TODAY, OUR FIRST SPEAKER JILL SMITH, THE MEDICAL DOCTOR. SHE USED TO WORK AT PENN STATE, THEN SHE WORKED AT NIH. AND NOW, SHE'S A PROFESSOR OF MEDICINE AT GEORGETOWN AND HER TITLE: TRANSLATIONAL RESEARCH, BENCH TO BEDSIDE CLINICAL TRIALS. JILL. >> THANK YOU. THANK YOU. CAN YOU ALL HEAR ME? LET'S Z., I GUESS THE MOST IMPORTANT THING IS CAN THE GUY IF THE BACK HEAR ME OR SOMETHING. CAN HE HEAR ME OKAY IN WHATEVER. SO HOW MANY OF YOU ARE MD'S? ANYBODY? ANYBODY PH.D.? OKAY. GOOD. AND ARE ALL OF YOU DOING RESEARCH? OKAY. GOOD. SO I'M CLINICIAN SCIENTIST. SO I TAKE CARE OF PATIENTS, AND I ALSO DO BENCH RESEARCH SO WE'RE AN ENDANGERED SPECIES. [LAUGHING] SO WHATEVER. THIS IS WHAT THE NIH WANTS BUT YOU KNOW, WE'RE AN ENDANGERED SPECIES. I HAVE SOME DISCLOSURES. I'M A CO-INVENTOR ON SOME PATENTS AND DO I SOME CONSULTING WORK FOR SOME BIOTECH COMPANIES CAN YOU HEAR ME BACK THERE? OKAY. THE OBJECTIVES OF WHAT WE'RE GOING TO TALK ABOUT TODAY IS TO UNDERSTAND HOW AN IDEA CAN BE TAKEN FROM THE RESEARCH LAB TO PATIENT CARE. WE'RE GOING TO LEARN ABOUT THE STEPS IN CONDUCTING A CLINICAL TRIAL, UNDERSTAND SOME OF THE OBSTACLES TO OVERCOME FOR DRUG DEVELOPMENT AND I'LL GIVE YOU SOME EXAMPLES FROM SOME OF MY RESEARCH AND HOW WE'RE TAKING THAT INTO THE CLINIC AND WHAT ARE THE PITFALLS OF DOING THIS ENTERPRISE. SO FIRST OF ALL, THIS IS KIND OF -- I DON'T KNOW IF THIS WORKS. DOES THIS WORK? I DON'T HAVE A POINTER. THERE WE GO. AS FAR AS MOST OF US ARE IN THIS PHASE, WHICH IS THE PRECLINICAL RESEARCH, AND THERE ARE LOTS OF IDEAS. THERE'S LOTS OF DRUGS BEING TESTED, A LOT OF COMPOUNDS THAT YOU'RE TESTING IN THE LAB BUT THEN AS FAR AS WHICH ONE OF THESE ACTUALLY MAKE IT THROUGH INTO DRUG DEVELOPMENT. SO THERE IS THIS BOTTLE NECK AND THERE'S VERY FEW DRUGS THAT ACTUALLY MAKE IT AND MAKE TALL WAY THROUGH. AND THIS WAS KIND OF AN OVERVIEW. THERE'S A PAPER THAT TALKS ABOUT DRUG DEVELOPMENT, AND THE OVERALL PROBABILITY OF SUCCESS, YOU KNOW, IF YOU LOOK AT THIS IS THAT IT SHOWS YOU THAT, SO OF ALL THE DRUGS, ABOUT 30% OF THOSE DRUGS THAT ARE TESTED PRECLINICAL, ACTUALLY MAKE IT TO PHASE 1 TRIALS THIS SHOWS YOU THE PROBABILITY OF SUCCESS, AND THE PROBABILITY OF MOVING ON TO THE NEXT STAGE. SO YOU ONCE YOU GET OVER TO HERE, AND IF YOU'VE GOTTEN APPROVAL AND A NEW DRUG APPLICATION, THINGS ARE PRETTY GOOD. YOU'RE MOST LIKELY GOING TO MAKE IT. BUT IN THE EARLY STAGES, YOU KNOW, IT'S VERY, YOU KNOW, LESS THAN HALF OF THE DRUGS OR EVEN FEWER MAKE IT THAT FAR. THEN THE OTHER THING TO JUST KIND OF POINT OUT FROM THE SLIDE IS HOW LONG DOES IT TAKE. YOU KNOW, PEOPLE ALWAYS SAY HOW LONG DID IT TAKE YOU FROM WHEN YOU DID THAT CELL CULTURE EXPERIMENT AND TESTED IT IN ANIMALS AND TOOK IT TO A TRIAL, WHEN DID IT GET APPROVED. SO THE PRECLINICAL. AND HERE, IT SAYS, PRECLINICALS TAKES ONE TO SIX YEARS. YOU KNOW, IF YOU CAN DO THAT DURING YOUR POST DOC TRAINING AND GET SOMETHING DONE IN THAT PERIOD OF TIME, THAT'S GREAT. BUT THEN IT TAKES US SIX TO 11 YEARS TO GET THROUGH ALL THE CLINICAL TRIALS, AND TO GET APPROVAL, IT MOVES FASTER ONCE YOU GET THROUGH THE DIFFERENT PHASES OF TRIAL AND THERE'S ALL THIS POST MARKETING AND THAT'S WHERE THE PHARMACEUTICAL COMPANIES MAKE THEIR MONEY BACK. SO AS FAR AS DRUG DEVELOPMENT IN THE UNITED STATES IT TAKES AN AVERAGE OF 12 YEARS FOR AN EXPERIMENTAL DRUG TO GO FROM THE LAB TO THE CLINIC. SO THAT'S LONGER THAN MOST OF YOUR TRAINING. AND ABOUT ONLY 5 IN 5,000 DRUGS THAT ENTER PRECLINICAL TESTING CAN GO AHEAD AND MOVE ON. TO HUMAN TESTING SO ONE OF THESE FIVE DRUGS TESTED IN HUMANS IS ACTUALLY APPROVED. THAT MEANS THE CHANCE FOR A NEW DRUG MAKING IT TO THE MARKET IS APPROXIMATELY ONE IN 5,000. BUT IT'S GOT TO BE YOUR DRUG, RIGHT? SO DON'T LET THIS DISCOURAGE YOU. THIS IS ACTUALLY