEDICATED TALENTED PROGRAM TEAM ADS SHOWN ON THIS SLIDE AN WHO I REPRESENT HERE TODAY. THANK YOU. PROMOTE USE OF TOOLS AND HAS HAD A SIGNIFICANT IMPACT ALREADY WITHOUT RFA. MAY MAJOR CONCERN WITH THIS PROPOSAL IS THIS IS A NEAR PITTANCE OF WHAT THE PROGRAM SHOULD GET IN FUNDING BUT CURRENT FINANCIAL TIMES PLANT A MUSTARD SEED TO GROW RIGHT DOWN THE ROAD AND CADENCE OF MEMBERS OF THIS GROUP THOUGHT A DOUBLING MIGHT BE A GOOD START TO GROW THAT MUSTARD SEED. >> THANK YOU. ANY OTHER COMMENTS FOR MEMBERS OF THE SUBCOMMITTEE? ALL RIGHT. OKAY. WE HAVE A MOTION. CAN WE HAVE A MOTION >> MOTION TO MOVE ENTHUSIASTICALLY AS EXCEPTIONAL PROGRAM. >> ALL IN FAVOR? ALL RIGHT. UNANIMOUS. ALL RIGHT. THANK YOU. LET'S NOT PUSH OUR LUCK. THE NEXT CONCEPT OPTIMIZING MANAGEMENT AND OUTCOME FOR CANCER SURVIVORS TRANSITIONING TO FOLLOW-UP. THIS IS AN RFA PRESENTED BY DR. MOLLICA PROGRAM DIRECTOR OUTCOMES RESEARCH BRANCH DIVISION OF CANCER CONTROL AND POPULATION SCIENCE, MICHELLE. >> THANK YOU VERY MUCH. THANK YOU FOR THE OPPORTUNITY TO PRESENT THIS RFA CONCEPT IN ADULT, FOCUSED ON ADULT SURVIVORSHIP CARE. THIS WAS A TRANSDCCPS EFFORT AND I WOULD LIKE TO ACKNOWLEDGE THE WORK OF THE MEMBERS LISTED HERE ON THIS FIRST SLIDE. SO THE NCI RECOGNIZES A DEFINITION FROM CANCER SURVIVOR, A DEFINITION FROM CANCER SURVIVOR FROM TIME OF DIAGNOSIS THROUGH THE END OF HIS OR HER LIFE. THE INSTITUTES OF MEDICINE NOW NATIONAL ACADEMY OF MEDICINE POINTED TO A CRITICAL PERIOD FOR CANCER SURVIVORS. THAT IS THE TRANSITION PERIOD IMMEDIATELY FOLLOWING ACTIVE TREATMENT. THIS IS WHEN TREATMENT ENDS AND SURVIVORS ARE FACED WITH LIFE AFTER CANCER. WHILE WE KNOW THIS IS A DIFFICULT TIME FROM RESEARCH ON CANCER SURVIVOR, THIS IS EVIDENT CLINICALLY. SO AS AN ONCOLOGY NURSE I CARED FOR MANY PATIENTS, WHERE THEY HAVE REACHED THE END OF TREATMENT AND ARE UNCLEAR AS TO WHAT HAPPENS NEXT. ONE PATIENT WHO STANDS OUT IN MY MIND WAS OLDER WOMAN WHO WAS COMPLETING THERAPY FOR BREAST CANCER AND AS I ADMINISTERED CHEMOTHERAPY SHE SAID WHAT HAPPENS NOW? WHAT DO I DO NOW? SHE WAS EXPERIENCING PAIN, FATIGUE, NEUROPATHY, DIABETES HAD BEEN EXACERBATED BY HER CHEMOTHERAPY TREATMENT. AND IT WAS VERY CLEAR THAT HER CARE WAS GOING TO REQUIRE COLLABORATION FROM MANY DIFFERENCE TYPES OF PROVIDERS. INCLUDE PRIMARY CARE PROVIDER NOT ENGAGED DURING HER CARE WITH ACTIVE PARTS OF HER TREATMENT, SO THE INSTITUTE OF MEDICINE CALLED FOR COMPREHENSIVE POST TREATMENT SURVIVORSHIP CARE, WITH THAT'S THREE COMPONENTS, SECOND CANCERS SURVEILLANCE AND MANAGEMENT OF THE EFFECTS OF CANCER AND ITS TREATMENT, AS WELL AS HEALTH PROMOTION AND PREVENTATIVE CARE. THESE COMPLEX NEEDS NECESSITATE DELIVERY OF COMPREHENSIVE COORDINATED CARE THAT OCCURS AFTER COMPLETION OF TREATMENT AND OFTEN INVOLVES MULTIPLE PROVIDERS. SO MODEL OF SURVIVORSHIP CARE IS USED TO DESCRIBE DELIVERY OF POST TREATMENT CARE INCLUDING WHAT TYPE OF CARE IS DELIVERED, WHEN AND BY WHOM. AN EXISTING WIDELY USED MODEL INVOLVES ONCOLOGISTS OR OTHER ONCOLOGY HEALTHCARE PROVIDERS FOLLOWING SURVIVORS FOR PROLONGED PERIODS OF TIME. AFTER TREATMENT ENDS. THIS MODEL OF SURVIVORSHIP CARE IS NOT APPROPRIATE FOR ALL SURVIVORS NOR IS THIS SUSTAINABLE GIVEN GROWING NUMBER OF SURVIVORS AND OVERBURDENED ONCOLOGY WORK FORCE. SEVERAL STAKEHOLDERS INCLUDING IOM ASCO AND ONS RECOMMENDED TEAM BASED CONTINUING CARE THAT PROMOTES CROSS SPECIALTY PROVIDER COLLABORATION, PARTICULARLY BETWEEN THE ONCOLOGY SPECIALIST AND OTHER PROVIDERS. TWO EXAMPLES OF THIS INCLUDE THE MULTI-DISCIPLINARY SURVIVORSHIP CLINIC WHERE CARE IS PROVIDED BY SPECIALIZED TEAM IN A SEPARATE CLINICAL AREA, THIS OFTEN OCCURS IN HIGHER RESOURCE SETTINGS AND IS MOST BENEFICIAL FOR HIGHER RISK SURVIVORS. BUT NOT NEEDED FOR ALL SURVIVORS. THE SHARED CARE MODEL IS CONSIDERED OPTIMAL BY MANY, SURVIVORSHIP FOLLOW-UP CARE IS PARTNERSHIP BETWEEN ONCOLOGY SPECIALIST, PRIMARY CARE PROVIDERS AND OTHER SPECIALISTS. SEVERAL CONSENSUS STATEMENTS HAVE ACKNOWLEDGED LOWER RISK SURVIVORS ARE PARTICULARLY BENEFIT FROM SHARED CARE SURVIVORSHIP CARE. THAT INCLUDES EARLY STAGE DIAGNOSES, THOSE WITH LOW RISK FOR RECURRENT OR LATE EFFECTS THOSE WITH MILD OR NO PERSISTENT TOXICITIES. THOUGH THIS IS CONSIDERED BY MANY TO BE OPTIMAL IN REIALIALITY THERE'S CHALLENGES TO IMPLEMENTING THIS MODEL. FIRST UNCLEAR WHO IS RESPONSIBLE FOR SPECIFIC COMPONENTS OF SURVIVORSHIP CARE, THIS IS COMPLICATED BY LACK OF COMMUNICATION AND COORDINATION BETWEEN PROVIDERS. IN ADDITION IT'S NECESSARY TO MAKE SURE PROVIDERS NOT ENGAGED IN ACTIVE COMPONENTS OF CANCER TREATMENT HAVE ADEQUATE ONGOING EDUCATION AND THE KNOWLEDGE TO DEAL WITH THE ADVANCES AND NEW CANCER TREATMENTS. THE SURVIVORSHIP CARE PLAN WHICH IS A DOCUMENT THAT PROVIDES A SUMMARY OF CANCER TREATMENT AND DIAGNOSIS INFORMATION AS WELL AS RECOMMENDATIONS FOR FOLLOW-UP CARE WAS ORIGINALLY ENVISIONED TO BE A TOOL TO AMELIORATE MANY ISSUES. UNFORTUNATELY SURVIVORSHIP CARE PLANS HAVE NOT SHOWN IMPACT ON OUTCOMES AND DEEMED NECESSARY BUT NOT SUFFICIENT. SEVERAL STAKEHOLDERS INCLUDING THE COMMISSION ON CANCER ASCO AND OTHERS SHIFTED FROM SURVIVORSHIP CARE PLANS INTO COLLUDE SURVIVORSHIP CARE PLANS BUT SHIFTING MORE TOWARDS PROVIDING COORDINATED CARE, HIGH QUALITY KARAER THIS THAN JUST PROVISION ON A DOCUMENT. SO OVERALL THE RESEARCH QUESTION THAT NEEDS TO BE ANSWERED IS WHAT ARE EFFECTIVE -- AND EFFICIENT WAYS TO ENHANCE COMMUNICATION ENGAGEMENT AND CARE COORDINATION BETWEEN ONCOLOGY SPECIALISTS AND PROVIDERS NOT INVOLVED IN ACTIVE TREATMENT. TO ADDRESS THIS ISSUE WE ARE PROPOSING AN RFA TO STIMULATE RO1 APPLICATION THAT DEVELOP TEST NEW INNOVATIVE MODELS OF SURVIVORSHIP CARE DELIVERY. HERE WE ARE PLACING A MAJOR EMPHASIS ON FOSTERING GREATER COLLABORATION BETWEEN ONCOLOGY SPECIALISTS AN NON-ONCOLOGY PROVIDERS. WE ARE FOCUSING THIS RFA ON PATIENTS WITH ADULT ONSET CANCERS WHO ARE APPROPRIATE TO HAVE PART OF THEIR FOLLOW-UP CARE TRANSITIONED OUT OF ONCOLOGY. THIS RFA MAY OR MAY NOT INCLUDE SURVIVORS WHO ARE RECEIVING LONG TERM ADJUVANT HORMONAL THERAPY BUT DOES NOT INCLUDE THOSE ON MORE INTENSIVE LONG TERM THERAPY OR METASTATIC DISEASE. I LISTED RESEARCH TOPICS RESPONSIVE TO THIS RFA BUT THOUGHT I WOULD GIVE A SPECIFIC EXAMPLE OF A STUDY CONSIDERED RESPONSIVE. ONE STUDY COULD HAVE THE GOAL ENGAGING PRIMARY CARE PROVIDERS IN FOLLOW-UP CARE AND TEST INTERVENTION FOR PATIENT RANGES FOR GOALS OF CARE VISIT WITHIN THREE MONTHS OF THE COMPLETION OF TREATMENT OR AT A TIME DEEMED APPROPRIATE BY THE ONCOLOGIST. PRIOR TO THAT GOALS OF CARE VISIT, THE PRIMARY CARE PROVIDER WOULD RECEIVE SURVIVORSHIP CARE PLAN, RESOURCES THAT INCLUDE RECOMMENDED SURVEILLANCE AND COMMON SYMPTOMS RELATED TO THE CANCER DIAGNOSIS AND TREATMENT AS WELL ADS EXPLICIT RECOMMENDATIONS FOR THE PRIMARY CARE PROVIDER'S ROLE IN THAT FOLLOW-UP CARE. THE INVESTIGATOR COULD FOLLOW SURVIVORS LONGITUDINALLY TO SEE IF THE RYE MARE CARE PROVIDER IS ENGAGED, IF SPECIFIC ASPECT OF FOLLOW-UP CARE ARE CARRIED OUT AND EXAMINE PATIENT AND PROVIDER EXPERIENCES OF THE CARE. YOU CAN SEE EXAMPLE END POINTS HERE IN THE AREAS OF HEALTHCARE UTILIZATION, QUALITY OF CARE AND PATIENT CENTERED OUTCOMES. TO BE CONSIDERED RESPONSIVE APPLICANTS MUST PROPOSE PROVIDER AND SYSTEM LEVEL HEALTH INTERVENTION CONDUCTED DURING TRANSITION FROM ACTIVE TREATMENT AND INCLUDES AT LEAST ONE PROVIDER NOVEMBER INVOLVED IN ACTIVE TREATMENT FOR EXAMPLE, A P CCP, NURSE PRACTITIONER OR PHYSICIAN ASSISTANT OR OTHER SPECIALIST. INTERVENTIONS MUST FOCUS ON MORE THAN WOULDN'T COMPONENT OF SURVIVORSHIP CARE AND THE INVESTIGATOR TEAM SHOULD INCLUDE ONCOLOGY AND NON-ONCOLOGY PROVIDER. IN ORDER TO ENHANCE FUTURE DISSEMINATION AND IMPLEMENTATION, APPLICANTS WILL BE REQUIRED TO ADDRESS GALLIBILITY SUSTAINABILITY AND TRANSFERABILITY IN THEIR APPLICATIONS. IN ADDITION WE ARE STRONGLY ENCOURAGING APPLICATIONS ON MORE THAN ONE CANCER TYPE, UNDERSERVED POPULATIONS AND SURVIVORRING RECEIVING CARE IN COMMUNITY SETTINGS. APPLICATIONS WILL NOT BE CONSIDERED RESPONSIVE IF THEY PROPOSE OBSERVATIONAL RESEARCH ONLY IF THEY TARGET ONLY THE PATIENT AND SURVIVOR AND DO NOT FOCUS ON A PROVIDER IF THEY PROPOSE EXISTING MODELS OF SURVIVORSHIP CARE OR FOCUS ON PROVISION OF SURVIVORSHIP CARE PLAN ONLY. WE PERFORMED A COMPREHENSIVE PORTFOLIO ANALYSIS OF NIH SURVIVORSHIP GRANTS FUNDED OVER THE LAST FIVE YEARS. OF THE EIGHT GRANTS THAT OCCURRED DURING THIS PERIOD IMMEDIATELY FOLLOWING ACTIVE TREATMENT, ONLY ONE RO1 WAS AWE LINED WITH THE TYPE OF STUDIES WE CONSIDER RESPONSIVE. THAT WAS AN EMR DRIVEN INTERVENTION FOCUSED ON COMPLEX CANCER SURVIVORS IN A SAFETY NET SYSTEM AND FACILITATED TRANSITION BETWEEN PRIMARY CARE AND ONCOLOGY SPECIALTY CARE. WE ARE PROPOSING AN RFA BECAUSE THERE IS A NEED TO PROVIDE A BOLUS OF FUNDING TO SUPPORT PROJECT FOR SEVERAL REASONS. FIRST THE NIH DOES NOT HAVE A ROBUST PORTFOLIO THAT INTERSECTION DURING THIS CRITICAL TIME FOR CANCER SURVIVORS. OUR DIVISION PREVIOUSLY HAD A PROGRAM ANNOUNCEMENT FOCUSED ON SURVIVORSHIP CARE PLANNING WHICH IS LARGELY UNSUCKS ISFUL THOUGH WE HAD OVER 6 -- UNSUCCESSFUL. OVER 60 SUBMITTED NONE FUNDED. WE DID A COMPREHENSIVE ANALYSIS OF APPLICATIONS AND SUMMARY STATEMENTS AND THAT REALLY DEMONSTRATED A NEED TO FOCUS CURRENT RFA ON DELIVERY OF HIGH QUALITY KARAER THIS THAN PROVISION OF A DOCUMENT. IN ADDITION AN RFA WITH SET ASIDE FUNDS IS EFFECTIVE TO INCENTIVIZE SIMULTANEOUS WORK ON THIS COMMON ISSUE AND PROMOTE COLLABORATION ACROSS PROJECTS. THIS WILL BE ENHANCED BY HOLDING YEARLY GRANTEE MEETINGS WHO SHARE KNOWLEDGE, PROGRESS AND ALLOW FOR RAPID TRANSLATION OF RESULTS. TO DO THIS WORK WE ARE REQUESTING $5 MILLION PER YEAR IN TOTAL COST TO SUPPORT UP TO SIX RO1 GRANTS, THE TOTAL COST OF THIS INITIATIVE WILL BE UP TO 25 MILLION OVER FIVE YEARS. WE ANTICIPATE THIS RFA WILL HAVE SUBSTANTIAL IMPACT IN SEVERAL AREAS. FIRST IT WILL INCREASE THE DEVELOPMENT AND IMPLEMENTATION OF YOU KNOW INVESTIGATIVE MODELS OF SURVIVORSHIP CARE DELIVERY. IT WILL DEMONSTRATE EVIDENCE OF RESEARCH PRODUCTIVITY AND COLLABORATIONS AMONG SCIENTISTS FROM DIFFERENT SITES AND DISCIPLINES. AND TESTING OF THESE MODELS COULD OCCUR IN VARIETY OF CANCER POPULATIONS, AND CARE SETTINGS. FINALLY WE WANT TO THANK THE BSA SUBCOMMITTEE THAT WAS ASSIGNED TO REVIEW THIS APPLICATION, SHARE DR. CAROL FARRON AND DR. GRAHAM AND DR. ROBEISON THIS PRESENTATION INCORPORATED SEVERA RECOMMENDATIONS BASED ON FEEDBACK FROM THE SUBCOMMITTEES REVIEW AND YOU CAN SEE THE MORE SUBSTANTIVE CHANGES HERE. FIRST WE HAVE EXPANDED THE FOCUS OF THIS RFA TO FOCUS ON NEW INNOVATIVE MODELS OF SURVIVORSHIP CARE DELIVERY, CLARIFIED FOCUS OF AGE OF SURVIVOR OF ADULT ONSET CANCER. WE ARE STRONGLY ENCOURAGING APPLICATION ON MORE THAN ONE CANCER TYPE TO BE ABLE TO FUND BROAD NUMBER OF CANCER TYPES FOR THIS RFA AND FINALLY REQUIRING APPLICANTS TO ADDRESS FUTURE SCALABILITY SUSTAINABILITY AND TRANSFERABILITY. IN SUMMARY, CARE FOR CANCER SURVIVORS IS COMPLEX AND