WHAT HAPPENS. THAT'S WHY YOU HAVE TO THINK ABOUT THESE THINGS AND WHAT IS GOING TO MAKE YOUR DRUG OUTSTANDING OR YOUR TREATMENT. SO THE PROCESS OF GETTING A DRUG APPROVED OF COURSE, INVOLVES THE FOOFOOD AND DRUG ADMINISTRATION, OR THE FD AND THE FDA REQUIRES A SEQUENCE OF TEST AND I'LL GO THROUGH WHAT IS REQUIRED TO GET A DRUG DEVELOPED. SO MOST OF US ARE IN THIS STAGE. MANY OF YOU WORKING WITH ANIMALS? ANYBODY? SO A LOT OF THE PRECLINICAL TESTING DONE IN THE RESEARCH LAB, AND IT'S ABSOLUTELY NECESSARY. YOU HAVE TO DO THE CELL CULTURE WORK AND YOU HAVE TO TEST IT IN AN ANIMAL MODEL. SOME OF THE FDA REQUIRES TWO DIFFERENT ANIMAL MODELS BEFORE THEY'LL ALLOW YOU TO MOVE IT ONTO HUMAN TRIAL. SO THESE ARE ESSENTIAL AND THIS PART IS SO CRITICAL AND THE RECORD~KEEPING AND STUFF THAT YOU'RE DOING AT THIS PHASE, BECAUSE THIS IS THE AREA WHERE IF THERE ARE NOT GOOD RECORDS AND THERE ARE NOT GOOD RESEARCH DONE AT THIS STAGE, WHY THE DRUGS FALL OFF WHEN THEY DON'T MAKE IT TO THE PHASE 1 TRIALS. SO THIS IS IMPORTANT. RECORD EVERYTHING IN YOUR NOTEBOOK, WHETHER YOU THINK IT'S IMPORTANT OR NOT BECAUSE ANY OBSERVATION YOU SEE, MAY BECOME IMPORTANT IN A CLINICAL TRIAL. SO A PHASE 1 TRIAL IS ACTUALLY JUST TESTING A DRUG ONCE IT'S BEEN TESTED IN THE ANIMALS, THEN YOU WANT TO KNOW WELL, CAN YOU TEST IT IN A HUMAN BEING AND IF YOU CAN, IS IT SAFE TO GIVE TO A HUMAN BEING. THE PHASE 1 TRIAL DOES NOT CARE ABOUT EFFICACY. THEY DON'T CARE WHETHER IT WORKS OR NOT. SO SOME PHASE 1 TRIALS ARE ACTUALLY DONE IN NORMAL CONTROLS BUT THEY WANT TO KNOW, IS IT SAFE AND HOW SHOULD THE TREATMENT BE GIVEN? YOU NEED TO LEARN A LITTLE BIT ABOUT THE PHARMICOKINETICS. ONCE GIVEN TO THE HUMAN BEING, IS IT ORALLY ABSORBED. DO YOU HAVE TO GIVE TO INTRA INTRASEENOUSLY? SUBCUTANEOUSLY. >> SO IT'S MAINLY ABOUT TOXICITY, THAT'S WHAT THE PHASE 1 TRIAL IS B. AND IT DOESN'T TAKE A LOT PEOPLE TO DO THAT. THE PHASE 2 IS THE EFFICACY TRIAL. IN THE EFFICACY TRIAL, HAVE YOU TO HAVE MORE PATIENTS AND YOU HAVE TO HAVE A PRIMARY END POINT. IT'S USUALLY DONE A BLINDED STUDY OR UNBIAS. SO IT'S USUALLY A RANDOMIZED DOUBLE BLIND PLACEBO CONTROL TRIAL AND YOU REALLY WANT TO KNOW IN THE PHASE 2 DOES THE DRUG WORK, IS IT MORE EFFECTIVE THAN PLACEBO AND IT DOESN'T NECESSARILY COMPARE IT TO OTHER TREATMENTS, HOWEVER, IN CANCER THERAPY, IT'S A LITTLE BIT DIFFERENT BECAUSE OUR RESEARCH COMMITTEES, AND FDA WON'T ALLOW US TO PUT CANCER PATIENTS ON PLACEBOS WANT SO THYSELF PHASE 2 STUDIES ARE TYPICALLY COMPARED TO STANDARD OF CARE. AND THEN THE PHASE III TRIAL IS A LOT MORE PEOPLE. YOU HAVE TO HAVE AN EQUAL CHANCE OF BEING ASSIGNED TO ONE OR TWO OR EVEN THREE TREATMENT GROUPS, AND YOU WANT TO KNOW, HOW DOES THIS TREATMENT COMPAPER TO THE STANDARD OF CARE AND THERE ARE DIFFERENT PHARMACEUTICAL COMPANIES WILL TYPICALLY DO EITHER A SUPERIORITY TRIAL. IS THEIR NEW TREATMENT BETTER THAN WHAT'S OUT THERE OR IS IT A NON-INFERIORITY TRIAL, MEANS, IT'S JUST AS EFFECTIVE, BUT MAYBE THEY HAVE AN ADDED BENEFIT LIKE IT ONLY HAS TO BE GIVEN ONCE A DAY, RATHER THAN THREE TIMES A DAY OR IT'S LES EXPENSIVE. SO THERE MAY BE ANOTHER EDGE OF WHY THEIR DRUG, EVEN THOUGH IT'S JUST AS GOOD AS THE STANDARD OF CARE, THE FDA MIGHT CONSIDER IT AS A NON-INFERIORITY TRIAL TO APPROVE IT. ONCE THE DRUG GETS APPROVED BITE FDA YOU DO THE PHASE 4 TRIALS WHICH INVOLVE HUNDREDS TO THOUSANDS AND THIS IS CALLED THE POST MARKETING TRIALS AND THIS IS WHERE THEY WANT ADDITIONAL INFORMATION. WHEN THE HEPATITIS B VACCINE WAS APPROVED AND THEY DID HUGE STUDIES WITH HEPATITIS B AND WANT TO UNDERSTAND, DID IT DECREASE THE INCIDENTS OF HEPATITIS B AROUND THE WORLD. THOSE WERE THE LARGE PHASE 4 TRIALS BUT IT WAS ALREADY AFTER IT WAS APPROVED. SO THERE'S A PILOT TRIAL AND SO A PILOT