OFTEN REQUIRES MANY DIFFERENT PROVIDERS THE PROPOSED RFA ADDRESSES PRIORITIES ACROSS THE NIH AND AMONG EXTERNAL STAKEHOLDERS AND HAS THE POTENTIAL TO CHANGE FACE OF SURVIVORSHIP CARE WITH OVER 16 MILLION SURVIVORS AND THIS NUMBER ONLY GROWING THERE IS A VITAL NEED TO PROVIDE HIGH QUALITY SURVIVORSHIP CARE, THIS RFA PROVIDES THAT FOUNDATION TO IMPROVE OUTCOMES DURING THIS CRITICAL PERIOD. THANK YOU. >> GREAT COVERAGE OF THIS IMPORTANT TOPIC. SO SUBCOMMITTEE MEMBERS ARE KARL GRAHAM AND LS, CAROL IS CHAIR -- CAROL, WHY DON'T YOU FILL US IN. >> THANK YOU, MICHELLE. OUR GROUP WAS VERY ENTHUSIASTIC ABOUT THIS. CLEARLY THERE'S A NEED FOR BETTER SURVIVORSHIP CARE. THAT'S THROUGHOUT THE ENTIRE COUNTRY. WE HAVE A REALLY HUGE PROBLEM WITH THIS. THE SURVIVORSHIP CARE PLANS HAVEN'T DONE TRICK. WE KNOW THIS AND THERE'S RECENT PUBLICATIONS DOCUMENTING THIS VERY WELL, THERE'S PROBLEMSES WITH HAND OFF, THERE'S PATIENTS DROP AND THEIR NEEDS ARE HUGE. SO THIS IS -- WE SAW THIS AS A CRITICALLY IMPORTANT RFA, WE LIKE THE IDEA THAT IT WAS AN RFA, WE LIKE THE IDEA THAT IT WAS GOING TO FUND SIX RO1s, AND THERE WILL BE COMMUNICATION AMONG THE FUNDED GROUP SO THEY CAN SYNERGIZE EACH OTHER AS THEY MOVE FORWARD. WE ARE VERY HAPPY WITH MICHELLE AND HER TEAM, THAT THEY EMBRACE THE IDEA THAT THIS WOULD REALLY FOCUS ON DEVELOPING NEW INNOVATIVE MODELS. WHEN WE TALK WITH MICHELLE AND HER TEAM, OUR CONCERN WAS PEOPLE REVIEWING THIS AND READING THIS MIGHT THINK THAT ALL THEY NEED TO DO WAS BETTER COMMUNICATE OR BETTER IMPLEMENT SOME MODEL THAT ALREADY EXISTS AND WHAT WE WERE REALLY HOPING AS REVIEW GROUP WAS THIS WOULD STIMULATE DEVELOPMENT OF NEW WAYS OF THINKING, OF INNOVATIVE WAYS OF APPROACHING THIS PROBLEM, THERE COULD BE GROUP CARE, ALL KINDS OF THINGS, WE WAN PEOPLE TO THINK OUTSIDE THE BOX. AND THE OTHER PIECE, THAT WAS ONE OF THE CRITICAL PIECES AS WELL AS THE SECOND ONE WAS SECOND, THIRD, WHATEVER, SCAPIBILITY SUSTAINABILITY, TRANSFERABILITY WE THOUGHT ABOUT RIGHT FROM THE GET GO AND THAT THIS BE SOMETHING THAT COULD BE APPLIED ACROSS MULTIPLE CANCERS, ACROSS MULTIPLE INCOME GROUPS, URBAN SUBURBAN AS WELL AS DISADVANTAGED PATIENTS SO THAT ALL BOATS COULD RIDING TO. WE HAVE HIGH HOPES FOR THIS RFA. WE ARE STRONGLY IN SUPPORT. SO LES AND GRAHAM, IN ANY OTHER COMMENTS? >> THE OR PART OF THIS WE THOUGHT EXTREMELY IMPORTANT WAS TO RECOGNIZE THERE'S GREAT DIVERSITY ACROSS THE COUNTRY IN TERMS OF THE POPULATION WHERE THEY'RE SEEN, ACCESS TO HEALTHCARE AND VARIETY OF THINGS SO WE WANTED TO MAKE SURE THIS RFA HAD THE OPPORTUNITY TO ADDRESS THAT DIVERSITY, RECOGNIZING THAT WHAT MIGHT WORK WELL IN MAJOR CANCER CENTER MAY NOT WORK OUT WELL OUT IN THE RURAL COMMUNITY. >> OKAY. SO I'LL ASK THEN FOR A MOTION. LET'S WAIT FOR DISCUSSION. MOTION. >> MOVE TO APPROVE. >> SECOND. ANY DISCUSSION? >> I QUESTION THE DECISION TO EXCLUDE ADOLESCENCE. ADOLESCENCE WILL BECOME YOUNG ADULTS. >> FOLLOWING RFA -- >> I THINK THEY ARE DIFFERENT. UNLESS YOU TELL ME THE NEXT RFA IS IDENTICAL TO THIS EXCEPT IN CHILDREN, IT'S NOT. IT IS NOT IDENTICAL, IT IS DIFFERENT. IF YOU ARE LOOKING FOR INNOVATION, IF YOU ARE LOOKING TO UNDERSTAND THE DIFFERENCE BETWEEN HAND OFFS FROM ONCOLOGY AND NON-ONCOLOGY, WHY APRIORI CONSTRAIN WHERE THOSE APPLICATION COME FROM. I DON'T THINK IT MAKES SENSE. >> WE DEFINITELY DISCUSSED WHETHER OR NOT TO INCLUDE AYAs IN HERE IN THIS RFA AND KNOWING THAT THERE IS A PEDIATRIC RFA COMING THOUGH IT IS NOT EXACTLY THE SAME YOU ARE DEFINITELY CORRECT ON THAT. OUR TEAM REALLY FELT THE TRANSITION FOR AYA IS DIFFERENT THAN THE TRANSITION FOR ADULTS IN THAT AYA MAY TRANSITION TO ADULT CARE AND THAT'S ANOTHER SET OF CHALLENGE AN DEFINITELY MAY WARRANT A FUTURE FOA IN THE FUTURE. BUT THAT IN ORDER TO FUND RO1s HERE WITH THE CURRENT RFA THAT ARE ALONG THE SAME TRAJECTORY TO ADVANCE SURVIVORSHIP AND CARE WE CHOSE TO FOCUS BUT YOUR POINT IS A GREAT ONE. >> SO WE CAN -- ALL RIGHT. >> VERY NICE CONCEPT. ONE QUESTION ABOUT THE EVALUATION CRITERIA. IS THIS AT A POINT WHERE IT COULD BE EVALUATED BASED ON IMPLEMENTATION AND RESULTS? YOUR SLIDE IS REALLY, IT'S FOUR THINGS THAT WILL BE CREATED BY ISSUANCE OF AWARDS. >> CORRECT. >> I WAS STRUCK BY HOW MUCH THE CONCEPT TALKS ABOUT EVALUATE BASED ON PROCESS. WHEN I THINK THERE'S AN OPPORTUNITY TO EVALUATE BASED ON TREATMENT AND CLINICAL AND ACTUAL OUTCOMES. CAN YOU TALK ABOUT YOUR THINKING AN DISTINCTION? >> GREAT QUESTION. SO REALLY IN SURVIVORSHIP CARE WE ARE MORE FOUNDATIONAL AND WE'RE NOT QUITE TO IMPLEMENTATION YET. SO BECAUSE IT WOULD BE A FIVE YEAR RO1 THERE'S NOT NECESSARILY TIME THE LOOK AT RECURRENCE AND OTHERS. WE EXPECT THAT APPLICANTS MAY PROPOSE OUTCOME SUCH AS SYMPTOM BURDEN. BUT WE ARE REALLY MORE ON THE PROCESS STAGE IN TERMS OF EVALUATION. ONE POINT THAT I TRIED TO MAKE BUT WASN'T CLEAR IN TERMS OF APPLICANTS ADDRESSING FUTURE SCALABILITY AND TRANSFERABILITY IS REALLY THAT THEY NEED TO SET THE STAGE FOR HOW THIS INTERVENTION MIGHT DO THAT IN THE FUTURE. SO MAY NOT BE READY FOR THAT AT THIS POINT BUT SETTING STAGE AND FOUNDATION TO DO SO. >> THIS IS A FANTASTIC CONCEPT, LIVING IN A STATE WITH RURAL INCREDIBLY UNDERSERVED POPULATIONS, BUT WHAT YOU SAID IS REALLY CRITICAL. I JUST WORRY THERE'S NOT ENOUGH MONEY TO DO THAT. ALL I'M GOING TO SAY IS THIS SHOULD GO. I'M VERY EXCITED. BUT I DON'T SEE HOW YOU CAN WITH THIS FEW GRANTS WITH THIS MONEY, GET AT THE PROBLEM IN TEALING WITH LARGELY DIVERSE COMMUNITIES. THAT WORRIES ME -- DEALING WITH THE LARGELY DIVERSE COMMUNITIES. THIS IS TERRIFIC BUT LOVE TO HAVE SCALE UP MODEL IT IS THE FUTURE SO MANY MAYBE A QUESTION FOR BOB, WE PROPOSED A 35 MILLION RURAL CANCER FUND INITIATIVE, ARE THERE WAYS TO TAKE PROJECTS LIKE THIS AND TIE THAT TO THAT SO YOU CAN FOCUS RURAL SURVIVORSHIP CARE USING THE SAME RFA MODEL AND HAVE MORE FUND TO FUND DIVERSE SITES. >> THAT'S DEFINITELY SOMETHING WE CAN TALK ABOUT FOR THE FUTURE. >> GREAT IDEA. AS NED SUGGESTED MAYBE SOME OF THESE CAN BE DISCUSSION CAN BE CONTINUED BY EMAIL. SO NOW I THINK WE CAN GO FOR VOTING. ALL WHO WOULD LIKE TO APPROVE. DISAPPROVE. DEFER. WE'RE GOING TO HAVE COFFEE BREAK THE FIFTH CONCEPT TODAY IS RESEARCH ON PEDIATRICS ADOLESCENT IN YOUNG ADULT SURVIVORSHIP, CHILDHOOD CANCER SURVIVORSHIP TREATMENT ACCESS AND RESEARCH ACT. DR. DANIELLE DAEE, RESEARCH PEDIATRIC ADOLESCENT YOUNG ADULT CANCER SURVIVORSHIP. >> SO HAPPY TO HAVE YOU HERE TO LISTEN TO THIS AFTER CAFFEINE BREAK SO THANK YOU FOR YOUR ATTENTION. THANK YOU FOR THIS OPPORTUNITY TO PRESENT OUR RFA WHICH WE DEVELOPED IN RESPONSE TO THE STAR ACT. IT'S ENTITLED IMPROVING OUTCOMES FOR PEDIATRIC ADOLESCENT YOUNG ADULT CANCER SURVIVORS. THIS WAS DEVELOPED WITH A TEAM WITHIN THE DIVISION OF CANCER CONTROL POPULATION SCIENCES AND MY TEAMMATES SANDRA MITCHELL ARE HERE TO HELP WITH QUESTIONS AT THE END AND IT WAS ALSO DEELOPED WITH WENDY NELSON. SO I WANT TO START BY INTRODUCING ONE OF THE MAIN REASON WE'RE HERE WHICH IS THE CHILDHOOD CANCER SURVIVORSHIP TREATMENT ACCESS AND RESEARCH ACT OR STAR ACT. THIS ACT WAS PASSED IN MAY OF 2018 DEVELOPED OF MANY YEARS BY A BIPARTISAN GROUP IN COLLABORATION WITH ADVOCACY ORGANIZATIONS. WITHIN THIS ACT CONGRESS ENCOURAGES EFFORTS TO INFLUENE PEDIATRIC ADOLESCENT AN AND AUTHORIZE IMPROVEMENTS IN FOUR DOMAINS THIRD WHICH IS FOCUS OF RFA PROPOSAL WHICH IS RESEARCH TO IMPROVE THE CARE OF AND QUALITY OF LIFE FOST FOR SURVIVORS. FROM EFFORTS TO ADDRESS DOMAINS ARE BEING DONE IN PARALLEL ACROSS THE AGENCY. SO THE SPECIFIC SECTION OF THE STAR ACT CALLS SIX KEY RESEARCH AREAS OF INTEREST, SURVIVOR OUTCOMES BARRIERS TO FOLLOW-UP CARE, FAMILIAL SOCIOECONOMIC AND ENVIRONMENTAL FACTORS, INDICATORS FOR LONG TERM FOLLOW-UP, RISK FACTORS, PREDICTORS AND MOLECULAR BASIS IDENTIFICATION, AND TARGETED INTERVENTION TO REDUCE BURDEN OF MORBIDITY. IMPORTANTLY CONSIDERATION OF HEALTH DISPARITY MINORITIES AND OTHER MEDICALLY UNDERSERVED POPULATIONS IS CALLED OUT ADS HIGH PRIORITY FOR THE STAR ACT. WITH THE RFA WORK WE'RE PROSING TODAY IS TRY THE I AWE DRESS KEY RESEARCH AREAS AS POSSIBLE WITHIN A FOCUS RFA. THE NEED FOR ADDITIONAL RESOURCES IN THIS AREA IS HIGHLIGHTED BY TWO KEY OBSERVATIONS WHICH I SHOW THE NEXT TWO SLIDES, FIRST WHICH IS THAT THERE'S A GROWING POPULATION OF SURVIVORS WE HAVE SEEN GREAT TREATMENT SUCCESS IN RECENT YEARS AND CURRENTLY OVER 85% CHILDHOOD CANCER SURVIVORS ARE EXPECTED TO SURVIVE BEYOND FIVE YEARS. SIMILARLY FOR ADOLESCENT YOUNG ADULT THERE'S SUCCESS IN TREATMENTS AND THAT POPULATION IS GROWING AS WELL. IMPORTANTLY THERE'S STILL PERSISTENT DISPARITIES AND YOU CAN SEE THAT HERE IN THIS FIVE YEAR SURVIVAL CURVE WHERE LACK SURVIVORS, BLACK PATIENT VERSUS A LOWER FIVIER SURVIVAL RATE COMPARED TO WHITES. SO USING PREVALENCE WE CAN ESTIMATE NUMBER OF SURVIVORS SO WITHIN THIS AGE RANGE THERE'S 630,000 CANCER SURVIVORS AGE 0 TO 39 IN THE US. THIS IS ACTUALLY AN UNDERESTIMATE BECAUSE MANY CHILDHOOD CANCER AND AYA CANCER SURVIVORS HAVE AGED BEYOND 39. THE SECOND KEY OBSERVATION IS THE COST OF SURVIVORSHIP IS ACTUALLY A LIFETIME WITH CHRONIC CONDITIONS. THAT'S SHOWN HERE WHERE IN THIS COHORT OF CHILDHOOD CANCER SURVIVORS SURVIVORS OF ALL, HODGKINS WELL. TUMOR AND NEUROBLASTOMA HAVE ON AVERAGE MORE CON CHRONIC CONDITIONS PER PERSON THAN COMMUNITY CONTROLS. THIS HOLDS TRUE AT ALL AGES LOOKED AT IN THE STUDY SO 30, 40, 50-YEAR-OLD SURVIVORS, ALSO HOLDS TRUE FOR OTHER CANCER THAT I DON'T SHOW HERE. IN THIS STUDY THEY LOOKED AT A VARIETY OF CHRONIC CONDITIONS THAT SPAN A VARIETY OF ORGAN SYSTEMS AND ALSO INCLUDES SECONDARY NEOPLASMS. SO WE LOOKED A LITTLE DEEPER INTO THE OBSERVATIONAL RESEARCH AND IT TURNS OUT PEDIATRIC AND A 1A CANCER SURVIVORS DEAL WITH A VARIETY OF ISSUES IN THEIR SURVIVOR DURING THEIR SURVIVORSHIP. THESE INCLUDE THOSE ISSUES WITHIN HEALTHCARE DELIVERY SUCH AS UNMET NEEDS FOR LONG TERM FOLLOW-UP, THEIR CARE IS OFTEN NOT DELIVERED BY A PROVIDER THAT'S FAMILIAR WITH LATE EFFECTS AND ISSUES WITH CONTINUITY OF CARE. IN TERMS OF ADVERSE EFFECTS THERE'S PHYSICAL PSYCHOSOCIAL AND BEHAVIORAL ADVERSE EFFECTS AND I'LL SHOW A COUPLE OF EXAMPLES HERE. THERE'S NEURAL COGNITIVE IMPAIRMENT, LATE TREATMENT AFFECTS AND ACCELERATED AGING WITH THIS POPULATION. THERE'S PSYCHOLOGICAL DISTRESS DISRUPTED SOCIAL DEVELOPMENT FINANCIAL HARDSHIP AND THERE'S REDUCED PHYSICAL ACTIVITY POTENTIAL NORRIS SKI BEHAVIOR IN OBESITY. NOW I WILL NOTE THERE ARE RACIAL DIFFERENCES FOR SOME OF THESE ADVERSE EFFECTS IN BOTH OUTCOMES, AND INCIDENCE SO NOTING THAT THERE ARE THESE OBSERVATIONAL STUDIES WE RECOGNIZE THERE'S STILL MORE WORK TO BE DONE IN THE OBSERVATIONAL SPACE BUT THERE ARE OBSERVATIONS THAT ARE READY TO BE MOVED INTO THE INTERVENTION SPACE. SO WITH THAT IN MIND WE THEN LOOK AT OUR PORTFOLIO AND WITHIN NIH THERE ARE 102 PROJECTS RELATED TO THIS POPULATION AN SURVIVOR RESEARCH MOST HELD BY NCI AND MOST NCI GRANTS ARE HELL WITHIN THE DIVISION OF CANCER CONTROL. AND POPULATION