TRIAL, AND THIS IS WHERE MANY OF US, WHERE WE'RE GOING FROM THE BENCH TO THE BENCH SIDE AND WE WANT TO TEST IT IN A COUPLE OF PEOPLE. LOTS OF US CAN GET, YOU KNOW, DEPARTMENTAL FUNDING OR A PILOT GRANT TO DO PILOT TRIALS, JUST TO TEST SOMETHING OUT THAT'S WHAT IT IS, THE FIRST VENTURE INTO AN AREA, TO WORK OUT SOME OF THE DIFFICULTIES AND TO DETERMINE THE SAMPLE SIDE. WE TEST WE TESTED IT IN LIKE, 25 PATIENTS, AND IT WAS AN OPEN LABEL STUDY. WE KNEW EVERYBODY WAS GETTING THE COMPOUND. THAT GAVE US SOME INFORMATION ABOUT HOW WELL IT WAS TOLERATED, WHAT WAS THE BEST DOSE TO USE AND THEN I KNEW KIND OF HOW WELL IT WORKED SO THEN MY STATISTICIANS COULD TELL ME, OKAY. THESE ARE HOW MANY PATIENTS YOU'RE GOING TO NEED TO SHOW EFFICACY GOING INTO A PHASE 2 TRIAL. AND YOU'RE GOING TO NEED TO HAVE THOSE CALCULATIONS FOR THE FDA OR FOR YOUR IRB SO YOU KNOW HOW MANY PATIENTS FOR YOUR SAMPLE SIZE. AND THAT'S WITH THE RANDOMIZED CLINICAL TRIALS ARE. WITH THE RANDOMIZED CLINICAL TRIALS, YOU HAVE AN EQUAL CHANCE OF BEING IN ONE OR TWO GROUPS AND THE ONE GROUP, YOU KNOW, IS USUALLY THE MOST WIDELY ACCEPTED TREATMENT OR THE STANDARD OF CARE, AND THE OTHER GROUP -- I MEAN, THE NEW TREATMENT, AND THE OTHER GROUP IS THE PLACEBO OR THE STANDARD OF CARE. THE IMPORTANT THING IS, YOU WANT THESE GROUPS TO BE AS SIMILAR AS POSSIBLE BECAUSE WHEN YOU RANDOMLY ALLOCATE PEOPLE, IF YOU'RE TESTING, FOR EXAMPLE, YOU WANT TO KNOW IF THEIR TUMORS SHRINK ON THIS TREATMENT, YOU WANT TO MAKE SURE THAT ALL THE PATIENTS WHO GET RANDOMIZED TO THE TREATMENT ARM DON'T HAVE TUMORS THAT ARE SIGNIFICANTLY SMALLER THAN THOSE THAT ARE GETTING THE PLACEBO BECAUSE THAT WILL FALSELY SKEW YOUR DATA. SO WHATEVER YOUR OUTCOME IS GOING TO BE FOR YOUR END POINT OF THE STUDY, THAT'S WHAT YOU HAVE TO RANDOMIZE BY. SO IF YOUR OUTCOME IS GOING TO BE RESPONSE WITH SIZE TO THE THERAPY, THEN YOU WANT TO MAKE SURE THAT WHEN YOU ENROLL PATIENTS, THEY HAVE PRETTY MUCH EQUAL SIZE AT THE BEGINNING. SO THAT'S AN IMPORTANT POINT BECAUSE PEOPLE DON'T ALWAYS DO THAT. AND OTHER THINGS, YOU KNOW, SOMETIMES PEOPLE RANDOMIZE BY GENDER. SOMETIMES PEOPLE RANDOMIZE. BUT IF THAT'S NOT GOING TO CHANGE YOUR OUTCOME, THOSE POINTS MAY NOT BE IMPORTANT AS WHATEVER YOUR OUTCOME IS GOING TO BE. THAT'S WHAT HAVE YOU TO RANDOMIZE BY. SO THEN HOW ARE THE PATIENTS'S' RIGHTS PROTECTED? L THERE ARE LEGAL AND ETHICAL CODES INVOLVED AND THE MOST IMPORTANT THING YOU HAVE TO DO AN INFORMED CONSENT. THAT MEANS NOT JUST THAT THEY SIGN A PIECE OF PAPER, BUT THEY ACTUALLY ARE INFORMED AND THEY KNOW WHAT THEY'RE DOING. AND IT CAN BECOME SO COMPLICATED. I CAN REMEMBER WHEN I STARTED DOING THIS. THERE WERE A COUPLE PAGES LONG. NOW, THEY'RE ABOUT 28 PAGES AND YOU'RE TRYING TO GET PATIENTS TO READ THROUGH THESE AND SIGN IT RESPOND IT. BUT IT'S REQUIRED. AND THEN, IN ORDER TO DO A STUDY, IT HAS TO BE APPROVED BY DIFFERENT COMMITTEES LIKE THE IRB IS THE BIG COMMITTEE THE LAST THING IS, IF YOU'RE DOING GOING WHERE YOU'RE COLLECTING BLOOD SAMPLES OR YOU'RE GOING TO DO DNA ANALYSIS OR SEQUENCING, OR GOING THAT MIGHT SHOW LIKE, YOU'RE LOOKING FOR A SNIP IN A POPULATION OF PATIENTS, IT MIGHT PREDISPOSE THEM TO CANCER YOU NEED TO HAVE A SPECIAL PARAGRAPH IN THERE ABOUT GENETIC TESTING AND IF THEY CAN LEAVE THEIR SAMPLES WITH YOU AFTER THE END OF THE STUDY, WHERE IF THEY HAVE TO DISPOSE OF ALL OF THEIR SAMPLES AT THE END OF THE STUDY. >> >> AUDIENCE MEMBER: [SPEAKING AWAY FROM MICROPHONE] >> EVERY CLINICAL TRIAL HAS TO BE APPROVED BITE IRB, IF IT'S INVOLVING A DRUG OR A THERAPEUTIC OR A DEVICE, IT HAS TO GO THROUGHOUT FDA. IF YOU'RE JUST DOING LIKE, POPULATION STUDIES OR EPIDEMIOLOGICAL STUDIES, THAT DOESN'T HAVE TO GO THROUGH THE FDA BECAUSE YOU'RE NOT APPLYING A TREATMENT. IF YOU'RE DOING A RETROSPECTIVE STUDY AND YOU'RE LOOKING AT DATA MAY A YOU DON'T HAVE TO GET THE APPROVAL OF THE FDA. SO THE FDA IS INVOLVED WHEN YOU'RE TESTING A NEW TREATMENT BUTT IRB, ANY TIME YOU'RE DOING ANY SORT OF RESEARCH ON PATIENTS, YOU HAVE TO HAVE THE IRB APPROVAL. NOW, THERE ARE SOME, YOU STILL HAVE TO GO THROUGH THE IRB IF YOU'RE DOING, SAY, SPIES MENS THAT ARE IN A BIOREPOSITORY AND THEY HAVE ALL BEEN, YOU KNOW, THE CODING ON IT, SO THERE'S NO IDENTIFIERS. YOU STILL HAVE TO GET PERMISSION FROM THE IRB SAYING THAT YOU'RE EXEMPT FROM IRB APPROVAL. SO THE PATIENTS WON'T HAVE TO SIGN A CONSENT BECAUSE SOME OF THOSE SAMPLES ARE FROM DECEASED PATIENTS. SO YOU CAN'T GET CONSENT. BUT YOU STILL HAVE TO GET APPROVAL FROM THE IRB OR SAY THAT YOUR PROTOCOL IS IRB-EXEMPT AND YOU GET THAT IN WRITING FROM THE IRB. SO THERE ARE CERTAIN CIRCUMSTANCES. SO THANK YOU FOR ASKING. IF YOU ARE DOING GENETIC TESTING, THAT'S AFTERNOON IMPORTANT THING BECAUSE IF SOMEBODY FINDS OUT THEY HAVE A GENE THAT PREDISPOSES THEM TO CANCER, AND IT'S IN THEIR RECORDS. IT COULD AFFECT THEIR INSURANCE. SO THEY HAVE TO KNOW THAT WHAT THEY'RE SIGNING AND THEY HAVE TO GIVE PERMISSION. HOW DO YOU GET AN FDA APPROVAL. THERE'S A PROCESS, AND THE FIRST THING YOU DO, YOU APPLY FOR WHAT YOU CALL AN INVESTIGATIONAL NEW DRUG OR THE APPLICATION FOR THAT OR AN IND. THERE ARE TWO FORMS THAT YOU NEED TO START THIS PROCESS CALLED THE 1571 AND THE 1572 FORM. AND I HAVE A COPY OF THAT SO YOU CAN SEE WHAT THEY LOOK LIKE. AND THEY'RE ON LINE. YOU JUST LOG IN. FDA1571 OR 72, AND YOU CAN FILL THEM OUT. IF YOU SUBMIT YOUR APPLICATION TO THE FDA AND IF THE FDA DOES NOT DISAPPROVE OF IT IN 30 DAYS, YOU GET YOUR NUMBER. SO THE FDA, THE CLOCK STARTS TICKING AS SOON AS THEY RECEIVE YOUR APPLICATION. AND THE APPLICATION HAS TO INCLUDE A LOT OF IMPORTANT INFORMATION AND IT HAS TO INCLUDE THINGS -- IF I CAN GET MY THING TO WORK HERE. I DON'T KNOW IF I CAN GET THE POINTER TO WORK. BUT HAVE YOU TO SAY, WHEN IS THE STUDY GOING TO BE DONE? WHAT'S THE CHEMICAL STRUCTURE OF THE COMPOUND? HOW DOES IT WORK IN THE BODY? WHAT ARE THE TOXIC EFFECTS FOUNDS IN THE ANIMAL STUDIES? THIS IS WHERE THE ANIMAL STUDIES ARE CRITICAL. EVERYTHING YOU'VE DONE IN THE LAB, HAVE YOU TO SUBMIT ALL OF THAT TO THE FDA. THEY WANT TON THE ANIMAL STUDIES, THE TOXICOLOGY STUDIES, IC-50 STUDIES, AND CELL CULTURE. THEY NEED TO HAVE ALL THAT INFORMATION. AND THEN, HOW ARE YOU GOING TO MAKE THE COMPOUND? IS IT A SYNTHETIC? IS IT A NATURAL COMPOUND, WHATEVER. AND THEN AFTER THE IND, YOU KNOW, MOST OF THE IRB'S, AT THE UNIVERSITIES OR AT THE INSTITUTES REQUIRE YOU TO HAVE AN IND NUMBER IN ORDER TO MOVE FORWARD WITH YOUR RESEARCH. SO TYPICALLY WHAT I DO, I APPLY FIRST TO THE FDA FOR MY IND NUMBER, AND I SUBMIT ALL THE RECORD AND IT IS PROTOCOL TO THE FDA BECAUSE THE FDA MAY ASK YOU FOR CHANGES. ONCE THE FDA APPROVES YOUR PROTOCOL, I SEND IT TO OUR IRB AND SAY, THIS HAS BEEN APPROVED BITE FD A AND THEN THE IRB REVIEWS IT. IF IT'S SUBMITTED THROUGH THE FDA IT'LL MOVE FASTER OR IF IT'S PEER REVIEWED THROUGHOUT NIH OR ONE OF THOSE COMMITTEE MEETINGS AND IT'S BEEN APPROVED AND PEER REVIEWED AND THEN IRB WILL USUALLY, YOU KNOW, THEY'LL READ THROUGH IT AND SEE IF THEY HAVE ANY CRITICISMS OR CHANGES THAT HAVE YOU TO MAKE. BUT TYPICALLY, THAT MAKES THE PROCESS MOVE FASTER. THIS IS WHAT A 1571 FORM LOOKS LIKE. IT'S VERY HARD TO SEE AT THIS STAGE. BUT IT ASKS YOU MAINLY FOR YOUR NAME. WHEN YOU GET ASSIGNED AN IND NUMBER, YOU HAVE TO INCLUDE THAT NUMBER ON EVERY SINGLE ONE OF THESE FORMS THAT YOU SUBMIT. THE OTHER THING IS, WITH YOUR INITIAL APPLICATION, YOU WON'T HAVE THE IND NUMBER BUT THEY'LL ASSIGN THAT TO YOU. YOU HAVE TO ALWAYS INCLUDE THE SERIAL NUMBER. SO THE FIRST