SCIENCES. CURRENTLY WE'RE SUPPORTING MORE OBSERVATIONAL WORK THAN INTERVENTION WORK. SO TAKEN WITH OUR REVIEW OF THE WILL LITERATURE AND PORTFOLIO REVIEW, WE SEE AN OPPORTUNITY TO MOVE OBSERVATIONAL STUDIES INTO THE INTERVENTION SPACE AND LEVERAGE THESE -- LEVERAGE THESE INVESTMENTS IN OBSERVATIONAL STUDIES TO DEVELOP INTERVENTION INTERVENTIONS. THAT'S THE PURPOSE OF OUR RFA WE WANT TO SUPPORT THE SCIENTIFIC DEVELOPMENT OF INTERVENTIONS TO ADDRESS ADVERSE PHYSICAL BEHAVIORAL AN PSYCHOSOCIAL EFFECTS OF SURVIVORS OF PEDIATRIC AND AYA CANCERS. THESE INTERVENTIONS CAN BE PROPOSED ACROSS THE SPECTRUM OF DEVELOPMENT TO IMPROVE HEALTHCARE DELIVERY OR PREVENT OR MITIGATE ADVERSE EFFECTS. MORE SPECIFICALLY WE'LL SOLICIT APPLICATIONSES TO DEVELOP TEST OR SCALE INNOVATIVE FEASIBLE EFFECTIVE INTERVENTIONS TO ADDRESS THE PHYSICAL BEHAVIORAL AND PSYCHOSOCIAL AT VERSE EFFECTS SURVIVORS OFPEDIATRIC AND AYA CANCERS. INTERVENTIONS CAN BE PROPOSED TO BE TARGETED AT THE INDIVIDUAL LEVEL, PROVIDER LEVEL OR CAREGIVER LEVEL AND ALSO PER STAR ACT WE WILL PRIORITIZE INTERVENTIONS THAT ADDRESS ADVERSE EFFECTS IN MINORITY OR MEDICALLY UNDERSERVED POPULATIONS. RESPONSIVE PROPOSALS MAY INCLUDE THE DEVELOPMENT AND PRELIMINARY TESTING OF NOVEL INTERVENTIONS EFFICACY TESTING AND PHASE 2 OR 3 TRIALS EFFECTIVENESS TESTING IN REAL WORLD SETTINGS OR DISSEMINATION IMPLEMENTATION STUDIES. RESPONSIVE PROPOSAL SHOULD INCLUDE MEANINGFUL PROXIMAL END POINTS AND I WOULD LIKE TO NOTE THAT USING COLLECTION OF BIOMARKERS TO EVALUATE PROXIMAL END POINTS IS ABSOLUTELY ALLOWED WITHIN THE RFA. FOR THIS RFA WE REQUIRE CLINICAL TRIALS AND RECOGNIZE THE IMPORTANCE OF THIS RESEARCH AREA, WE PROPOSE TO USE A UO 1 MECHANISM TO ALLOW NCI TO PROVIDE SCIENTIFIC SUPPORT AND FACILITATE COLLABORATION OF THE INDIVIDUAL OF AWARDS, WE HAVE ANNUAL MEETING OF AWARDEES. WE ANTICIPATE A VARIETY OF PROJECT SIZES APPROPRIATE FOR THIS RFA AND ALLOW MODULAR AND DETAILED BUDGETS. WE'RE REQUESTING $4.8 MILLION FOR FIRST YEAR OF THIS RFA AND THAT'S SPREAD ACROSS TWO RECEIPT DATES. IN SUMMARY WE'LL ADDRESS PRIORITIES BY THE STAR ACT AND LEVERAGE INSIGHT FROM PREVIOUS NCI INVESTMENTS AND OBSERVATIONAL RESEARCH. WE HOPE YIELD RESEARCH TESTED INTERVENTIONS TO IMPROVE OUTCOMES FROM THE GROWING NUMBER OF SURVIVORS OF PEDIATRIC CANCER. WE RECOGNIZE THIS IS A WAY THAT WE CAN QUICKLY STIMULATE OUR PORTFOLIO IN THIS IMPORTANT AREA. BUT MORE WORK TO BE DONE. AS SUCH WE PLAN TO -- WE PLAN FOR FUTURE CON IDEAS TO BROADLY ADDRESS THE STAR ACT AREAS. SO WE THINK OUR BSA SUBCOMMITTEE FOR THEIR CONSIDERATION OF OUR RFA PROPOSAL. THEIR FEEDBACK WAS CRITICAL FOR CLARIFYING THIS PRESENTATION AS WELL AS IMPROVING SUBSTANCE OF OUR RFA PROPOSAL. WE HOPE WE HAVE ADDRESSED THESE CLARIFICATIONS WITHIN PRESENTATION TODAY AND THERE ARE THREE SPECIFIC RECOMMENDATIONS, FIRST THE COMMITTEE RECOMMENDED TO HAVE TWO RECEIPT DATES AND WE HAVE MODIFIED OUR RFA PROPOSAL ADS SUCH. THE SUBCOMMITTEE ALSO EMPHASIZED THE IMPORTANCE OF BIOSPECIMEN COLLEGE MORE GENERALLY FOR FUTURE EXPLORATION OF HYPOTHESES, AT THIS POINT WE AGREE WITH THIS SUGGESTION AND EMPHASIZE INTERVENTION PROPOSALS MAY INCLUDE BIOMARKER STUDIES AND THAT IF BIOMARKER STUDIES THAT EVALUATE THE PROXIMAL END POINTS OR EVALUATE MECHANISM OF INTERVENTIONS PROPOSE. ALSO UO 1 MECHANISM, NCI WILL BE ABLE TO FACILITATE CONCURRENT ENROLLMENT BIOBANKING STUDIES WITHIN NCI. THE FINAL RECOMMENDATION WAS THAT IT WAS NOTED THAT SOME INSTANCES FOLLOW-UP OF PARTICIPANTS MAYBE WARRANTED WE AGREE WE WOULD LIKE TO FACILITATE MEANINGFUL FOLLOW-UP FOR SOME OF THESE AWARDS. WHERE IT'S APPROPRIATE WHEN APPROPRIATE NCI IDENTIFY MECHANISMS OF FUTURE SUPPORT TO SUPPORT THE LONG TERM FOLLOW-UP OF PARTICIPANTS. WITH THAT I WOULD LIKE TO TAKE ANY QUESTIONS, MY TEAMMATES ARE WELCOME TO COME UP IF YOU WOULD LICK TO. >> THANK YOU VERY MUCH, DANIELLE. THE SUBCOMMITTEE MEMBERS ARE KEVIN SHANNON WHO COULDN'T BE HERE, LES AND WE ASK LES MAYBE TO SUMMARIZE DELIBERATION OF THE COMMITTEE. >> WE FELT VERY POSITIVE ABOUT THIS RFA IN THE SPIRIT OF THE STAR ACT ENACTED WITH THE INFORMATION DANIELLE PROVIDED OVERALL LEVEL OF BURDEN PEDIATRIC CANCER SURVIVORS EXPERIENCE IS SUBSTANTIAL BUT ALSO IN A SITUATION WHERE WE KNOW A LOT, WE HAVE BEEN ABLE TO CHARACTERIZE WITH CURRENT THERAPIES WHAT HIGH LISK POPULATIONS ARE AND WHAT THE LEVEL OF LATE EFFECTS AND BURDEN THAT MIGHT BE EXPERIENCED AND THAT'S THE IDEAL SETTING ON WHICH TO MOVE INTO INTERVENTIONS. WE KNOW THE HIGH RISK POPULATION, WE KNOW WHAT IF RISKS ARE. NOW IS TIME THE TAKE THE KNOWLEDGE AND TRANSLATE INTO INTERVENTION APPROACHES SO THE SPIRIT OF THIS RFA TO REALLY FOCUS ON INTERVENTIONS THAT WILL EITHER PREVENT OR AIDS -- OR AMELIORATE ADVERSE EFFECTS OF THERAPY ARE RIGHT ON TARGET WHERE THINGS SHOULD GO. I WON'T GO THROUGH THE INDIVIDUAL POINTS THAT DANIELLE MENTIONED BUT WE FEEL THE RESPONSE IN TERMS OF THE ISSUES THAT WE RAIDED ABOUT BIO-- RAISED AFTER BIOSPECIMENS IS WELL DONE, IT'S IMPORTANT THAT THE BANKING TAKE PLACE EVEN IF IT ISN'T PART OF THE APPLICATION KNOWING THAT THE BUDGETS AND FOLLOW-UP AND SO ON BUT WE DO FEEL PART OF THE INTERVENTIONS THAT ARE PROPOSED AND CARRIED OUT HAVING THE ABILITY TO UNDERSTAND WHAT THE UNDERLYING BIOLOGIC MECHANISMS, PATHOPHYSIOLOGY OF THE INTERVENTION ITSELF RELATIVE TO THE OUTCOME BEING TESTED TO HAVE THAT ABILITY IS KEY FOR FUTURE RESEARCH. SO WITH THAT, WE WERE EXTREMELY POSITIVE ABOUT THIS RFA. >> I TOO AM EXTREMELY POSITIVE ABOUT IT. I THINK THE BIGGEST POSITIVE IS IT'S BROAD AND ALLOWS PEOPLE FROM COMMITTEE COME UP WITH IDEAS STRESSES INTERVENTIONS, VISIT COOPERATIVE AGREEMENT WHICH ALLOWS NCI TO REALLY GET INVOLVED WITH THIS, I ACTUALLY DO BELIEVE THIS IS SOMETHING LATER REGISTRY FOR LONG TERM SIDE EFFECTS BECAUSE WE LOOK AT SIDE EFFECTS OF 35-YEAR-OLDS WHO VALIDATE, IT LOOKS AT PSYCHOSOCIAL THINGS, THERAPEUTIC THINGS, SIDE EFFECTS, THIS IS MY OWN PROBLEM, I DON'T SEE AS MUCH OF A NEED TO STRESS BIOBANK BUT IT'S BROAD AND IT DOES NOT NECESSARILY REQUIRE BIOBANK, ALLOWS PEOPLE WHO ARE APPLYING TO MAKE THE -- WHAT THEY WANT TO DO SO THIS IS GREAT. >> THANK YOU, CAN WE HAVE A MOTION? SECOND? OKAY. DISCUSSION. OKAY. >> HAVING LISTENED ON MANY DISCUSSIONS ABOUT THE STAR ACT I THINK YOU HAVE DONE A SUPERB JOB, YOU AND THE TEAM FOR THE WORK YOU HAVE DONE ON THIS. >> THANK YOU VERY MUCH. >> ANOTHER POINT THE STAR ACT PASSED IN JUNE AND THIS IS DECEMBER AND THAT'S LIGHT SPEED FOR THE NCI SO CONGRATULATIONS FOR GETTING THIS DONE SO QUICKLY. >> IT WAS SUPER EASY. >> WE LIKE TO HEAR THAT. OKAY. SO I THINK WE CAN MOVE NOW TO VOTING. ALL IN FAVOR? DISAPPROVE? THANK YOU VERY MUCH. [APPLAUSE] >> OKAY. SO THE NEXT THREE CONCEPTS ARE MOON SHOT CONCEPTS. FIRST IS ADVANCING CANCER IMMUNOTHERAPY BY MITIGATING IMMUNE RELATED ADVERSE EVENTS. DR. SUSAN MCCARTHY PROGRAM DIRECTOR PROGRAM HEMATOLOGY AND DIVISION OF CANCER BIOLOGIES PRESENTING SUSAN. >> THANK YOU. SO I'M HERE AS THE SPEAKER FOR A BITEAM CANCER MOON SHOT EFFORT. THIS IS BEING PRESENTED BY BOTH ADULT AND PEDIATRIC IMMUNOTHERAPY IMPLEMENTATION TEAMS. SO WHAT WE WANTED TO DO WAS TO WORK ON AND FULFILL RECOMMENDATION B OF THE BLUE RIBBON PANEL BY POINTED OUT WE NODE TO ACCELERATE IMMUNOTHERAPY FOR BOTH ADULT AND PEDIATRIC PATIENTS. THERE HAD BEEN ALREADY SEVERAL RFAs FY 18 AND NOW FY 19 RFAs ON CANCER THERAPY EFFICACY, WE SAW THE NEED TO SUPPORT THE COMPLIMENTARY RESEARCH WHICH WOULD SEEK TO REDUCE THE UNINTENDED IMMUNE RELATED BY STANDARD EVENTS SO WHAT WE HAVE TODAY THEN IS A PROPOSAL FOR RFA FOR ONE TIME SOLICITATION FOR UO 1s, SO AGAIN USING COOPERATIVE AGREEMENT MECHANISM SO NCI CAN HAVE CONTINUING INPUT. THIS IS A TRANS-NIH EFFORT WE HAVE BUY IN FROM NIAID AMS DCR AND DDK. THOSE ARE INSTITUTES WHOSE TARGET ORGANS ARE FREAKILY THE VICTIMS OF THESE UNINTENDED BYSTANDER EVENTS. THE THINKING IS TO DO A ONE TIME DEAL TO -- THIS WOULD THEN LEVERAGE ONGOING SUPPORT ALREADY FOR BOTH COLLABORATIVE SUPPLEMENTS THAT HAVE BEEN FUNDED AND STARTED LAST SUMMER AND NEXT SUMMER IN GOOD TIMING FOR THIS. AND THEN ALSO THE FIRST ROUND AND THEN THE SECOND ROUND OF THE UO 1s ON THE EFFICACY FRONT. WE WILL INCORPORATE NEW PIs FROM THIS EFFORT INTO EXISTING CANCER MOON SHOT NETWORKS SO WE WILL BE ABLE TO EXPAND IT AND STRENGTHENING THOSE NETWORKS AND MAKING SURE THAT OUR NEW GRANTEES ARE NOT IN ISOLATION. JUST A COUPLE OF SLIDES ON THE ISSUE OF IMMUNE RELATED ADVERSE EVENTS THIS IS A COMPLEX SLIDE THAT CERTAINLY I CAN'T SEE ALL THE WORDS ON, I KNOW YOU CAN'T BUT THE IDEA IS THAT THERE'S A NUMBER OF REASONS THAT IMMUNOTHERAPY CAN FAIL. NUMBER OF ESCAPED MECHANISMS SO WHOLE BROWN FAMILY, IT'S CALLED IMMUNE DESERT. THE IDEA IS THERE'S NOT GOOD ANTIGEN SPECIFIC LYMPHOCYTES IN THE TUMOR. TUMORS HAVE LOTS OF WAYS TO BECOME INVISIBLE. THEY CAN HAVE NO NEOANTIGENS THEY CAN HAVE NO MHC PRESENTING THOSE ANTIGENS THEY CAN DOWN REGULATE VARIOUS AUXILLARY CO-STIMULATORY LIGANDS, THERE'S A WHOLE SET OF TUMORS FREQUENTLY CALLED COLD TUMORS WHERE REALLY JUST THE T-CELLS AND THE IMMUNE CELLS ARE NOT THERE. THEN THERE'S ANOTHER CATEGORY WHICH GETS LESS ATTENTION, THESE ARE CALLED IMMUNE EXCLUDED TUMORS WHERE THERE ARE T-CELLS OR IMMUNE CELLS MOSTLY ON T-CELLS, IN THE BODY. AT THE TUMOR SITE BUT THEY'RE AROUND THE PERIPHERY. THEY'RE PHYSICALLY EXCLUDED FROM GETTING WHERE THEY NED TO BE TO ATTACK THE CLONAL TRANSFORM CELLS. IT'S A LOT OF TIMES DUE TO STROMAL ISSUES TO EXTRA CELLULAR MATRIX TO THE TUMOR FINDING WAYS TO MESS UP THE CHEMOKINE, TRACK OF DIRECTING CYTOKINES SO THAT'S A DIFFERENCE PROBLEM, IF THERE'S T-CELLS YOU HAVE TO GET THEM IN. THE THIRD CATEGORY, CALL THE IMMUNE INFILTRATED OR HOT TUMORS IS WHERE THERE ARE ANTIGEN SPECIFIC T-CELLS MANY THE TUMOR AND THEY DON'T WORK. EITHER BECAUSE THERE ARE T REGULATORY CELLS OR MYELOID DERIVED STRESSOR CELLS OR T-CELLS HAVE BEEN EXHAUSTED, SO YOU CAN IMAGINE EACH OF THESE THREE KIND OF TUMORS IS DIFFERENT PROBLEM AND SO IT WILL REQUIRE DIFFERENT SOLUTION IN TERMS OF IMMUNOTHERAPY. SO HERE IS ONE SIMPLE FIGURE WE FOUND TO THINK ABOUT DIFFERENT KIND OF IMMUNOTHERAPY, THAT MIGHT OVERCOME THIS IMMUNOSUPPRESSION AND THAT MIGHT TWO SLIDES FROM NOW LEAD TO DIFFERENCE KINDS OF ADVERSE EVENTS. SO YOU CAN THINK OF GOING FOR ANTIGEN SPECIFIC THERAPIES WHERE YOU GO FOR TRY AND INDUCE IMMUNE RESPONSE AGAINST TUMOR AND YOU CAN EITHER INDUCE ENDOGENOUS IMMUNE RESPONSE VACCINATING AND TRYING TO USAGE EVENTUALS TO REV UP THE IMMUNE RESPONSE AT THE TUMOR SITE OR LYMPH NODES ADJACENT TO THE TUMOR SITE, THAT'S ONE WAY TO HAVE AN ANTIGEN SPECIFIC RESPONSE. ANOTHER WAY IS TO TAKE CELLS OUT OF THE PATIENT FROM TUMOR OR BLOOD AND POWER THEM AND SHOOT THEM BACK IN. THE WAY YOU CAN EMPOWER THEM IS TO FOR INSTANCE GROW THEM UP AND GET THEM TO BE THE RIGHT T-CELL STAGE AND YOU CAN EITHER LET THEM RELY ON THEIR -- IF THEY CAME FROM TUMOR ON THEIR ENDOGENOUS T-CELL RECEPTORS TO GIVE YOU A NICE POLYSPECIFIC POLYCLONAL RESPONSE OR IF THEY CAME FROM THE BLOOD YOU CAN GIVE THEM A T-CELL RECEPTOR GENETIC TRANSFORMATION OR CAR T-CELLS NEW CHIMERIC ANN GENERAL RECEPTOR T-CELLS, THOSE T-CELLS THEY'RE GOING TO BE MONOSPECIFIC SO YOU MAY HAVE POLYSPECIFIC YOU MAY HAVE MONOSPECIFIC T-CELLS, IN EITHER CASE THOSE ARE ANTIGEN SPECIFIC THERAPY. BUT THERE'S NON-SPECIFIC SPECIFIC THERAPY, WE JUST NEED TO GET THEM GOING AND THINK THAT ONE MIGHT PROVIDE POSITIVE SIGNALS TO REV UP THE SYSTEM, AGONISTIC ANTIBODIES OR IMMUNOMODULATORS THAT HELP CELLS GET OVER THE HUMP. OR YOU CAN BLOCK NEGATIVE SIGNAL, EVERY T-CELL HAS A PANOPLY OF POSITIVE AND NEGATIVE SIGNALS AND IT'S REALLY A BALANCE SO YOU CAN THINK THEN THAT EITHER OF THESE IN ADDITION COULD BE PAIRED WITH EITHER TOP ONE. YOU COULD TAKE CAR T-CELLS AND GIVE THEM BETTER CYTOKINES SO THEY TRACT BETTER. EACH, THE WAY YOU DO THERAPY LEADS TO PONE TENIALLY DIFFERENCE OHIO POTENTIALLY DIFFERENT ADVERSE EPIS. I'LL SHOW YOU ONE FOR CHECK POINT BLOCKADE, THE FURTHEST ALONG THERAPIES SEEN ON TV AND USED IN CLINIC. FOR CHECK POINT BLOCKADE THERE ARE A LOT OF DIFFERENT TARGET TISSUES THAT BECAUSE WHEN YOU RELEASE IMMUNE RESPONSE IN TUMOR, FROM THE BREAKS FROM THE BLOCKADE YOU NOT ONLY RELEASE TUMOR SPECIFIC CELLS YOU WANT BUT IF THERE ARE OTHER T-CELLS ACTIVATED IN OTHERWISE READY TO GO AND YOU RELEASE FROM THE NORMAL CHECKS THEN YOU CAN GET A POLYSPECIFIC NON-TUMOR DIRECTED IMMUNE RESPONSE. SO THERE'S LOTS OF TARGET TISSUES. AS I ALLUDED TO, DIFFERENCE THERAPIES ARE LIKELY ASSOCIATED WITH DIFFERENT IMMUNE RELATED ADVERSE EVENTS. THINK ABOUT TOP ONES THEY WERE ANTIGEN SPECIFIC THERAPIES. THE LIKELY PROBLEM IS YOU'RE GOING TO HAVE AN ON TARGET OFF TUMOR EFFECT. TARGET ANTIGENS IN TUMOR UNBEKNOWNST TO YOU ARE EXPRESSED ON OTHER TISSUE AND NO MATTER HOW HARD YOU CHECK THAT CAN HAPPEN BECAUSE ANN GENERALS ARE SHAPES IS NAY NOT BE AKNEE KNOW ACID SIMILARITY BETWEEN DESIRED ANTIGEN AND CROSS REACTIVE ANTIGEN. CONVERSE -- SO THERE YOU HAVE ON TARGET OFF TISSUE, OFF TUMOR EFFECTS. ON THE BOTTOM WHERE YOU'RE DOING A NON-SPECIFIC SIMULATION YOU CAN HAVE OFF TARGET, OFF TARGET OFF TUMOR EFFECTS. THOSE ARE HARDER TO DEAL WITH. YOU SAW IN THE CHECK POINT BLOCKADE HOW MANY TARGET TISSUES THERE CAN BE SO WHEN YOU THINK ABOUT ON TARGET OFF TISSUE YOU ARE TALKING ABOUT AUTOCROSS REACTIVITIES AND THESE BOTTOM ONES YOU ARE THINKING CYTOKINE STORMS FOR INSTANCE IF YOU STIMULATE CELLS A ONCE YOU ARE THINKING ABOUT CHANGING TRAFFICKING PATTERNS AND GETTING INVASION INTO NOR MILLIONLY IMMUNE PROTECTED SITES. SO IT'S A BIG PROBLEM AND THERE'S LOTS OF DIFFERENT VRIATIONS ON A THEME OF PEOPLE WHO APPLY TO THIS RFA. WHEN I TRIED TO KIND OF -- WHEN WE THOUGHT ABOUT, IN GENERAL HOW CAN WE PRESENT A SLIDE TO MAKE THIS PALATABLE? THINKING IS THERE'S THREE KINDS OF PIs, THREE TOPICS THAT WOULD BE SUBMITTED PEs TWO OR THREE. THERE'S STUFF ABOUT IMMUNE SYSTEM, THERAPY OR THE TOLERANCE INDUCING MECHANISM OR THE REGULATORY MECHANISM, STUFF ABOUT THERAPY. ANOTHER CATEGORY STUFF ABOUT THE PATIENTS WHO GET THAT THERAPY. SO WE CERTAINLY OUR COLLEAGUES IN DIVISION OF CANCER TREATMENT AND DIAGNOSIS ARE VERY INTERESTED IN PATIENT CHARACTERISTICS, BIOMARKERS OF SUSCEPTIBILITY TO ADVERSE EVENTS, SO THAT'S ANOTHER CATEGORY OF TOPICS THAT PI TEAMS COULD POTENTIALLY INVOLVE. SO CERTAINLY WE WANT TO SUPPORT NEW RESEARCH TOOLS TO HELP THIS FIELD. WHETHER IT'S COMPUTATIONAL TOPICS, NEW ANIMAL MODELS, IN SILL DOE MODELS. WE SUSPECT -- IN SILICO MODELS. MOST APPLICATIONS WILL HAVE TWO. THESE WITH SHARE OR FIRST AN THIRD BUT WE ARE LEAVING THAT OPEN TO PIs. THEN YOU CAN THINK WHAT KIND OF -- HOW COULD YOU ACTUALLY STOP IMMUNE RELATED ADVERSE EVANS? YOU READ THE DOCUMENT AND SAW PAGES OF BULLETS BECAUSE EACH IC HAD ITS BULLETS IN EACH DIVISION AT NCI HAD ITS BLEATS BUT WHEN ASTARE FOR DAY STRAIGHT, I CAME UP WITH I THINK THESE ARE THE WAYS THAT YOU ACCOMPLISH THE GOAL OF RETAINING EFFICACY WHILE PREVENTING ADVERSE EVENTS. EITHER YOU COMPARTMENTALIZE THE IMMUNE RESPONSE TO TISSUE, WHICH MEANS YOU COME UP WITH A GREAT TISSUE SIGNATURE FOR TUMOR CELLS THAT NO OTHER NORMAL CELL HAS THAT COMBINATION OF ANTIGEN AND YOU DO SPECIFIC AND GENERAL RESPONSE. -- ANTIGEN RESPONSE AND/OR YOU SAY WE'RE GOING TO ONLY LET IMMUNE RESPONSE HAPPEN AT TUMOR SITE SO GET RID OF REGULATORY CELLS AT TUMOR SITE OR T-CELLS TO EFFECTOR CELLS AT THANK YOU MANY SITE THAT'S ONE STRATEGY, COMPARTMENTALIZE JUST TUMOR SITE. YOU PROTECT BYSTANDER TISSUES BY WORKING ON IMMUNE RESPONSE TO MAKE IT NOT OR WORKING ON STANDARDS TISSUE THEMSELVES SO THAT YOU SOMEHOW RESIST THE DAMAGE OR YOU REPAIR THE DAMAGE IN REAL TIME THESE ARE DIFFERENT INVESTIGATOR, THIS BULLET HERE IS A OF WHAT OUR OTHER IC COLLEAGUES ARE INTERESTED IN AS WELL AS NIAID FOLKS INTERESTED IN IN CELL TOWERS AND REGULATING IMMUNE RESPONSE. THEN THIRD IS YOU WORK ON PATIENT. YOU ONLY GIVE THERAPIES TO PATIENT WHO CAN TOLERATE IT, YOU CAN DO THAT BY SELECTING PATIENTS OR IN A GREAT WORLD WE LEARN ENOUGH TO ANTICIPATE WHICH PATIENTS GET WHICH ADVERSE EVENTS SO THAT YOU CAN THEN PROACTIVELY TRY TO PROTECT TISSUES THAT ARE VULNERABLE IN THAT PARTICULAR PATIENT. I'LL GET THESE INVESTIGATOR AND PUT THEM INTO OUR COMMUNITY OF RESEARCHERS BY ADDING TO EXISTING IMMUNOTHERAPY NETWORKS. ADULT AND PEDIATRIC THERAPY NETWORK, THEY EACH HAVE SOME FY 18 AWARDEES, SO MOSTLY UO 1s, ONE U-54, THOSE FOLKS START AT JUST TWO MONTHS SEPTEMBER, JUST BEFORE THE END OF FISCAL YEAR. NOW WE HAVE -- THOSE ARE THE EFFICACY PIs. NOW WE HAVE ANOTHER SET OF EFFICACY AWARDS THAT ARE ON THE SREET NOW, THEIR FY 19 SO THEY WILL START THEIR NETWORK JOINING NETWORKS WHEN THEIR AWARDS ARE MADE NEXT SEPTEMBER. WE GO RIGHT AT THE DEADLINE OF THE END OF THE FISCAL YEAR. ONCE TODAY ADVERSE EVANS FOLKS WILL BE FY 20 IF WE CAN WORK EFFICIENTLY THEY CAN START DECEMBER 1st 2019 SO WORST 15 MONTHS BEHIND OLDEST MEMBERS OF NETWORK SO WE THINK THEY CAN EASILY INTEGRATE NETWORKS AND NOT FEEL LIKE THEY'RE THE ROOKIES ON THE BLOCK. SO THAT'S THE PLAN, JUST SET OF BULLETS TO SUMMARIZE WHAT I HAVE SAID, WE ARE GOING FOR UO 1, FIVE YEAR AWARDS TO START FY 20, ONE TIME SOLICITATION. WE TALK ABOUT THE BUDGET, WE EXPECTED A LOT OF THESE WILL BE MULTI-PI APPROXIMATE MR. CAN'T, WE WANTED TO GO ABOVE MODULAR. 375, ONE AND A HALF TIMES MODULAR, EXPERIENCE 60% INDIRECT IS ABOUT AVERAGE, SOME ABOVE, SOME BELOW, WE'RE THINKING THAT GENERATES AWARD OF 600,000 EACH. WHAT OUR REQUEST IS 3 MILLION PER YEAR FOR FIVE YEARS. THAT GETS US FIVE TO EIGHT AWARDS. IF ALL THE AWARDS WERE FUNDED BY NCI IT GIVES EXACTLY -- IF ALL AWARDS FUNDED BY OTHER INSTITUTES, IT COULD GET -- BECAUSE WHEN OTHER INSTITUTES HAVE GRANTEES THAT PARTICIPATE IN CANCER MOON SHOT EFFORT MOON SHOT TWO-THIRDS, OTHER ICs PAY A THIRD SO EXPERIENCE IS SOMEWHERE BETWEEN THOSE EXTREMES. WE WILL HAVE THEM JOINED THESE EXISTING NETWORKS THAT I TOLD YOU ABOUT, WE HAVE ALL I THINK BUT ONE OF THESE PARTNERS HAS SAID WE HAVE OUR LETTER READY TO GO, THE OTHER ONE SAYS I'M WORKING ON IT. AND IT WOULD BE REVIEWED IN HOUSE HERE BY NCI. NCI'S STUDY SECTION TEAMS. THAT'S IT. >> OKAY. SO THIS CONCEPT WAS REVIEWED BY KEN ANDERSON AND IAN THOMPSON UNFORTUNATELY NONE WHICH COULD BE PRESENT HERE SO LIZ IS GOING TO SUMMARIZE THEIR COMMENTS, THEY PROVIDED WRITTEN COMMENTS THEN WE'LL JUST PROCEED WITH DISCUSSION AN VOTING. FROM >> SUE, GREAT SUMMARY. ALL THREE REVIEWERS WERE ENTHUSIASTICALLY SUPPORTIVE AND OVERARCHING QUESTION IS HOW THE INVESTIGATORS WILL INTEGRATE OTHER PROGRAMS, PEDIATRIC ADULT NETWORKS BUT YOU EXPLAINED IT WELL AND THEY WILL BE INTEGRATED. THOUGH WE FELT THE ARGUMENT WAS BROAD INCLUDING ELEMENTS FROM VARIOUS SPONSORING INSTITUTIONS, IT WAS FELT THIS COULD REPRESENT A STRENGTH AS ALL THE BULLETED ELEMENTS OF THE RFA ARE IMPORTANT REGARDING THE ISSUES OF IMMUNE RELATED ADVERSE EVENTS. STRENGTH OF THE PROPOSAL BUZZ FELT TO BE OPPORTUNITY LEVERAGE RESOURCES FROM OTHER INSTITUTES NOT JUST IN RESOURCES BUT IN EXPERTISE. DR. VON KER HIDE EXPRESSED ENTHUSIASM, THE QUESTION WAS RAISED ABOUT THE RFA VALIDATION NEW TARGETS, HE FELT THE MAIN THRUST SHOULD BE AUTOIMMUNE -- ON AUTOIMMUNE BREAK THROUGH, HE FELT IT SEEMED BEYOND THE SCOPE OF RFA TO FUND DEVELOPMENT OF NEW THERAPEUTIC. NOTABLY IN THE FIRST ROUND OF GRANTS APPLICATIONS WERE RELATED TO NOVEL TREATMENTS. ANOTHER COMMENT WAS SPECIFIC WORDING AND RFA SHOULD EMPHASIZE THE PEDIATRIC APPLICATIONS FOR SOLICITED AND IT WAS CLARIFIED THE FOA WOULD BE OPEN TO APPLICANTS WOULDN'T BE LIMITED TO PREVIOUSLY FUNDED INDIVIDUALS FROM ADMINISTRATORS OFFICE. >> I THINK WHEN WE HAD PHONE CONVERSATION A WEEK AGO MONDAY REALLY ONE QUESTION BECAME IS THIS BROAD ENOUGH TO NEED TWO DIFFERENT STUDY SECTIONS. FROM THE EFFICACY FOAs OF A YEAR AGO WE FOUND THAT THEY WERE SURPRISINGLY ACCOMMODATING ONE PEDIATRICS BY CSR, ADULT BY NCI, AND THE SROs WERE FANTASTIC AND THEY GOT US TO AN EQUALLY BROAD SET OF APPLICATIONS GOT US A GREAT PANEL OF REVIEWERS SO THEY'RE ON BOARD TO DO THAT AGAIN. >> LIZ CAN I HAVE A MOTION? >> HAVE A MOTION TO APPROVE. >> SECOND. OKAY. ANY DISCUSSION? >> LIKE TO PICK UP ON THE THEME BOB HIGHLIGHTED. SO FROM -- NOT NUMBERED IN THE DECK YOU GAVE US BUT IN THE SLIDE OVERVIEW OF UO 1 RFA CONCEPT YOU PERFECTLY CRYSTALLIZE WHAT YOU WANT. BUT ELSEWHERE IN THE SLIDES AND AS I WAS SKIMMING THROUGH THE OUTLINE WRITTEN DOCUMENT, I'M QUITE CONCERNED THERE'S CONTENT THERE THAT WILL INVITE IN THERAPY AND NOT MITIGATION OF TOXICITY. SO STRIKES ME A NEW CAR T TARGET& OR NEW IMMUNOSUPPRESS SUV MECHANISM IN THE PLACENTA AND IN TUMOR AND LIKE NO TISSUE IN BETWEEN OR A NEW INJECTABLE THERAPY OF ALMOST ANY KIND INTO A TUMOR, SO THERAPY CONTEST, WOULD COME FORWARD WITH A SECTION SAYING WE DON'T THINK WE'RE GOING TO CAUSE TISSUE TOXICITY BECAUSE THE ANTIGEN IS EXPRESSED IN TUMOR TISSUE AND DECLARE VICTORY. I DON'T THINK YOU WANT THOSE, THERE ARE OTHER MECHANISMS NCI TO SUPPORT NEW THERAPY CONCEPT WHICH HAS HIGHER THERAPEUTIC INDEX, BOTTOM PART INDEX BEING PIECE YOU'RE INTERESTED IN. SO I WOULD TRUST THAT YOU'LL GET PLENTY OF THOSE COMING IN OTHER MECHANISMS PRESERVED FOR CONTENTS OF OVERVIEW OF UO 1. >> I THINK THE WAY -- WE USUALLY TAKE A LOT OF CONCEPT USE ON FOA BUT WE CAN MAKE IT WE WANT YOU THE DEAL WITH KNOWN IMMUNE RELATED ADVERSE EVENTS, NOT AVOIDING THEM BY TRYING A DIFFERENT EFFICACY STUDY. NICE THING ABOUT RFA WE GET -- WE CLEAR THEM SO NOT ONLY CONVINCE PIs SOMETHING IS OFF BASE THAT NOT ONLY DOES IT NOT STRIKE US AS RIGHT BUT NOT CONSTRUCTING VIEWERS AS RIGHT AND KIND OF BARKING UP THE WRONG TREE. SO THAT WON'T BE A PROBLEM. >> WE DIDN'T GET TOO MUCH FROM THE EFFICACY. THEY WERE SOPHISTICATED SCIENTIFIC STUDIES, NOT JUST WE THINK WE HAVE NEW MAGIC ANTIGEN. >> ANY FURTHER DISCUSSION? IF NOT YOU APPROVE? PLEASE RAISE YOUR HAND. DECEMBER APPROVE? OKAY. UNANIMOUS. THANK YOU. COFFEE BREAK? JUST KIDDING. SO THE NEXT MOON SHOT CONCEPT