TIME YOU SUBMIT YOUR APPLICATION TO THE FDA NUMBER IS GOING TO BE ZERO. EVERY OTHER COMMUNICATION AFTER THAT, IF THEY SAY OH, PLEASE, SEND US YOUR BIOSKETCH, YOU HAVE TO SEND THEM ANOTHER 1571 AND WITH YOUR BIOSKETCH, AND THAT WILL SAY THIS IS NUMBER ONE. AND YOU HAVE TO KEEP RECORDS OF THE COMMUNICATION. EVERY TIME YOU COMMUNICATE WITH THE FDA YOU HAVE TO SUBMIT A 1571 AND KEEP RECORDS OF WHICH COMMUNICATION IS THIS. AND THEN THEY ASK YOU WHAT IS INCLUDED IN THIS. SO DOWN AT THE BOTTOM, THERE'S CHECKED BOXES AND THEY ASK YOU WHAT ARE YOU INCLUDING WITH THIS 1571. IS IT RESPONSE TO WHAT F DA ASKS YOU TO DO? IS IT A NEW PROTOCOL? IS IT A CHANGED YEAR PROTOCOL, WHATEVER, AND YOU JUST CHECK THE BOX OF WHAT YOU'RE INCLUDING WITH THIS 1571 FORM. SO THE, THING I WANT TO MENTION IS INTELLECTUAL PROPERTY. YOU KNOW, WE DON'T OFTEN THINK ABOUT THAT WHEN WE'RE IN THE LAB WORKING WITH ANIMALS OR WITH THE BENCH OR WHEN YOU'RE IS GETTING READY TO PREPARE FOR YOUR POSTER PRESENTATION. YOU'VE SUBMITTED YOUR ABSTRACT IF YOU'RE GOING TO GO AND PRESENT YOUR RESEARCH AT ANY MEETING, WHETHER IT BE BEFORE YOU DO THAT. YOU HAVE TALK TO THE INTELLECTUAL PROPERTY OFFICE AT THE UNIVERSITY OR INSTITUTION BECAUSE AS SOON ALWAYS DO A PUBLIC DISCLOSURE OF YOUR RESEARCH, IT NOTICE LONGER CAN BE PATENTED. AND THE REASON WHY IT'S IMPORTANT IS BECAUSE PHARMACEUTICAL COMPANIES ARE NOT INTERESTED IN TAKING YOUR PRODUCT, NO MATTER HOW GOOD IT IS, INTO THE CLINIC UNLESS THEY CAN HAVE PATENT RIGHTS. SO SO IT'S REALLY IMPORTANT, IF YOU'RE SUBMITTING AN ABSTRACT, BEFORE YOU SEND THAT IN, THAT YOU TALK TO THE I.P. PEOPLE. SEND IN YOUR ABSTRACT AND SAY, IS THERE GOING IN HERE WE SHOULD PATENT FIRST. AND THE PROCESS IS EASY. WHAT THEY DO IS THEY SUBMIT A PROVISIONAL PATENT, WHICH ONLY COSTS WITH 500 BUCKS, I THINK. AND THE UNIVERSITIES WILL DO THAT AND THAT WILL PROTECT YOUR RIGHTS TO THIS INTELLECTUAL PROPERTY, EVEN AFTER YOU GO AND YOU SUBMIT YOUR ABSTRACT AND THEN YOU DO YOUR POSTER AND THEN YOU HAVE ONE YEAR FROM THE TIME YOU SUBMIT YOUR PROVISIONAL PATENT, UNTIL YOU HAVE TO SUBMIT THE FULL PATENT. THEN YOU DECIDE, AFTER A YEAR GOES BY, IS THIS SOMETHING THAT'S GOING TO MOVE FORWARD IN THE SCIENCE, AND I CAN TAKE THIS OUT AND MAYBE WE'LL GET A GOOD DISCOVERY. YOU HAVE ONE YEAR FROM THE TIME YOU SUBMIT YOUR PROVISIONAL. BUT THAT PROTECTS YOU. THINK ABOUT THAT IF YOU'RE GOING OUT TO RESEARCH MEETINGS. SO THESE ARE JUST SOME OF THE THINGS YOU DO FOR A CLINICAL TRIAL. WRITING THE PROTOCOL, WHICH IS ALWAYS HARD TO D. WRITING THE CONSENT FORM, GETTING YOUR IRB APPROVAL AND THOSE THINGS, YOU KNOW, MAY BE HARD. BUT THE HARDER THING IS IS GETTING THE FUNDING, FINDING A SPONSE OSOMEBODY WHO'S GOING TO PAY FOR YOUR RESEARCH. AS RESEARCH MONEY IS BECOMING LESS AND LESS, THAT'S HARD TO DO. UNDERSTAND THE RESPONSIBILITIES OF BECOME A PRINCIPLE INVESTIGATOR AND IN ORDER TO DO CLINICAL TRIALS, WHETHER AN MD OR PH.D. HAVE YOU TO DO WHAT WE CALL A "CITY TRAINING," AN ON LINE TRAINING, ON HOW TO CONDUCT ETHICALLY, CLINICAL TRIALS, AND HAVE YOU TO DO THE CITY TRAINING AND PASS YOUR CITY TRAINING IN ORDER TO HAVE AN IR APPROVAL. SO EVERYBODY HAS TO BE WHAT THEY CAL CITY TRAINED. AND THEN THE OTHER THING S BEFORE YOU START, IF YOU GET APPROVAL, AND YOU MOVE FROM THIS PROCESS, BEFORE YOU ENROLL YOUR FIRST PATIENT, YOU HAVE TO REGISTER YOUR CLINICAL TRIAL ON THE CLINICAL TRIALS.GOV WEBSITE AND THAT'S REQUIRED. IF YOU DON'T DO THAT AND YOU ENROLL A PATIENT AND THEY SIGNED A CONSENT FORM AND IT'S DATED ON A DATE THAT PRECEDES YOU REGISTERING YOUR TRIAL, YOU'RE NOT ALLOWED TO PUBLISH YOUR RESULTS. SO THAT'S A HARD LINER BUT YOU'RE N. ONCE YOU FINISH YOUR RESULTS OF THE TRIAL, YOU ARE REQUIRED TO UPLOAD THEM ON THE WEBSITE. IIF YOU