IS PATIENT ENGAGEMENT FOR PRIORITY CANCER SEQUENCING PE 4PC. DR. MECHANIC, PROGRAM DIRECTOR GENOMIC EPIDEMIOLOGY BRANCH, DIVISION OF CANCER CONTROL AND POPULATION SCIENCE WILL BE PRESENTED. >> HI. ON BEHALF OF MY CO-LEADS, LIZ LANDERS AND SYLVIA, WE APPRECIATE THE OPPORTUNITY TO PRESENT OUR CONCEPT ON PATIENT ENGAGEMENT FOR PRIORITY CANCER SEQUENCING. AFTERWARDS THE TEAM IS HERE, WE WILL BE HAPPY TO ANSWER ANY QUESTIONS. THIS IS A RESUBMITTED CONCEPT TO THE BSA. I'LL START BY GOING OVER THE GOALS AND BACKGROUND FOR THIS CONCEPT AND I'LL DESCRIBE HOW WE'RE ADDRESSING THE BSA FEEDBACK AND PROVIDE DETAILS FOR THE REVISED CONCEPT. THE NET PORK OR PATIENT ENGAGEMENT WAS AMBITIOUS, WE BROKE IT DOWN TO KEY COMPONENTS TO DESIGN THIS PROJECT AND TO INFORM LARGER NETWORK. THESE KEY COMPONENTS ARE DIRECT PATIENT ENGAGEMENT, TUMOR SEQUENCING, DATA SHARING, AND THE NEED INTO COLLUDE MINORITY AND UNDERSERVED POPULATIONS. THEREFORE THE GOALS OF OUR PROJECT ARE TO GENERATE COMPREHENSIVE GENOMIC LANDSCAPE OF CANCERS OR CANCER SUBSETS THAT ARE CURRENTLY POORLY CHARACTERIZED. SOME EXAMPLES INCLUDE RARE CANCERS, OR HIGHLY LETHAL CANCER OR CANCER WITH EARLY AGE ONSET, OR CANCER WITH DISPARITIES OR CANCER IN UNDERSTUDIED POPULATIONS. WE WILL DO THIS USING AN INNOVATIVE DIRECT VOLUNTEER APPROACH. OUR SECOND AIM IS TO OPTIMIE DIRECT PATIENT ENGAGEMENT APPROACHES TO INFORM FUTURE NCI ACTIVITIES. GENOME CHARACTERIZATIONS EFFORTS SUCH AS CANCER GENOME ATLAS HAVE BEEN SUCCESSFUL BUT RESEARCH GAPS REMAIN. ON THIS SLIDE IS ONE EXAMPLE OF RESEARCH GAP. IF YOU LOOK AT THE RACE DISTRIBUTION OF TUMORS AND TCGA ONLY 14% COME FROM MINORITY UNDERSTUDIED POPULATIONS. EXAMINING ETHNICITY DISTRIBUTION TCGA ONLY 3% TUMORS COME FROM HISPANIC OR LATINO POPULATIONS. TO QUOTE RECENT COMMENTARY RESULTS SUCH AS THESE HAVE RESULTED IN SUBSTANTIAL GAINS IN UNDERSTANDING OF CANCER PREVENTION AND TREATMENT, YET THEY'RE GENERALIZABILITY TO ALL U.S. POPULATIONS IS LIMITED DUE TO LACK OF RACIAL ETHNIC DIVERSITY. IT'S IMPERATIVE MOON SHOT NOT REPEAT HISTORY. ONE STRATEGY THAT COMPLIMENTS OUR EXISTING APPROACHES IS DIRECT PATIENT ENGAGEMENT STRATEGY. ON THIS SLIDE IS ONE OF THE EARLIEST EXAMPLES OF SUCCESS OF DIRECT PATIENT ENGAGEMENT. AT THE TIME OF THE STUDY LITTLE IS KNOWN ABOUT THE GENETIC BASIS FOR MYELOPROLIFERATIVE DISORDERS. THESE INVESTIGATORS USED AN INTERNET-BASED PROTOCOL TO COLLECT CLINICAL INFORMATION AND BIOLOGICAL SPECIMENS FOR SEVERAL HUNDRED PATIENTS. THEY DETERMINED A SIGNIFICANT NUMBER OF PATIENTS HAVE CURRENT MUTATION WHICH WERE POTENTIAL TARGET FOR INHIBITION. WHAT THIS STUDY HIGHLIGHTS HOW INTERNET EXPANDS REACH BEYOND CLINIC BASED APPROACHES AND ADDRESS RESEARCH GAPS AND IN THIS CASE FOR STUDY OF RARE DISEASE. WE MADE SEVERAL CHANGES TO CONCEPT BASED ON BSA FEEDBACK. WE WERE ASKED TO DEFINE DIRECT PATIENT ENGAGEMENT. WHAT WE MEAN HERE IS INTERACT DIRECTLY WITH PATIENTS AND TALK ABOUT THIS MORE IN THE NEXT SLIDE. WE WERE ALSO ASKED TO ADDRESS SPECIFIC PATIENT ENGAGEMENT QUESTIONS RELATED TO CANCER SEQUENCING PROJECTS. TO DO THIS WE HAVE CHANGED MECHANISM FOR THIS CONCEPT, SO THAT WILL ALLOW RESEARCH PATIENT ENGAGEMENT RESEARCH QUESTIONS SPECIFIC TO THE CANCER SEQUENCING PROJECT TO BE ASKED. WE'RE ALSO ASKED TO BROADEN OUR RETURN OF INDIVIDUAL RESULTS POLICY, TO ADDRESS THIS WE HAVE CHANGED TO A COLLIEIA SEQUENCING PIPELINE TO ALLOW RETURN OF GENETIC INFORMATION. IN RESPONSE TO CONCERNS ABOUT OUR BUDGET BEING INADEQUATE WE INCREASED OUR BUDGET AND THIS WILL SUPPORT THE COLLIEIA SEQUENCING, THE INFORMATICS SUPPORT FOR INTERPRETATION AND THE ENGAGEMENT OF HARD TO REACH POPULATIONS. WE'RE DEFINING PATIENT ENGAGEMENT AS ONGOING BIDIRECTIONAL MUTUALLY BENEFICIAL INTERACTION BETWEEN PATIENTS AND RESEARCHERS WHERE PATIENTS ARE INCLUDED AS INTEGRAL PART OF ALL PHASES OF THE RESEARCH PROCES. INCLUDING IDENTIFICATION OF RESEARCH PRIORITIES AND DESIGN CONDUCT AND UPTAKE OF RESEARCH. BY DIRECT PATIENT ENGAGEMENT WE MEAN RESEARCH TEAMS WILL REACH OUT AND RECRUIT PATIENTS DIRECTLY VIA THE WEB SOCIAL MEDIA AND ONLINE PATIENT COMMUNITIES AND NOT THROUGH PROVIDERS OR THE CLINICAL CARE SETTING. WE ALSO MEAN WILL INCORPORATE PATIENT RESEARCH INPUT THROUGH THE PROCESS THROUGH SURVEY INTERVIEWS AND CONSENTING OF RETURN RESULTS. I WANT TO CLARIFY WHAT I MEAN BY PATIENTS. WE MEAN INDIVIDUAL ANY POINT IN THEIR CANCER JOURNEY SO THEY MAY NOT BE UNDERGOING ACTIVE TREATMENT AT TIME OF RECRUITMENT TO THE STUDY. WE'RE PROPOSING TO SUPPORT THIS USING U 19 AND U 24. PROGRAM PROJECT GRANTS ARE U 19s WILL BE USED TO AWE DRESS RESEARCH GAP IN PROFILES OF CANCER USING DIRECT PATIENT ENGAGEMENT STRATEGY. EACH U 19 FOCUSES ON CANCER OR CANCER SUBSET AND EACH WILL SUPPORT THREE HIGHLY INTEGRATIVE PROJECTS AND CORES. PROJECT ONE IS THE IMPLEMENTATION OF PATIENT ENGAGEMENT CANCER SEQUENCING RESEARCH, PROJECT 2 IS SEQUENCING AND ANALYSIS AND PROJECT THREE IS RESEARCH TO OPTIMIZE PATIENT ENGAGEMENT AND COMMUNICATION TO I A DRESS THE BSA CONCERN AND ENSURES THAT RELEVANT PATIENT ENGAGEMENT RESEARCH SPECIFIC TO CANCER SEQUENCING PROJECTS WILL PLAY A ROLE IN THE U 19. WE'RE ALSO ASKING FUND TO SUPPORT U 24 COORDINATION CENTER TO ENSURE SYNERGY ACROSS THE PROGRAM. TO SUMMARIZE EACH WILL BE TAYLORED TO A SPECIFIC CANCER RESEARCH QUESTION OR POPULATION AND COORDINATING CENTER WILL SHARE BEST PRACTICES ACROSS THE NETWORK AND WILL BE ABLE TO PILOT STUDIES TO SUPPORT CONSORTIA NEEDS. I'LL GO INTO INDIVIDUAL PROJECTS IN THE NEXT FEW SLIDES. PROJECT ONE IS IMPLEMENTATION PROJECT THAT WILL DIRECT PATIENT ENGAGEMENT RECRUITMENT, TISSUE ACQUISITION, DATA COLLECTION AND RETURN OF INFORMATION TO PARTICIPANTS. THE NUMBER OF PATIENTS INCLUDED WILL BE JUSTIFIED BASED ON RESEARCH QUESTION, CANCER FREQUENCY AND THE CHARACTERISTICS OF THE CANCER. KEEPING IN MIND YOU WANT THE ADEQUATE NUMBER OF PATIENTS TO ADDRESS THE RESEARCH QUESTION. ONCOLOGIST AND GENETIC COUNSELORS ON THIS TEAM. PROJECT TWO IS SEQUENCING ANALYSIS AND INTERPRETATION PROJECT. IN RESPONSE TO BSA CONCERNS SEQUENCING WILL BE PERFORMED IN EXTRAMURAL LABORATORY CERTIFIED WITH COLLIEIA -- KLIA TO ALLOW GENETIC INFORMATION AND GRANTS FUND SEQUENCING. TWO WILL BE RESPONSIBLE FOR PROCESSING CHARACTERIZATIONS, DATA ANALYSIS AN INTERPRETATION. THE PLAN CHARACTERIZATIONS INCLUDES WHOLE EXOME SEQUENCING RNA SEQUENCING AND LOW HOUSEHOLD GENOME SEQUENCING. DATA IS ANYTIME SUBMITTED TO CANCER TO COMMON AN SHARE IN MANNER CONSISTENT WITH PARTICIPANT INFORMED CONSENT. PROJECT THREE IS OPTIMIZE PATIENT ENGAGEMENT AND COMMUNICATION. THIS PROJECT WILL SUPPORT RIGOROUS EMPIRICAL RESEARCH ON OUTREACH RECRUITMENT, COMMUNICATION AN EDUCATION ABOUT CANCER SEQUENCING GOALS AND DISCOVERIES. EXAMPLES INCLUDE DETERMINING PATIENT PREFERENCE AND NEEDS OF PARTICIPATION AND RETURN OF GENETIC INFORMATION AND DEVELOPING AND TESTING INTERVENTIONS ON OPTIMAL APPROACHES TO REACH UNDERSTUDIED POPULATIONS TO RETAIN PARTICIPANTS AN EFFECTIVELY COMMUNICATE AND EXPLAIN RESULTS. THROUGH PROJECT THREE SOCIAL BEHAVIORAL RESEARCH WILL BE FULLY INTEGRATED INTO THE U 19. SO I WANT TO TRY TO PUT THIS TOGETHER SO PROJECT ONE WE'LL START WITH WHAT WE KNOW AND USE INNOVATIVE APPROACHES THE CAPTURE PREFERENCE AND INFORM STUDY DESIGN AND RECRUIT PATIENTS. THEY WILL CONCEPT PATIENTS IN THE PATIENTS WILL GRANT THE U 19 PERMISSION TO CHECK TISSUE SAMPLES IN CLINICAL DATA AND THE U 19 COLLECT EPIDEMIOLOGY DATA. THE PROJECT WILL PROVIDE REGULAR STUDY UPDATES IN PATIENTS AND BE COMMUNICATING WITH THEM. THEY WILL ALSO INCLUDE U 19 ONCOLOGIST GENETIC COUNSELORS PART OF TEAM TO MANAGE RETURN INFORMATION TO PATIENTS AND THEIR ONCOLOGISTS. PROJECT TWO SUPPORTS CLINICAL SEQUENCING PIPELINE, SUPPORT ANALYSIS INTERPRETATION AND IDENTIFICATION OF THOSE VARIANT TO REPORT BACK TO PATIENTS. PROJECT THREE SUPPORTS THE RESEARCH AND PATIENT ENGAGEMENT AND COMMUNICATION AND SHOWN IN THESE GREEN BOXES ARE TYPES OF QUESTIONS THAT THEY COULD BE INCLUDED ADS PART OF PROJECT THREE. FOR EXAMPLE, YOU MAY INVESTIGATE QUESTIONS ABOUT METHODS AND REACHING AND RECRUITING PARTICIPANTS WHICH CAN INFORM THE RECRUITMENT OF PROJECT ONE. MAY ASK QUESTIONS ABOUT COMMUNICATION OF STUDY GOALS, WHICH CAN INFORM THE STUDY CONSENT PROCESS. MAY ALSO EXPLORE QUESTIONS ABOUT EFFECTIVE AND PARTICIPANT CENTERED APPROACH TO RETURNING RESEARCH RESULTS WHICH INFORMS PROCESS FOR RETURN. AND FINALLY MAY ASK QUESTIONS ABOUT UNDERSTANDING PATIENT PREFERENCES FOR THE RETURN WHICH CAN INFORM THE DEVELOPMENT OF THE REPORT. SO PROJECT ONE WILL START WITH INITIAL PROTOCOL BUT THIS WILL BE FLEXIBLE SO THAT IT CAN BE ADAPTED AND MODIFIED BASED ON RESEARCH RESULTS IN PROJECT THREE. SO ONE OF THE MOST IMPORTANT CONCERNS RAISED BY THE BSA REGARDING RETURN OF INFORMATION TO PARTICIPANTS. THIS IS BECAUSE RETURN OF INDIVIDUAL RESEARCH RESULTS IS A CRITICAL WAY FOR US TO ENGAGE AND RESPECT OUR RESEARCH PARTICIPANTS. THEREFORE THIS PROGRAM PARTICIPANTS MAY OPT TO RECEIVE DEPENDING ON THEIR PREFERENCES SUMMARY OF INDIVIDUAL HEALTH INFORMATION USED IN STUDY, ONGOING STUDY UPDATES, AGGRAVATED RESULTS, SCIENTIFIC FINDINGS AND RESULT AND INDIVIDUAL GERM LINE AND SOMATIC GENETIC RESULTS. I WILL TALK ABOUT THIS MORE ON THE NEXT SLIDE. WE SHIFTED TO A KLIA PIPELINE TO ALLOW BROADER RETURN OF GENETIC INFORMATION. WE DEVELOPED AN NCI RETURN POLICY SIMILAR TO WHAT'S USED FOR OTHER NCI PROJECTS WHERE WE REPORT BACK TO PATIENT AND THEIR ONCOLOGISTS PATHOGENIC VARIANT WITHIN THE ACMG CANCER GENES. WE'S ALSO DEVELOP NCI RECOMMENDED SOMATIC RETURN POLICY WHICH WILL FOLLOW SIMILAR PROCESS OF REPORTING BUT IN THIS CASE POTENTIALLY ACTIONABLE VARIANT. ADDITIONAL PLAN DETAILS FOR REPORTING BACK RELEVANT TO SPECIFIC CANCER TYPE OR POPULATION STUDY CAN BE SUGGESTED BY THE U 19 INVESTIGATORS. BUT THIS IS AN EVOLVING AREA AND POLICY WILL PERIODICALLY EVALUATED AND REVISED. SO WE'RE ASKING FOR FUNDS TO SUPPORT FOUR U-19 AWARDS OF 2.5 MILLION DIRECT COST EACH PER YEAR, FUNDS FOR COORDINATION CENTER OF 500,000 DIRECT COSTS PER YEAR FOR TOTAL OF 52 MILLION. TO SUM RIDES THIS PROJECT WILL ADDRESS RESEARCH GAPS AND PROFILES OF CANCER, IT WILL DETERMINE THE EFFECTIVENESS OF DIRECT PATIENT ENGAGEMENT APPROACH TO ADDRESS THESE RESEARCH GAPS, IT WILL PROVIDE INSIGHT INTO DEVELOPMENT AND SUSTAINABILITY OF LARGER NETWORK FOR DRUG PATIENT ENGAGEMENT, WHEN WE LEARN AND RESPOND TO PATIENT PREFERENCES AND IT WILL IDENTIFY OPTIMAL METHODS OF ENGAGEMENT AND COMMUNICATION. FINALLY DATA WILL BE SHARED BROADLY AS A RESOURCE FOR RESOURCE COMMUNITY. I WANT TO END BY THANKING OUR BSA SUBCOMMITTEE THEY HELPED US TO REFRAME THIS PRESENTATION TO MAKE IT MUCH CLEARER FOR YOU TODAY. AND THANK YOU AND I'M HAPPY AN ME AND MY TEAM ARE HAPPY TO TAKE ANY QUESTIONS. >> THANK YOU VERY MUCH, LADIES FOR THIS CLEAR PRESENTATION. SUBCOMMITTEE MEMBERS WHO REVIEW THE CONCEPT ARE JAMES -- SORRY, JAMES CHERYL AND MICHAEL. SORRY. AND SO JAMES. TAKE IT AWAY. THERE'S