GET A PUBLICATION, IT'S EASIER. YOU CAN UPLOAD THE PUBLICATION AND IT HAS TO BE AVAILABLE FORTUNATE PUBLIC DOMAIN TO SEE WHAT ARE THE RESULTS OF YOUR TRIAL. BUT THIS IS AN IMPORTANT THING. JUST LITTLE THINGS TO THINK ABOUT, BEFORE YOU'RE ALL EXCITED AND YOU'RE GOING TO ENROLL YOUR FIRST PATIENT, YOU HAVE TO PUT IT OUT OF LINE, OTHERWISE, YOU CAN'T PUBLISH T. THIS IS JUST KIND OF THE FORMAT OR A PROTOCOL THAT YOU HAVE, YOU KNOW, WHAT'S THE TITLE. WHAT'S YOUR RATIONALE, ETHICAL CONSIDERINGS, THE TIMETABLE AND ET CETERA. AND THIS IS JUST AN EXAMPLE OF A PROTOCOL THAT I DID, AND IT TELLS YOU, FOR EXAMPLE, WHAT'S THE STUDY TITLE. IS IT A PHASE 1 OR PHASE 2 OR BOTH A PHASE 1, PHASE 2 TRIAL. HOW LONG IS THE STUDY GOING TO LAST, WHAT DRUGS ARE YOU USING IN THE TRIAL AND WHAT ARE YOUR OBJECTIVES. WHAT ARE YOUR PRIMARY AND SECONDARY OBJECTIVES, AND THEN HAVE YOU TO TELL THEM WHAT YOUR STUDY DESIGN IS, AND HOW MANY CENTERS YOU'RE USING, HOW MUCH PATIENTS YOU'RE GOING TO ENROLL. WHO'S GOING TO BE YOUR PATIENTS, WHAT ARE INCLUSION, EXCLUSION CRITERIA, ET CETERA. YOUR SIMPLE SIZE AND SO FORTH. SO THAT'S LIKE AN OUTLINE OF WHAT YOU HAVE TO PUT IN A PROTOCOL. SO THEN, THE NEXT THING IS, IS WHERE MOST OF US ARE STILL WORKING WITH THE MICE. SO YOU'VE GOT A 25-GRAM MOUSE, GIVING HIM 5 MILLIGRAMS PER KILO AND YOU'RE GETTING A GOOD RESPONSE IN YOUR TUMOR AND YOU WANT TO TEST IT IN A HUMAN BEING. HOW DO YOU KNOW HOW MUCH TO GIVE HIM? YOU DON'T WANT TO KILL THE HUMAN BEING. SO YOU WANT TO STUDY THE SAFETY AND TOXICITY. YOUR FIRST IN HUMAN TRIAL AND I DID A STUDY AND A DRUG CALLED OGF. AND WE ACTUALLY STARTED, YOU KNOW, I DID ALL THE DOSING IN THE MICE. AND THEN I HAVE TO FIGURE OUT HOW MUCH AM I GOING TO GIVE A HUMAN BEING? WELL, THERE IS A FORMULA THAT YOU CAN USE AND HERE'S THE REFERENCE FOR IT. IT SHOULD BE IN YOUR HANDOUT. DEPENDING ON WHAT YOUR ANIMAL MODEL WAS THAT YOU WERE USING, AND THE SURFACE AREA, YOU COULD ACTUALLY CALCULATE WHAT THE HUMAN EXPECTED DOSE IS. AND THERE'S THIS FORMULA DOWN HERE, BASED UPON THE HUMAN EXPECTED DOSE. BASED UPON THE WEIGHT OF YOUR ANIMAL AND THE DOSE THAT YOU FOUND THAT CAUSED NO OBSERVED ADVERSE EFFECT LEVELS, WHICH IS NAEL. BUT THAT WILL CALCULATE WHERE DO YOU START, RATHER THAN GUESSING. WHEN I DID A CLINICAL TRIAL. WE USED THIS, AND FIGURED OUT WHAT WOULD BE THE DOSE AND THEN WE DON'T KNOW WELL, HOW HIGH CAN WE GO BEFORE WE REACH TOXICITY. SO WHEN YOU DO A PHASE 1 TRIAL, YOU USUALLY PICK YOUR DOSE, BASED UPON WHAT ANIMAL MOLDS YOU USE, AND YOU TEND TO START LOWER THAN WHAT YOU THINK YOU MIGHT NEED IN A 60- 70-KILOGRAM PERSON AND THEN YOU ENTER, IT'S CALLED A THREE PLUS 3 PHASE 1 TRIAL. YOU ENTER THREE PEOPLE AT ONE DOSE AND WE STARTED AT 50 MICROGRAMS PER KILO AND THEN YOU LOOK AND SEE IF YOU HAVE ANY TOXIC EFFECTS. IF YOU GET TWO TO THREE TOXIC EFFECTS IN THREE PEOPLE, YOU USUALLY HAVE TO STOP. THAT'S THE WRONG DOSE. YOU PICKED THE WRONG DOSE. IF YOU GET NO EFFECTS, YOU CAN GO UP TO THE NEXT DOSE AND SO FORTH. SO THAT'S HOW YOU DO IT. THIS IS A CLASSIC 3 + 3 STUDY DESIGN. THE PURPOSE OF THAT IS WITH THE SAFETY AND TOXICITY, FINDING OUT WHAT WE CALL THE MTD OR THE MAXIMUM TOLERATED DOSE. SO THAT'S WHAT WE DID IN THIS ONE STUDY AND I WANT YOU TO KNOW, I STARTED OFF, I CALCULATED THE DOSE TO GIFT FIRST PATIENT, BASED UPON MY ANIMAL STUDIES AND THE FIRST PATIENT, YOU KNOW, HAD ABDOMINAL PAIN, AND WAS VOMITING, AND I THOUGHT, OH, DOOR WHAT DID I DO? BUT IT TURNED OUT, IT WAS HER PANCREATIC CANCER I WAS TRYING TO TREAT. I DOSED THE, TWO PATIENTS IN THE STUDY AND THEY DID JUST FINE. SO WE MOVED ON TO THE NEXT DOSE, AND WE MOVED ON AND MOVED OUNTIL WE GOT UP TO THE MAXIMUM TOLERATED DOSE. THE DOSE I START OUT AT 50 WAS ACTUALLY WHAT I TESTED IN TWO OTHER PEOPLE, IT WAS JUST FINE. SO WE WERE ABLE TO ESCALATE AND WE FOUND IT WAS 250. IF I STOPPED BACK HERE, WE WOULDN'T HAVE REACHED OUR MAXIMUM TOLERATED DOSE. IT'S IMPORTANT TO KNOW. SOMEONE WITH BANK RATIC CANCER, IT MIGHT NOT BE DUE TO THE DRUG, BUT THE DISEASE. SO HAVE YOU TO TAKE THAT INTO CONSIDERATION. BUT THIS IS HOW YOU DO A 3 + 3 STUDY DESIGN. SO SOME OF MY RESEARCH AND I'LL JUST SHOW YOU SOME OF THE EXAMPLES ABOUT WHAT WE'RE DOING AND WHAT WE'RE PLANNING TAKE TO THE CLINIC AND WHAT WE HAVE DONE. SO BANK CREATIC CANCER IS ANYBODY WORKING ON PAN CREATIC CANCER? OH, DARN. SO IT'S THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS IN THE UNITED STATES. ABOUT 56,000 A YEAR, WITH OUR BEST DRUGS, THE MAXIMUM MEDIUM SURVIVAL IS 11 MONTHS. IT'S THE WORSE PROGNOSIS AND IT DOESN'T EVEN MAKE IT TO ONE YEAR. WE DON'T EVEN TALK ABOUT 5 YEAR SURVIVALLINGS WITH PANCREATIC CANCER. 6%, MAYBE, IF YOU'RE SURGICALLY OPERATED O. BUT MOST PATIENTS PRESENT WITH ADVANCE DISEASE. MOST PEOPLE ARE NOT DIAGNOSED EARLY AND CURRENTLY, THERE IS NO REAL EFFECTIVE THERAPY THAT CURIOUS PANCREATIC CANCER, UNLESS YOU CAN CUT IT OUT WITH SURGERY. SO THESE ARE THE DEATHS, TO SHOW YOU THAT THE CASES OF COURSE RISING AND LIKE I SAID, IT'S ALREADY SURPASSED COLORECTAL CANCER AND IT'S PASSED BREAST CANCER SO DR. MOODY STILL HAS ME BEATEN. LUNG CANCER IS STILL UP THERE. BUT IT IS ON THE RISE. SO IT'S BECOMING THE SECOND OR THIRD LEADING CAUSE OF CANCER. THERE IS NO TREATMENT. THERE'S NO EARLY DIAGNOSIS. SO SOME OF THE RESEARCH I'VE BEEN DOING IS WITH PANCREATIC CANCER AND DIETARY FAT AND AS WE ALL KNOW, THERE'S THIS EPIDEMIC WITH THE METABOLIC SYNDROME IN THE UNITED STATES. IF YOU LOOK AT THE SAME MAP, SHOWING WHERE THE HIGH FAT CONSUMPTION S IT'S THE SAME AREAS. SO THE COUNTRIES THAT CONSUME HIGH FAT DIETS, HAVE A HIGHER INCIDENCE OF PANCREATIC CANCER. SO THAT'S KNOWN. SO THEN THE OTHER THING IS THE METABOLIC SYNDROME. AND WE ALL KNOW, AND IT'S TRUE IN BREAST CANCER AND MANY OTHER CANCERS. THAT OBESITY INCREASES THE RISK OF CANCER AND WITH THE METABOLIC SYNDROME, YOU ARE WHAT YOU EAT. WE THINK IT'S ALSO RELATED AND IT'S BEEN SHOWN THAT OBESITY AND HIGH FAT DIET IS REALITIED TO PANCREATIC CANCER ALSO. WHY IS THAT? THIS JUST SHOWS THE OBESITY, BESIDES CANCER, SERGEANT CAN HAVE A LOT OTHER EFFECTS, AND CAN EFFECT OTHER ORGANS, BESIDES THE DIABETES AND OTHER THINGS. BUT OUR RESEARCH IS LOOKED AT A G.I. PEPTIDE CALLED CCK. COL, A G.I.PROTEIN. WHAT HAPPENS IS CCK RESPONDS TO FREE FATTY ACIDS AND CERTAIN AMINO ACID IN THE DIET Z. IF YOU EAT FAT IN YOUR DIET. CCK IS RELEASED AND IT IS RELEASED IN THE EYE CELLS OF YOUR DUODENUM, IT ENTERS THE BLOODSTREAM AND CIRCULATES THROUGH THE BLOOD TO COME BACK AND ACT ON THE RECEPTORS THAT ARE IN THE PANCREAS AND IT CAUSES THE RELEASE OF DIGESTIVE ENZYMES TO HELP YOU DIGEST YOUR FAT. THE OTHER THING IT DOES, IT CAUSES CONTRACTION OF THE GALLBLADDER SO THE BILE CAN BE RELEASED INTO THE INTESTINE TO HELP EMULSIFY THE FAT. SO CCK GOES UP WHEN YOU EAT HIGH FAT DIETS OR ANY FAT. THAT'S ITS ROLE TO, HELP YOU DIGEST YOUR FAT. SO MANY YEARS AGO, WE LOOKED AT L WHAT IS CCK AND GASTRUM. WHAT WE FOUND IN CELL CULTURE IS THAT I TOOK PANCREATIC CANCER CELLS AND WE TREATED THEM, THINKING PEOPLE ON A HIGH-FAT DIET, MAYBE THEIR CCK LEVEL GOES UP. MAYBE CCK IS STIMULATING PANCREATIC CANCER. WE DID THIS STUDY IN CELL CULTURE AND SHOWED INDEED N A DOSE-RELATED FASHION, IF YOU ADD CCK TO PANCREATIC CANCER CELLS, YOU CAN STIMULATE THE GROWTH OF PANCREATIC CANCER, THAT HELPS THROUGH A CCK RECEPTOR. SO THEN WE DO STUDIES IN OUR ANIMALS. YOU TESTED IN A CELL CULTURE. THEN YOU GO TO THE ANIMALS AND WE PUT ANIMALS ON A HIGH FAT DIET. SO YOU COULD ORDER THESE SPECIAL DIETS AND WE HAD THE