A LOT ABOUT THIS CONCEPT AND GENESIS OF IT EVERYONE CAN BE PROUD OF FROM IDEA TO DEVELOPMENT TO THE INITIAL REVIEW IN THE SUMMER AND TO MODIFICATIONS AND COMMUNICATIONS WE HAD WITH PROGRAM STAFF, REALLY WANT TO COMMEND LIA LIZ, CATHY, SYLVIA, MIC AND CHARLOTTE. WE HAD GOOD DISCUSSION. OVERALL THERE WAS A GOOD DEAL OF EXCITEMENT AMONG THE THREE OF US ABOUT THIS. OUTSTANDING EXCEPTIONAL, WONDERFUL WERE SOME WORDS KICKED AROUND. AS YOU RECALL THERE WERE SOME QUESTIONS IN JUNE ABOUT THE SCOPE, YOU JUST DESCRIBED CHANGES MADE TO THE CONCEPT THAT I A DRESSED THOSE NICELY, THE GOALS WERE A LOT -- COUPLE OF THINGS JUMPED OUT, I WANT TO GO THROUGH THEM BRIEFLY IN THE INTEREST OF TIME, THEY WERE BROUGHT UP IN JUNE. OVERALL THIS CONCEPT I THINK HAS REALLY STRONG STRUCTURE, WE LIKE REFORMATTED ORIGINAL AWARDS, INDIVIDUAL AWARDS, REQUIREMENTS FOR GENETIC COUNSELORS TO BE PART OF THE PROCESS, IT WAS A KEY STRENGTH, THE FOCUS ON KLIA SEQUENCING RETURN ON RESULTS AND ALSO ONE THING THAT I THINK YOU UNDERESTIMATED IN YOUR PRESENTATION BUT WAS A KEY PART OF OUR DISCUSSION WAS YOUR RECOGNITION FOR THE NEEDTOR THERE TO BE SOME FLEXIBILITY BECAUSE ENGAGEMENT IS A BROAD TERM IT CAN MEAN SO MANY THINGS. MANY WAYS LIKE POLITICS, ALL LOCAL. SO THE RECOGNITION FOR SOME FLEXIBILITY IN RELATION TO THE SPECIFIC FOCUS OF AWARDS, DATA SHARING, TO PRIVACY TO CONSENT TO TISSUE COLLECTION, STRONG LEVEL OF ENTHUSIASM, THIS CONCEPT HAS A LOT OF POTENTIAL TO DO A LOT OF GOOD. MIKE, ANYTHING ELSE TO ADD? >> I HAVE TO COMPLIMENT THIS TEAM FOR BEING RECEPTIVE TO THE TOUGH LOVE APPROACH IN THIS PROCESS. SO KUDOS, GREAT JOB, TEAM, YOU'RE READY TO GO. >> I ALSO WANT TO ECHO THAT AND WE WON'T SUMMARIZE THIS, YOU HEARD AN EXCELLENT PRESENTATION. I THINK THIS IS AN EXAMPLE WHERE SOMETIMES WE DEFER AN RFA AND EVERYBODY GETS UPSET. AND I THINK WE DID IT FOR GOOD REASONS AND I JUST REALLY WANT TO CONGRATULATE LEA, YOU AND THE ENTIRE TEAM ADS -- AS JAMES ALREADY DID BECAUSE IT'S BEEN A PLEASURE TO WORK WITH YOU OVER THE SUMMER AND RESTRUCTURE THIS INTO A PROGRAM THAT I THINK IS GOING TO BE SUPER EXCITING. AND I THINK TREMENDOUSLY SUCCESSFUL. SO IT WAS A PLEASURE TO WORK WITH ALL OF YOU. CONGRATULATIONS. YOU REALLY DID A NICE JOB. >> SINCE CHERYL DIDN'T SAY THIS T THIS IS A TREMENDOUSLY IMPORTANT GAP ACROSS THE NCI COMMUNITY STRUGGLING WITH GETTING SEQUENCING SO KUDOS, THIS IS GOING TO HAVE A BIG IMPACT. >> OKAY. SO WE'LL MOVE TO A MOTION NOW. MOTION IS APPROVED. JUST CHECKING. DISCUSSION. ANY DISCUSSION? >> I HAVE A COUPLE OF QUESTIONS. KUDOS TO YOU GUYS. WE WERE HARD ORANGE YOU LAST YEAR WHEN -- ON YOUR LAST YEAR WHEN YOU PRESENTED THIS, AND YOU RESPONDED TREMENDOUSLY TO OUR CONCERN. COUPLE OF QUESTIONS. SINCE THESE ARE RARE TUMORS IN UNREPRESENTED POPULATIONS IN SOME CASES, YOU DIDN'T EXPLICITLY SAY THAT YOU WERE COLLECTING TUMOR AND NORMAL TISSUE FROM ALL THESE PATIENTS, WAS IT GOING TO BE CRITICAL TO SEQUENCE BOTH. >> SHOULD BE TUMOR AND NORMAL. AND -- >> NOT EXPLICIT WHAT I READ HERE. >> WE CAN MAKE THAT CLEAR AND WHEN WE DO THE FOA. >> HAS TO BE DONE THAT WAY. >> DEFINITELY. I AGREE. >> ANYTHING THAT'S IMPORTANT, I THINK THE SEQUENCING LANDSCAPE IS CHANGING SO RAPIDLY BECAUSE OF THE ADDITION OF THE SEQ AND X 4 AND HOSTICE COLLAPSING FOR WHOLE GENOMES, I DON'T THINK THE PROPOSAL IS MODERN AS IT SHOULD BE AS YOU'RE JUST LAUNCHING IT. I DON'T THINK A LOW PASS WHOLE GENOME IS NEEDED ANY MORE. SHOULD BE ENHANCED WHOLE GENOME WITH EXON, DO IT IN MOST MODERN COST EFFECTIVE WAY. DO WHOLE GENOMES BECAUSE THE DATA WILL SERVE YOU WELL LONG TERMs SPECIAL SPECIALLY FOR THESE BIZARRE -- ESPECIALLY FOR THE BIZARRE TUMORS DO THE BEST SEQUENCING YOU CAN WITH THE BEST TECHNOLOGY, DON'T COMPROMISE ON THAT, IT'S GOING TO BE IMPORTANT I THINK. >> WE CAN MAKE -- >> FINALLY, I JUST GOOGLEED A NON-CATCHY ACRONYM AND 4 P SEQ CAME UP. CAN YOU CHANGE -- >> IT'S DEFINITELY ON OUR TO DO LIST. >> SO WE REALLY WANT TO CONCUR WITH TIM. THAT WITH THE DRAMATIC REDUCTION IN SEQUENCING PROCESS EVEN BY ANOTHER THIRD TO A HALF OF THEM THE LAST THREE MONTHS, I DO THINK DEEP OR WHOLE GENOME SEQUENCING WOULD BE USEFUL BECAUSE I THINK GIVEN THAT WE'RE GOING TO STORE SAMPLES IN THE INSTITUTIONS BUT MAKE DATA AVAILABLE THERE'S THE OPPORTUNITY FOR A LOT OF GREAT SCIENCE ON THE COHORTS THAT ARE DEVELOPED. SO MY FOLLOW-UP QUESTION I THOUGHT TIM WOULD GO THERE, SOME OF THE RARE CANCERS WERE GOING TO DO DISPARITIES CANCERS THE POPULATIONS THAT ARE NOT REPRESENTED ARE NOT NECESSARILY LARGE POPULATIONS. SO LIA ARE YOU THINKING OF FLEXIBILITY IN THE RFA? LIVING WHERE I LIVE IN TRIBAL NATIONS, HUGE DISPARITIES IN KIDNEY, LIVER AND NOW COLORECTAL CANCER, SOME OF THAT MAYBE DISPARITIES, SOME IS BIOLOGY. THAT REMAINS TO BE DISCOVERED BUT IF YOU LOOK AT THAT POPULATION IN TOTAL, THAT'S NOT A HUGE NUMBER. SO WILL THERE BE FLEXIBILITY IN THE RFA WITH SOME POPULATIONS TO DO MORE COMPREHENSIVE SEQUENCING OF A COUPLE OF CANCERS RATHER THAN JUST ONE, FOR INSTANCE? >> I THINK THAT'S A VERY GOOD POINT. I SEE WE'RE AIMING TO ADDRESS SCIENTIFIC QUESTION AND RESEARCH GAP. I THINK WE HAVE TO BE MINDFUL CONSIDERING THE IMPORTANCE OF SEQUENCING A PARTICULAR POPULATION OR PARTICULAR CANCER, BALANCE THAT ALSO WITH HAVING ADEQUATE NUMBERS TO BE ABLE TO MAKE MEANINGFUL CONCLUSIONS. BUT I THINK THAT'S SOMETHING WE CAN DEFINITELY CLARIFY. >> THANK YOU VERY MUCH. I WAS ONE OF THE PEOPLE WHO WAS A LITTLE HARD ON YOU. BUT YOU HAVE DONE A GOOD JOB. I THINK WHEN YOU DEVELOP THE RFA FULLY I THINK YOU'RE GOING TO HAVE TO BE A LITTLE SPECIFIC IN A FEW THINGS. COUPLE OF THINGS. FIRST OF ALL, YOU'RE REALLY NOT ASSESSING THE EFFECTIVENESS OF THESE APPROACHES, EFFECTIVENESS OF DIRECT PATIENT ENGAGEMENT APPROACH, YOU'RE NOT. SO BE CAREFUL WITH THE WORDS YOU USE WHEN LOOKING AT EFFECTIVENESS. THE WAY YOU'RE SEQUENCING THIS IS NOT ALLOWING YOU TO DO THAT. ALSO USUALLY WHEN WE DO ENGAGEMENT OF PATIENTS OR COMMUNITIES AND GET THEIR INPUT ON THE TYPES OF WAYS TO RECRUIT PEOPLE, TO CONTACT PEOPLE, TO CONSENT THEM AND SURVEY THEM, ET CETERA, WE DO THAT SEQUENTIALLY AND NOT CONCURRENTLY. SO YOU'RE PROPOSING PROJECT 3 BE CONCURRENT WITH PROJECT ONE. WHICH I THINK IS GOING TO COST SOME PROBLEMS BOTH IN LOGISTICS AS WELL AS IN ANALYSIS. UNLESS THE GRANTEES HAVE BLOCKS WHERE THEY'RE TESTING ONE THING, ET CETERA. YOU'RE ASSUMING YOU'RE GOING TO START FROM DAY ONE WITH PROJECT THREE AND PROJECT ONE SO PROJECT ONE WILL START WITH CONTACTING AND CONSENTING PEOPLE. RIGHT? >> JUST TO CLARIFY, PROJECT ONE WE'LL START WITH REACHING OUT TO PATIENTS AND IDENTIFYING OUR STUDY PROTOCOL. PROJECT 3 IS RESEARCH OF EVALUATING THESE DIFFERENT ENGAGEMENT STRATEGIES. SO -- >> I UNDERSTAND BUT WHEN YOU'RE DOING ENGAGED RESEARCH, WHETHER IT'S WITH INDIVIDUALS LIKE PATIENTS OR COMMUNITIES, THERE'S USUALLY A LOT OF QUALITATIVE WORK THAT IS BEFORE YOU DO THE QUANTITATIVE WORK, THAT LOOKS AT EFFECTIVENESS. SO I THINK WHEN YOU WRITE THE RFA YOU HAVE TO BE VERY CLEAR THAT YOU WANT SOME QUALITITATIVE WORK TO PERCEIVE THE BEGINNING ESPECIALLY IN PROJECT ONE. IT'S NOT GOING TO BE -- YOU'RE NOT GOING TO GET THE INPUT FROM THE COMMUNITY IF YOU START FROM THE GET GO. >> THAT MAKES SENSE. WE'LL MAKE IT CLEAR. >> DISCUSSION. YEAH. >> >> ONE MORE QUESTION. >> OKAY. COMPELLING CASE ON ONE OF YOUR FIRST SLIDES HERE ABOUT THE RESEARCH GAPS IN THE MOLECULAR PROFILING AND STATUS AS IT EXISTS TODAY. WITH THE BUDGET THAT YOU PROPOSED HERE -- >> MARY, CAN YOU GET CLOSER TO THE MICROPHONE? >> SORRY. I WAS JUST SAYING THAT I THOUGHT THAT WAS A COMPELLING CASE MADE THE RESEARCH GAPS AND MOLECULAR PROFILING IN CANCER SPECIFICALLY VIS-A-VIS DISTRIBUTION OF RACE AND ETHNICITY OF THE PARTICIPANTS. AND I'M CURIOUS IF YOU CAN GIVE ME AND US A PERSPECTIVE WITH THE BUDGET YOU PROPOSE HERE WITH FOUR U 19s WHAT WILL THE GRAPH LOOK LIKE WHEN YOU COME BACK IN FIVE YEARS? >> SO WE'RE ENVISIONING TO FUND FOUR DIFFERENT TYPES OF PROJECTS, TO KIND OF LOOK AT HOW ENGAGEMENT RESEARCH WORKS IN THESE DIFFERENCE TYPES OF PROJECTS. SO ONE EXAMPLE MAYBE LIKE A RARE CANCER, ANOTHER EXAMPLE MAYBE AN UNDERSTUDIED POPULATION. SO I DON'T THINK WE'RE GOING TO TOTALLY SOLVE THAT GRAPH BUT MAYBE WE CAN SOLVE LIKE ONE OF THE BAARS OR TWO OF THE BARS WITH THIS PROJECT. >> ALL RIGHT. >> JUST VERY QUICKLY YOU SAY YOU ARE GOING TO STUDY HIGHLY LETHAL CANCERS. IS THIS SORT OF A CONCERN THAT YOU HAVE IS SUBSTANTIAL SURVIVOR BIAS IF YOU FOCUS ON -- THINK ABOUT THAT. >> OKAY. >> JUST A LITTLE MINOR THING, WHEN WE PRESENT THE CLASS WE NORMALLY PRESENT TOTAL COST. AND THIS SLIDE SPECIFICALLY SAYS DIRECT COST. SO THAT WOULD ADD LIKE -- WE HAVE BEEN DOING JUST DIRECT COST? OKAY. I THOUGHT IT WAS TOTAL COST. >> ANY OTHER DISCUSSION? >> ONE OTHER JUST HIGHLIGHT -- SORRY. TO GO BACK. CONCEPT OF PAYING FOR THE SEQUENCING AND GRANTS FOR THE PARTICIPANTS TO THE LIFE CYCLE OF THIS IS ONE OF THE SIGNIFICANT INNOVATIONS HERE. AND IT DOES ADDRESS SOME OF THE ISSUES THAT DEGRADES THE DISCUSSION A LITTLE BIT. >> GREAT. SO I THINK WE CAN MOVE TO VOTING. ALL IN FAVOR OF APPROVING. DISAPPROVAL. OKAY. I'LL BUY THE DRINKS, LEAH. >> THANK YOU. >> ALSO WE'RE HAVING TWO SETS, FINISHING ON TIME. >> OKAY. GO AHEAD. >> PERFECT. OKAY. SO THE FINAL MOON SHOT CONCEPT FOR OUR VOTING CONSIDERATION TODAY IS TECHNOLOGIES DEVELOPMENT FOR USE IN NEXT GENERATION CANCER MODEL. DR. DANIELLE GERHARD, DIRECTOR OF THE YOU YOU PGH AT THIS OF CANCER GENOMICS AND OFFICE OF DIRECTOR IS PRESENTING. DANIELLE. >> I APPRECIATE THE METHODOLOGIES TO DEVELOP NOVEL MODELS, ONE OF THEM IS AS CULTURES LED BY HANS IN THE NETHERLANDS USING GROWTH FACTORS CONDITIONALLY REPROGRAM LABS FROM THE SCHLAGEL LABS FIRST AT NIH NOW AT GEORGETOWN. USING INHIBITORS OR GROWTH FACTORS ON IRRADIATED MOUSE CELLS. AND THE GROUP IS OPTIMIZE OPTIMIZING GROWTH CONDITIONS SPECIFICALLY FOR EACH TUMOR TYPE WHAT THIS LED TO, FOR EXAMPLE, DEVELOPING PROSTATE ORGANOIDS FROM THE LABORATORIES WHERE THE TRANSLOCATION WHICH IS FOUND IN ABOUT 20% OF PROSTATE CANCER IS NOW FOUND IN TWO OUT OF THE SEVEN MODEL, IS THAT THEY DEVELOPED A NUMBER OF YEARS AGO WHILE IN CCLE I THINK THERE WAS ONLY ONE MODEL. ANOTHER EXAMPLE WHICH I DON'T HAVE SLIDE FOR IS PROTOCOL TO DEVELOP A MODEL FROM OVARIAN CANCER IMPROVED THE SUCCESS RATE FROM LESS THAN 20% TO 50% AND THAT'S ONE THING I SHOULD BE STRAIGHT ABOUT, NONE OF THESE PROTOCOLS DEVELOP MODELS 100%. WE DON'T QUITE UNDERSTAND WHY. THESE TYPES OF MODELS HAVE NOW BEEN USED TO TRANSLATE TO THE PATIENT, FOR EXAMPLE, JEFF ENGLE MAN DEVELOPED PROGRAM MODEL S FROM LUNG CANCER PATIENTS WHICH WERE RESISTANT TO TREATMENT. AND WHAT THEY IDENTIFIED IS INSTANCES WHERE THEY WOULD TAKE THOSE MODELS, DO SMALL MOLECULE SCREENS, THEY IDENTIFIED TREATMENTS WHICH COULD THEN BE APPLIED TO THE PATIENTS. WHAT IS THE HUMAN CANCER MODEL'S INITIATIVE. WE STARTED TALKING ABOUT IT WITH THE NCI LEADERSHIP THREE OR FOUR YEARS AGO SO PRIOR TO THE BLUE RIBBON PANEL, MOONSHOT RECOMMENDATIONS, YET THEY INCLUDED IN THEIR RECOMMENDATIONS INVESTMENT IN TUMOR MODEL SUCH AS OREGON NORTH DAKOTAS AND OTHER PATIENT DERIVED TISSUE MODELS TO ACCELERATE THE TESTING OF THERAPIES AND CHARACTERIZATION OF TUMORS AND NCI LEADERSHIP THOUGHT THIS WAS A GOOD FIT. IT'S AN INTERNATIONAL CONSORTIUM THAT CI-UK PROVIDES NEW TISSUES. THE TECHNOLOGY, I DON'T KNOW INDUSTRIAL ARM OF HANS' AND SO THEY ARE PART OF THE CONSORTIUM. AND NCI IS FUNDING CANCER MODEL DEVELOPMENT CENTERS RIGHT NOW THERE ARE TWO, ONE OF THEM IS COLD SPRING HARBOR THE OTHER IS AT AN INSTITUTE. THERE MAY BE OTHERS SOON TO BE ANNOUNCED TO ACCELERATE THE MODEL DEVELOPMENT. THE HCMI WAS -- BUILDS THE INFRASTRUCTURE WAS QUITE CHALLENGING WE HAD TO COME UP WITH INFORMED CONSENT SO DISEASE MODEL CAN BE USED BY INDUSTRY AS WELL AS ACADEMIA. WE HAD TO COME UP WITH HOW WE ARE GOING TO DO THE CHARACTERIZATION, WE WANTED THIS TO BE A COMMUNITY RESOURCE. SO MATERIAL DEPOSITION REQUIREMENTS, THE MTA TRANSFERS, THE PEOPLE WHO GET THOSE MODELS THEY HAD BEEN QUITE A LOT OF INFRASTRUCTURE, I POINT TO YOU THIS WEBSITE WHERE YOU CAN FIND NOT ONLY THE DRAFT DOCUMENTS OF INFORMED CONSENT AS WELL AS MTA s BUT ALSO THE CLINICAL REPORT FORMS FOR EACH TUMOR TYPE THAT WE ARE ADDRESSING RIGHT NOW , WE ARE USING THE EXPERTS FROM THE VARIOUS CENTERS TO TELL US WHAT ARE THE IMPORTANT DATA THAT WE SHOULD COLLECT. AND SHY MENTION THAT NOT ONLY DID WE WANT WHAT YOU WOULD WANT TO HAVE IN YOUR CLINICAL REPORT FORM, THE AGE, GENDER, WHAT MOLECULAR CHARACTERIZATIONS WERE DONE. WE HAVE DEVELOPED WAY TO DO THIS TO COLLECT OUTCOME DATA, IT'S NOT COMPLETE OUTCOME DATA BECAUSE WE ARE GOING TO DELINK FOR QUITE A NUMBER OF REASONS I CAN TELL YOU ABOUT AS NEEDED, BUT WE ARE ASKING FOR OUTCOME DATA, ABOUT SIX MONTHS OF WHEN THE PATIENTS WERE INCLUDED IN THE PROGRAM. THIS IS A SUMMARY OF THE INFRASTRUCTURE THAT WE BUILT FOR THE NCI PROJECT. WE HAVE THE CANCER MODEL DEVELOPMENT CENTERS AND THEY DO INTERNAL QUALITY CONTROL. I SHOULD MENTION THAT THE OPTIMAL MODEL IS ONE FOR WHICH WE HAVE A MODEL, THE PARENT TUMOR AS WELL AS THE NORMAL BECAUSE WE WANT TO DO WHOLE AXIOM SEQUENCING THE NORMAL IS ABSOLUTE REQUIREMENT, THE TUMOR IS NOT ALWAYS POSSIBLE. BUT EVERYTHING IS BEING PROCESSED THROUGH A CENTRAL LOCATION SO THAT THEY ARE NO TECHNICAL ISSUES, THEY ARE SENT TO THE GENOME CHARACTERIZATION CENTERS OR SEQUENCING CENTERS, C CG IS FUNDING. THE CLINICAL DATA IS QUALITY CONTROL THROUGH ANOTHER CONTRACTOR AND DATA CAN BE SUBMITTED EITHER LIMITED FORMAT OR WEBSITES OR EVEN THROUGH A P.I.s AND EVERYTHING, MOLECULAR DATA THE CLINICAL DATA IS -- SOME OF THE DATA THAT ALSO OFFICE OF CANCER DATA COORDINATING CENTER. THE MODELS ARE DISTRIBUTE -- SENT TO A DISTRIBUTE OR FOR EXPANSION AND WE ARE ALSO DOING ANOTHER QC, WE ARE TESTING HOW WELK THIRD PARTY EXPEND THE MODEL HOW STABLE THEY ARE AND WE ARE ALSO DEVELOPING SEARCHABLE CATALOG SO THAT THE PEOPLE WHO WILL BE USING THESE MODELS CAN ESSENTIALLY SAY, I WANT PANCREATIC MODELS WHICH DON'T HAVE MUTATIONS, FOR EXAMPLE. THAT'S WHAT THE SEARCHABLE CATALOG IS. THE CANCER FOR WHICH WE ALREADY HAVE MODELS IN VARIOUS STAGES. BREAST, COLORECTAL, ASTRO, GLIAL , PEDIATRIC RARE CANCERS AND UPPER GI. MELANOMA, OVARIAN CANCER ON BASE SO TO SPEAK THEY ARE BEGINNING TO BE ESTABLISHED. WE ARE ALSO EXPANDING THE TISSUE SITES FROM WHICH WE ARE GETTING THE TUMORS WITH THE COLLABORATION OF OUR COLLEAGUEA AT CRCHD WHO FUNDED FOUR SUPPLEMENTS. WE ARE GOING TO BE GETTING TISSUES FROM FOUR CENTERS TO GET LATINA POPULATION REPRESENTED AFRICAN AMERICAN AND ASIAN AND FOR PEDIATRIC CANCERS WHILE WE ALREADY HAVE 16 OR 18 MODELS WE WANT TO DO MORE AND CONSORTIUM WILL BE PROVIDING IT TO US. AGAIN, WE ARE UPDATING OUR WEBSITE TO EXPLAIN THE PROGRESS WE HAVE MADE. SORRY, THIS WAS INTRODUCTION SO THAT WE ALL KNOW WHAT HCMI IS. SO WHY DO WE -- WHAT DO WE THINK IS A NEED FOR THIS CONCEPT. NEXT GENERATION CANCER MODELS ARE CONSIDERED INFANCY OF THE MODEL, IF YOU WOULD LIKE. SO SINCE WE DO WANT TO ACCELERATE THE RESEARCH USING THEM, THE KIND OF TECHNOLOGIES THAT ARE EITHER USING THEM OR DEVELOPING THEM NEED TO BE DEVELOPED, THE TOOLS JUST LIKE THE SRNA AND OTHER REAGENTS THAT I WILL TALK ABOUT, INTERPRETATION OF THE DATA SINCE SOME OF THESE MODELS THEY ARE USING GROWTH FACTORS. HOW DOES THAT AFFECT THE INTERPRETATION OF SCREENING METHOD. AND TRANSITION INTO CLINICAL APPLICATIONS. THE GOAL IS TO MAKE THE USE OF THE NEXT GENERATION CANCER MODEL S MORE REPRODUCIBLE, INTERPRETABLE AND REUSE AND NEED FOR EVERY RO1 LAB TO DEVELOP THE SAME THING. THE OUTCOME WILL ALLOW SHARING AND VALIDATIONS. BY BASIC CLINICAL ONCOLOGY COMMUNITIES. THE FUNDING OPPORTUNITY IS TO REMEDY THE LACK OF THE EFFICIENT AND VETTED TECHNOLOGIES. TO DEVELOP PROTOCOLS AND CONDITIONS WHEN USING MOLECULAR AND ENSURE THAT THE KNOWLEDGE AND MATERIALS ARE AVAILABLE BROADLY AND EXPEDITIOUSLY. THE DEVELOPMENT OF ROBUST RE AGENTS AND I WILL -- OF ALL OF THESE I WILL SHOW YOU SOME EXAMPLES, NOT EVERYTHING. AND DEVELOPMENT OF NOVEL ANALYTICAL METHODS TO INTERPRET THE RESULTS. THE CONCEPT IS USING -- >> I HATE TO INTERRUPT YOU BUT YOU HAVE ABOUT FIVE MORE MINUTES >> PARDON? >> YOU HAVE FIVE MORE MINUTES. >> YES, MA'AM. WE ARE BUILDING ON NCI'S INVEST MENT FOR STANDARDIZE RE AGENT CONTRACTORS. SO, FOR EXAMPLE, OF FEW FUNDING OPPORTUNITY TOPICS AND THEY ARE FEW IS -- I KEEP ON REPEATING THIS ABOUT THE PLATFORMS AND TECHNOLOGIES. CANCER MODELS I HAVE ALREADY MENTIONED THAT SOME OF THE PROTOCOLS ARE VERY TUMOR TYPE SPECIFIC. CAN WE GROW THESE MODELS IN SIMILAR MANNER SO THAT WE CAN DO SCREENING WITHOUT HAVING TO GROW EACH TISSUE TYPE WITH DIFFERENT GROWTH FACTORS. HOW CAN WE REDUCE THE GROWTH CONDITIONS. OTHER BIOPHYSICAL PARAMETERS DO THEY IMPACT ON DRUG SCREENS. CAN WE OPTIMIZE THESE SCREENS. AND MOUSE IRRADIATED MOUSE CELLS ARE IMPORTANT FOR CRCs. WHAT CAN -- DO WE ESTABLISH DIFFERENT GENETIC BACKGROUND MUTATION CHARACTERISTICS WITH A DIFFERENT PROTOCOL. WE DON'T KNOW ANYTHING ABOUT D VERSUS 3D. WHAT HAPPENS IF A MODEL WHICH WAS ESTABLISHED IS GROWN IN 2D AND HOW DOES THOSE RESULTS AFFECT -- HOW DOES THAT AFFECT THE RESULTS AND THERE ARE ALREADY PAPERS. THERE WAS ONE OF THEM WHO HAS SHOWN THAT IN FACT IT DOES AFFECT RESULTS. MICRO ENVIRONMENT AND IMMUNE CELL, THERE ARE GROUPS WHO ARE ALREADY DEVELOPING MODELS WITH IMMUNE SYSTEM AND HOW TO DECREASE THE TIME. THE OTHER FOA IS CRISPER RE AGENTS. CRISPR ARE STILL A WORKING PROCESS. DO TO EXPERIMENT YOU INTRODUCE THEN SELECT FOR THEM THEN YOU INTRODUCE THE GUIDE RNA AND MANY PEOPLE USE LIKE TEN GUIDE RNAs GENE, IF YOU THINK ABOUT IT YOU NEED BILLIONS OF CELLS FOR THESE TYPES OF EXPERIMENTS. ONE OF THE THINGS WE WERE AIMING FOR JUST IN DIFFERENT CAS9s BECAUSE BACTERIAL IMMUNE RESPONSE BASICALLY. AND EACH ONE OF THEM HAS DIFFERENT CAST 9s. WE WANT IT TO BE TESTED AS PARTS OF A CONTRACT WORKING WITH OTHER CRISPR TO BECOME SINGLE CAST 9 GUIDE CONSTRUCT WHICH IS ROBUST LY EXPRESSED. >> I HATE TO INTERRUPT YOU AGAIN WE REALLY NEED TO WRAP UP SO MAYBE YOU SHOULD REALLY GO TO THE END OF THE PRESENTATION AND JUST DESCRIBE THAT. MAJOR POINTS THE RFA MAYBE DURING DISCUSSION THERE IS GOING TO BE OPPORTUNITY. >> OKAY. NOT ALL OF THE TOPICS THAT I MENTIONED WOULD BE ADDRESSED BY A CENTER. THE IDEA WOULD BE THAT THE PROPOSALS WOULD BE SELECTED BY THE QUALITY AND BY THE APPROACH TO VALIDATION AND BENCHMARKING AND WORK AS COLLABORATIONS. AND THAT EVERYTHING THAT WOULD BE SHARED THROUGH A WEBSITE WHICH I'LL LIST HERE. I WAS ASKED TO INCLUDE -- AS ONE OF THE COMPONENT OF THE ONE CONTRACTOR FUNCTION SO THAT EVERYBODY CAN BE USING THE SAME MATROGEL WHO IS USING OREGON NORTH DAKOTA THEN THEY CAN BE USED FOR MCI BENCHMARKING PROGRAMS AND OTHER CONTRACTOR WILL BE DEVELOPING THE CRISPR RE AGENTS THAT I INCLUDED AND IT WOULD BE DISTRIBUTED THROUGH LIKE ASAU. ADVANTAGE OF THIS APPROACH REDUCE REDUNDANT SEE, ALLOW ACCESSIBILITY. >> HEAR FROM THE REVIEWERS THEN SEE DURING DISCUSSIONS THERE NEEDS TO BE. THE REVIEWERS WERE DAVE MARTIN AND KIM. HOPE I'M PRONOUNCING IT OKAY. DAVE, WHY DON'T YOU START. >> THANK YOU. DURING THE BLUE RIBBON PANEL THAT LIZ COCHAIRED DURING THE CLINICAL TRIALS SUBSECTION, THE ORGANOIDS CAME UP AS A POTENTIAL NEW METHOD THAT WOULD ACCELERATE PERSONALIZED MEDICINE APPROACHES IN CANCER. IT ACTUALLY GOT THROUGH THE MULTIPLE COMMITTEES AND IN THE END WAS HIGHLIGHTED AS ONE OF TWO TECHNOLOGIES THAT WE WANTED TO TEST. THE EMPHASIS WAS TO USE THESE NEW CELL CULTURE METHODS TO EX VIVO ASSIST IN PERSONALIZED MEDICINE APPROACHES. RIGHT AROUND THE TIME THAT THE PANEL FINISHED, THE NCI STARTED HCMI PROGRAM WHICH WAS TO GET TOGETHER UP TO A THOUSAND NOVEL CANCER CELL CULTURES OF BOTH OREGON NORTH DAKOTA AND NON- OREGON NORTH DAKOTA -- TO DETERMINE HOW FAITH. THE MODEL IS. CELL MODELS ARE TO THE PRIMARY TUMOR. TO ME THESE ORGANOIDS, TWO QUESTIONS. ARE THEY FAITHFUL TO THE TUMOR OF THE PATIENT. THIS IS WHY WE INVEST A LOT OF OUR OWN EFFORT IN THIS SPACE. THERE ARE MANY PARAMETERS, ONE IS IT TAKES A WHILE TO GENERATE A MODEL EVEN WHEN YOU'RE PRETTY GOOD AT IT. TWO, COST INORDINATE AMOUNTS OF MONEY TO BUILD THESE MODELS SO THE COMPLAINT I GET FROM THE FIELD IS, SOUNDS GREAT BUT ARE YOU GOING TO PROVIDE MATRIGEL OR CASH. THERE ARE SERIOUS LIMITATIONS TO TRADITIONAL CELL CULTURE METHODS IT DOESN'T WORK EVERY TIME. PLACES THAT ARE REALLY GOOD AT IT PROBABLY RUN A THIRD TO 70% WHEN THEY GET SAMPLE FROM A PATIENT THAT COULD OBVIOUSLY BE BECAUSE YOU HAVE SAMPLE THAT DOESN'T HAVE CANCER CELLS OR COULD BE THE BIOLOGY OF THE TUMORS ONE THAT WE DON'T KNOW HOW TO CULTURE. SO, WHEN THIS ASSIGNMENT WAS PASSED TO ME, I READ IT WITH INTEREST AND DISCUSSED IT WITH OUR COMMITTEE. AS YOU SAW IN THE BEGINNING TWEAKED THE PROPOSAL TO BRING PERSONALIZED MEDICINE INTO IT, DID IDENTIFY MULTIPLE ISSUES THAT WE HAVE CURRENTLY, WHICH ARE OPTIMIZATION ISSUES, NUMBER ONE. ARE THERE BETTER MATRICES, BETTER MEDIAS ALLOW MODELS TO BE MADE MORE QUICKLY, GROWN MORE EASILY. NUMBER TWO, IF WE INCLUDED THE TUMOR MICRO ENVIRONMENT MIGHT THESE MODELS BE PERTINENT LIKE APPLICATION WE'VE HEARD ABOUT BEFORE. IMMUNE CELLS, THEN NUMBER THREE FOR THE ANALYSIS, BE THEY MEDICINES IN OUR CLINIC, BE THEY GENETIC METHODS FOR INTERROGATING CANCER CELLS, BETTER WAYS TO DEVELOP THEM. SO WHEN WE TALK TO HER ABOUT ALL COMMITTEE, WE REALIZE THAT THESE MODELS ACTUALLY MAY BE PREDICTIVE OF OUTCOMES IN PATIENTS AND SHOULD BE PUSHED BY OUR COMMUNITY. THERE ARE METHODOLOGICAL ISSUES THAT SHE IS HIGHLIGHTING HERE THAT YES, SMART PEOPLE, CLEVER PEOPLE TO WORK ON, TO HELP US DEVELOP POTENTIALLY THAT SHOULD BE DONE IN TANDEM WITH PEOPLE WHO ARE TRYING TO DEVELOP THESE AS COCLINICAL MODELS BECAUSE THEY'RE GOING TO LOOK AT THE PROBLEM FROM A DIFFERENT ANGLE AND PUSH LEVERS DIFFERENTLY IN EFFORTS TO DECREASE -- INCREASE THE SPEED OF MAKING THE MODEL, DECREASE COST, TESTING IN REALTIME AND PATIENTS WHETHER THE MODELS ARE PREDICTIVE OF OUTCOMES WHEN PATIENT IS BEING TREATED. THIS IS A BIG INVESTMENT BY THE NCI OVER THE YEARS ON THIS CONCEPT. ON THIS PROPOSAL SPECIFICALLY THIS IS A VERY MODEST INVESTMENT , I THINK MAYBE THE SMALLEST FINANCIAL OF ALL THE EIGHT THAT WE'VE LOOKED AT TODAY PERSONALLY THINK INVESTMENT SHOULD BE MUCH HIGHER BECAUSE I DO THINK THIS HAS CHANCE OF ACTUALLY CHANGING HOW WE TAKE CARE OF PATIENTS. BUT I'M GOING TO TURN IT NOW TO MY OTHER TWO COLLEAGUES GOES WHO ARE CONCOMMITTEE KIM AND MARTIN WHO MIGHT HAVE SOME COMMENTS. >> MARTIN? >> I DON'T HAVE MUCH TO ADD. I THINK WE WERE IN GENERAL INITIATIVE, IN OTHER WORDS, WE WERE NOT DOWN ON THE PROJECT. INITIALLY IT WAS A PROBLEM FOR ME IS THAT IT WAS NOT SURE WHETHER THIS NEW INITIATIVE WAS TO MAKE NEW REAGENTS OR ACTUALLY TO TEST NEW REAGENTS, THEN TEST TO FIND WAYS TO ASSESS THEN DOING DRUG TESTING OR SCREENING. MOST OF OUR CRITICISM, ALTHOUGH YOU DIDN'T HEAR SOME OF THEM, BUT I THINK OVERALL WE WERE RELATIVELY CLOSE. >> THANKS. MY PERSPECTIVE, WE DID HAVE SEVERAL CONCERNS, A BIG ONE WAS MAKING IT CLEAR THAT THIS WAS BUILDING ON AN EXISTING RESOURCE THAT IS ALREADY QUITE MATURE, BECAUSE THAT WASN'T CLEAR ORIGINALLY AND I THINK THAT LED TO THE EXTENSIVE BACKGROUND THAT WE GOT HERE TODAY. THAT'S HELPFUL. MY CONCERN AND I THINK ALSO DAVE HAD ALLUDED TO, HOW IS THIS PUSH ING THE ORGANOIDS TO MAKING THEM VALUABLE FOR MEDICINE. I THINK THAT IT WAS SOMEWHAT RESPONSIVE IN THAT WAY, PARTICULARLY IN THE TITLE BUT IT STILL FEELS TO ME TO BE A LITTLE BIT SCHIZOPHRENIC WHETHER DEVELOPING METHODOLOGY, IF IT'S MAKING STANDARDIZED PROCESSES OR IF IT'S PARTICULARLY MAKING THESE THINGS VALUABLE TO CLINICIANS. SO THAT REMAINS MY PROBLEM. >> SO IF I CAN, I WOULD LIKE TO ANSWER IN THE RESPONSE TO THE TECHNOLOGY DEVELOPMENT AND SO THE GOAL WAS TO MAKE THE PROTOCOLS SUCH THAT THERE CAN BE A NEXT STEP APPLY IN THE CLINICAL IN PARALLEL WITH CLINICAL TRIALS BUT I THINK THIS FIELD STILL NEEDS A DEVELOPMENT OF STANDARDIZED PROCESSES AND RE AGENTS WHICH CAN BE TESTED AND SO THIS IS TO ME THE FIRST STEP AND THE REASON WHY I KEPT HARP ING ON THE WEBSITE AND SHARING OF THE PROTOCOLS IS THAT OTHERS CAN APPLY IT AS THEY WOULD -- TO WHAT CLINIC IN THE PRECLINICAL ARENA. I SEE WE STILL NEED TO TAKE THE FIRST STEP IN HOW TO BE MORE ROBUST. >> OKAY. I'LL ASK FOR A MOTION. DAVE. >> SO THE MOTION IS TO INVEST IN THE OREGON NORTH DAKOTA AND RELATED PLATFORMS FOR PERSONALIZED MEDICINE. IN TILL. >> I NEED A SECOND. ANYBODY SECOND? MARTIN? OKAY, THANK YOU. ANY DISCUSSION? OKAY. NOW WE'RE TALKING. >> I STILL HAVE OF TRYING TO UNDERSTAND EXACTLY WHAT THIS IS -- I KNOW THIS IS SMALL AMOUNT OF MONEY BUT TRYING TO GET AT BECAUSE THEY ARE TWO VERY DIFFERENT THINGS. THEY'RE BOTH VALUABLE. I'M NOT SURE SAYING THAT IS GOING TO BE READY FOR THE CLINICAL OR VALIDATED IS GOING TO HAVE ANY CHANCE OF BEING DONE NOT ONLY SMALL AMOUNT OF MONEY BUT IT'S NOT REALLY SET UP TO DO THAT KIND OF VALIDATION. IT'S LEARLY IMPORTANT FOR THE FUTURE. BUT IT SEEMS THAT THE MORE VALUE HERE IS JUST REALLY STANDARDIZING THE MODELS THEN MAKING THEM AVAILABLE TO RESEARCHERS. IT SEEMS TO ME THAT THE BIGGEST VALUE TO RESEARCHERS WOULD BE GETTING THE ACTUAL TISSUE AND IF YOU ARE GOING TO DO THIS WHAT IS GOING TO BE IMPORTANT SET UP SOME KIND OF INFORMATIC SYSTEM SO THAT WHEN THE MODELS ARE DISTRIBUTED THAT INFORMATION COULD BE ADDED ON THESE MODELS AS RESEARCHERS DEVELOP ANALYSIS OF THESE MODELS THEY COULD PUT INTO SOME KIND OF WEBSITE TO DEVELOP VALUABLE WEBSITE THAT WOULD HAVE ANNOTATION. ENABLE YOU TO DO SOME VERY INTERESTING THINGS LIKE SINGLE CELL TRANSCRIPTOME. AND WHAT DOES THE TRANSCRIPTOMES IF YOU PUT THAT INTO A WEBSITE IT COULD BE REALLY VALUABLE. BUT IT'S VERY DIFFERENT FROM A CLINICAL ANNOTATION. I THINK IT'S IMPORTANT IF THIS IS GOING TO BE APPROVED NOT TO BE SCHIZOPHRENIC. >> WHAT IS THE REASON THAT THE COMPOSITION OF THE MODEL, IS THAT YOU HAVE DEVELOPED TO DATE? >> I WOULD NEED TO GO BACK, THIS IS SOMETHING THAT WE ARE JUST COLLECT CAN. >> MAYBE JUST A BALLPARK. >> OUR AIM IS TO HAVE ABOUT 20- 30% EITHER PEDIATRIC UNDER REPRESENTED MINORITIES. >> SO CLARIFICATION. WHAT DO YOU HAVE TO DATE? >> I WOULD BE LYING TO YOU IF I GAVE YOU A NUMBER. THAT'S WHY I SAID WE ALREADY HAVE A SOURCE OF TISSUE FROM 80 CASES TO MAKE SURE THAT WE ADDRESS THE UNDER REPRESENTED MINORITIES. >> JUST COUPLE OF CONCERNS. IT'S NOT CLEAR WE'RE EVEN GOING TO KNOW THE GENETIC COMPOSITION OF THE THINGS THAT ARE GOING IN, UP FRONT SEQUENCING OF EVERY SAMPLE. COORDINATION WITH THE PDX PROGRAM WOULD BE ESSENTIAL I THINK. THIS IS LIKE ALL THINGS TO ALL PEOPLE. ALL TUMORS SO BROAD AND DIFFUSE. IT HAS TO BE REFOCUSED ON SOMETHING MORE DOABLE. HAVE CLEAR SINGLE PURPOSE. >> LET ME -- HER PROPOSAL TO USE THE HCMI RESOURCE WHICH IS ALREADY VERY VETTED, VERY SEQUENCED, PRIMARY TUMORS AND ORGANOIDS ARE CONDITIONALLY RE PROGRAMMED NOT TO GENERATE NECESSARILY NEW MODELS BUT TO USE A LIBRARY OF SAMPLES THAT HAVE ALREADY GONE THROUGH THE QA QC. THEN TO DEVELOP IMPROVED TECHNOLOGIES FOR USING THEM THAT CAN BE DISSEMINATED TO THE COMMUNITY. THAT'S ACTUALLY THE PROPOSAL. WE BROUGHT IN FOR THE PURPOSE OF PERSONALIZED MEDICINE, BECAUSE THAT'S THE REASON WHY WE BROUGHT THAT UP IN THE MOONSHOT IN THE FIRST PLACE, THAT'S WHY IT WAS IN THE MOONSHOT, COULD THIS BE WAY TO HAVE PERSONALIZED MEDICINE. >> CLARIFICATION. A MOTION WAS MADE TO SUPPORT IN PRINCIPLE. MAKE A MOTION TO APPROVE, DIS APPROVE. >> IN PRINCIPLE, STRIKE FROM THE RECORD, GET YOUR PEOPLE TO STRIKE THAT, IN ACTUAL. THE MOTION WAS TO SUPPORT -- >> IT STILL DOESN'T DO IT. >> THE MOTION IS TO APPROVE THE PROPOSAL. >> WOULD HAVE MOTION TO APPROVE. WE NEED A SECOND. >> SECOND. >> WE NEED TO VOTE ON THIS MOTION. >> BUT DISCUSSION IS OVER, I THINK THAT SOMEONE -- [ Laughter ] >> I KNOW WHAT YOU'RE GOING TO DO. WE HAVE A MOTION ON THE TABLE TO APPROVE. THAT MOTION HAS BEEN SECONDED. >> NOT AMENDED WE CAN VOTE ON THAT MOTION IF IT DOESN'T CARRY, THEN WE CAN MAKE ANOTHER MOTION. >> WE'RE IN DISCUSSION. >> THE MOTION WAS TO APPROVE. >> PARLIAMENTARY PROCEDURE SAYS YOU CAN -- >> WE HAVE A MOTION. >> HE NEEDS TO GET THE FLOWERS AND CHOCOLATE. >> WE HAVE MOTION TO APPROVE. IT'S BEEN SECONDED. WE'RE STILL IN THE DISCUSSION BECAUSE WE HAVE NOT VOTED. >> THAT'S RIGHT. WE ARE IN A DISCUSSION. >> I DON'T WANT TO BELABOR THIS BUT I AM VERY CONFUSED AND I HEAR ONE REVIEWER'S INTENT WHICH IS DIFFERENT THAN WHAT YOU PRESENTED AND I JUST THINK -- IT'S MY VIEW THAT THIS WOULD REALLY BENEFIT FROM BEING DEFERRED AND HAVING YOU SET BACK AND THINK OF VERY CONCRETE SET OF GOALS THAT YOU WANT TO ACCOMPLISH. BECAUSE I THINK THIS IS ALL OVER THE PLACE, I'M SORRY. I DON'T MEAN TO BE DISRESPECTFUL THE RESOURCE THAT YOU'RE DEVELOPING IS EXCEEDINGLY VALUABLE AND ESSENTIAL FOR CANCER RESEARCH BUT WHAT EXACTLY YOU WANT TO DO IN THIS RFA IS WAY TOO BROAD IN MY ESTIMATION. I DON'T KNOW HOW YOU WOULD WRITE IT, QUITE FRANKLY. >> KEITH? >> JUST TO EXPAND THE VOCABULARY MORE GENERAL TO MORE SPECIFIC. PRECISION MEDICINE APPLICATION COULD BE I'M NOT HEARING THE ENERGY TO DO THIS, TO DEVELOP CL EA LAB LIVE FUNCTIONAL ASSAYS THAT'S ONE VERSION. ADJACENT VERSION RETROSPECTIVE ANALYSIS YOU DO ALL KINDS OF RESEARCH BUT YOU KNOW WHAT THE PATIENT GOT TREATED WITH, THE PATIENT WHOSE SAMPLE WAS RECEIVED. RETROSPECTIVE ANALYSIS MEANS THAT YOU THEN TEST AS ONE OF THE TEST CONDITIONS YOU PERTURB THAT SAMPLE WITH THAT VERY THERAPY. THAT IS YOUR CONTROL OF SORTS BECAUSE IF THAT PATIENT HAD A RESPONSE, DIDN'T HAVE A RESPONSE YOU'D LIKE TO KNOW IN THE ORGANOID HOW THAT TREATMENT P. IN RELATION TO ALL THE DIFFERENT THINGS -- BUT THAT'S -- WHEN YOU TALK ABOUT PRECISION MEDICINE THAT'S WHERE THAT IS HEADED. ONE OF THOSE TWO THINGS. EITHER PROSPECTIVE OR RETROSPECTIVE ANALYSIS OF WHAT ACTUALLY HAPPENED WITH THE PATIENT. >> CAN I ANSWER. YES, I DID ADD THE TERMINOLOGY OF PRECISION METED IS IN BUT I EMPHASIZE THAT THIS IS A TECHNOLOGY PROPOSAL, BECAUSE WHILE WE ARE DEVELOPING THESE NEW CANCER MODELS AND THE GOAL IS TO USE THEM TO BETTER INTERPRET SCREENING RESULTS AND UNDERSTANDING BETTER THE BIO CHEMISTRY AS WELL AS TO UNDERSTAND WHAT CAUSES INITIATION AND PROGRESSION. THAT ONCE THE TECHNOLOGY IS DEVELOPED IT CAN BE USED BY OTHERS FOR THAT USE. THAT WAS A GOAL, DEVELOPING CRIS PRS FOR ORGANOIDS AND PROGRAM CELLS. RIGHT NOW WE KNOW THAT CRISPRS HAVE QUITE A LOT OF ISSUES THAT ARE JUST COMING OUT AND SO MY CONCEPT WAS TO MORE EMPHASIZE THE TECHNOLOGY DEVELOPMENT KNOWING THAT WE ARE NOT YET READY FOR, LET'S CALL IT PRIME TIME. >> I WOULD LIKE TO SAY, STRONGLY SUPPORT WHAT CHERYL HAD SAID THIS SHOULD COME BACK. BECAUSE IT'S NOT REALLY FOCUSED OR READY, THE REASON IS, IT WOULD BE NICE TO BE ABLE TO EVENTUALLY GET THIS INTO THE CLIP CAN BUT NO WHERE NEAR READY FOR THAT. WHEN YOU ACTUALLY LOOK AT THIS THE TECHNOLOGY STILL HAS TO BE DEVELOPED. IF THIS WAS REFOCUSED AS TECHNOLOGY DEVELOPMENT ALONG WITH DISTRIBUTING THIS SO OTHER PEOPLE CAN LOOK AT THE TECHNOLOGY AND LOOK AT SOME OF THE BIOLOGY THEN IT WOULD HELP GET IT TOWARDS THE NEXT STEP OF THE CLINICAL APPLICABILITY BUT NOT TRY TO BITE OFF MORE THAN REALISTIC AND MOVE RIGHT INTO THE CLINIC, JUST NOT READY FOR THAT. >> THE PROPOSAL IS THAT WE TAKE A VOTE NOW DEPENDING ON THE RESULTS WE CAN -- THERE IS ANOTHER DISCUSSION? >> WE HAVE A MOTION ON THE FLOOR >> CAN I MAKE ONE MORE COMMENT OR IS THE DISCUSSION OVER? >> THERE'S A GOOD CHANCE THIS WON'T. I THINK THAT VEERING TOWARD -- THIS WAS -- BUT MY CONCERN ABOUT AS TECHNOLOGY FOCUS IT WAS REALLY ON CRISPR AND STOCKPILES WHICH WAS NOT FULLY DEVELOPED. I AGREE WITH TAKING IT BACK BUILT DO WANT TO SAY THAT WE HAVE TAKEN IT DOWN THIS RABBIT HOLE. >> ARE WE READY TO VOTE? ALL RIGHT. ALL IN FAVOR OF APPROVAL, THE MOTION WAS TO APPROVE JUST REMIND EVERYONE. ALL IN FAVOR OF APPROVAL. MOTION FAILED. PAUL LET, WE CAN NOW MOVE TO SECOND MOTION? >> NO. NO. NO. >> FINISH. OKAY. DISAPPROVAL. >> THE NOTION IS -- HOW MANY ARE AGAINST THE MOTION? >> HOW MANY -- ONE WAS FOR APPROVE NOW WE'RE ASKING WHO IS VOTING FOR DISAPPROVING. >> NO. NO. THE MOTION WAS NOT TO DISAPPROVE IT WAS FOR APPROVAL. >> I'M TAKING THE VOTE ON THE MOTION. >> WAIT, WAIT, WAIT. >> WE HAVE VOTE OF APPROVAL THAT WAS ONE YES. HOW MANY -- >> TWO. >> THERE WERE TWO YES, SIRES. HOW MANY OF YOU VOTE AGAINST, DO NOT VOTE FOR APPROVAL, VOTE AGAINST THE MOTION OR WHATEVER YOU WANT TO CALL IT. 14 -- THE MOTION FAILS. 14 SAID NO. DOES ANYONE WANT TO MAKE ANOTHER MOTION NOW? >> I WOULD MAKE A MOTION THAT WE DEFER AND WORK ON THIS AND BRING IT BACK. DO WE HAVE SECOND FOR THAT MOTION? >> DISCUSSION? VOTE. HOW MANY OF YOU VOTE FOR DEFERRAL OF THIS CONCEPT. 15. HOW MANY OF YOU VOTE AGAINST THE MOTION TO DEFER? THE MOTION CARRIES. IT'S BACK TO YOU. >> I BELIEVE THERE BEING NO FURTHER BUSINESS, THE MEETING IS ADJOURNED, THANK YOU VERY MUCH.