BLUE FOOD WHICH IS REAL GREASY, A HIGH-FAT DIET. OUR CONTROL DIET AND A LOW-FAT DIET. WE PUT ANIMALS ON A DIFFERENT DIAND THE GIVE THEM PANCREATIC CANCER, EITHER SUBCUTANEOUSLY OR ORTHRO TOPICALLY AND WE WANT TO KNOW, IS THE HIGH FAT DIET STIMULATING THE GROWTH OF THE CANCER. THE FIRST EXPERIMENT WAS IN NUDES MICE AND WE GREW THE TUMORS SUBCUTANEOUSLY. AND WE PUT THE MICE ON A HIGH FAT DIET OR A LOW FAT SORT OF DIET. THEN AFTER THE ANIMALS -- WE DID THIS AFTER THE ANIMALS HAVE THE TUMORS. THEN WE TREATED THEM WITH COLE SIFT KIND, AND WE'RE ASSUMING IF THE HIGH FAT DIET RAISES CCK LEVELS. IF WE BLACK BLOC THAT EFFECT AT THE RECEPTOR, MAYBE THE TUMOR WON'T GROW AS MUCH. INDEED, WHAT WE FOUND WAS THAT ANIMALS THAT WERE ON THE HIGH FAT DIET. THEIR TUMORS GOT BIGGER ON A HIGH FAT DIET. SO THE QUESTION IS WHY ARE THEIR TUMORS GETTING BIGGER? THE MICE THAT WERE ON THE HIGH FAT DIET, THEIR TUMORS WERE EVEN SMALLER THAN THE CONTROLS. SO IT LOOKS LIKE THE EFFECTS OF THE HIGH FAT DIET WERE MEDIATED THROUGH THE CCK RECEPTOR AND WE COULD BLOCK THAT EFFECT. SO THAT'S THE FIRST STUDY. BUT THAT WAS DONE IN HUMAN PANCREATIC CANCER. THEN WE WANTED TO WORK IN ASINGENAIC MODEL AND WE USED A MOUSE PANCREATIC CANCER, SO WE CAN TEST IN SAY NORMAL ENVIRONMENT. WE TOOK A PANCREATIC CANCER MOUSE CELL LINE, AND INJECTED T. THIS IS GROWING INSIDE THE PANCREAS ORANGE COUNTY TOPICALLY AND JUST TO SHOW YOU, WE MADE SOME MICE OBESE. THIS IS A FAT MOUSE. IF YOU DON'T CONTINUE OR NOT. A FAT MOUSE IS A MOUSE THAT WEIGHS 35 GRAMS OR MORE. THAT'S TECHNICALLY, ACCORDING TO THE LITERATURE, WHAT A FAT MOUSE IS. SO WE TOOK SOME MICE, MADE THEM FAT AND GAVE THEM CANSER AND CHECKD TO SEE WHAT HAPPENED. WE LOOKED AT THIS IN MICE THAT WERE OBESE. WE WAITED UNTIL THEY WERE OBESE BEES AND WE TOOK OTHER MICE AND WE GAVE THEM THE CANCER AND WE EUTHANIZED THE MICE BEFORE THEY BECAME OBESE. WE WANTED TO LOOK AT THE EFFECTS OF OBESITY ON CANCER GROWTH, AND LOOK AT JUST THE EFFECTS WITHOUT OBESITY, IS IT JUST CCK. BUT TO MAKE A LONG STORY SHORT. DO HIGH FAT DIETS RAISE CCK LEVELS AND INDEED, IT DOES. IN OUR MICE, THE CCK LEVELS WERE 10 FOLD HIGHER THAN THE MICE ON THE CONTROL OR THE LOW FAT DIET. LOW FAT ACTUALLY LOWERS IT. IN OUR ORTHRO TOPIC MODEL. THE MICE ON THE HIGH FAT DIET HAD BIGGER TUMORS, AND WE WERE ABLE TO BLOCK THAT EFFECT BY GIVING THEM THE CCK RECEPTOR ANTAGONIST. SO THE ANIMAL ON THE CONTROL DIET, THEY WERE NOT HAVING THE HIGH FAT DIET, THERE REALLY WASN'T MUCH OF THE ANTAGONIST BECAUSE THEY DIDN'T HAVE HIGH CCK LEVELS. WE THOUGHT, HOW DO WE PROVE THIS IS REALLY CCK? THIS ONE GRAD STUDENT DID CRISPER AND KNOCKED OUT THE CCK RECEPTOR ON OUR PANCREATIC CANCER CELLS. SHE TOOK CELLS THAT WERE RECEPTOR NULL AND SHE GREW THOSE TUMORS IN THE MICE, AND AND SHE HAD THE WILD TYPE TUMOR THAT IS HAD THE CCK RECEPTOR, PUT THEM ON THE HIGH FAT DIET. WHAT YOU CAN SEE IS THAT IF YOU HAVE THE RECEPTOR. CCK WILL STIMULATE THE GROWTH. IF YOU KNOCKOUT THE RECEPTOR YOU CAN EAT ALL THE FAT IN THE WORLD. IF YOU DON'T HAVE THE CCK RECEPTOR AND YOU'RE NOT GOING TO GET FOOT FAT DIETS AND JUROR NOT GOING TO STIMULATE THE CANCER GROWTH. WE TOOK MICE FROM A TRANSGENIC -- THEY HAD THE RECEPTOR BUT THEY DIDN'T MAKE THE PEPTIDE. THEN WE PUT THEM ON A HIGH FAT DIET. WE WONDERED, OKAY. THEY'RE EATING A HIGH FAT DIET. WHAT HAPPENED TO THE TUMOR SIZE AND THERE WAS NO EFFECTS. SO WE KNOCKED OUT THE RECEPTOR, WE KNOCKOUT THE PEPTIDE. YOU HAVE TO HAVE THIS PEPTIDE WITH THE CCK RESUPPORTOR AND THE PEPTIDE TO DO STIMULATE GROWTH OF PANCREATIC CANCER. SO, I GUESS THE MORAL OF THE STORY S IF YOU WANT TO EAT CHOCOLATE AND HAVE A HIGH FAT DIET. TAKE YOUR CC RECEPTOR AND IT'LL PREVENT THAT. SO I'M GOING TO TALK ABOUT GHAST RON, THE OTHER G.I. PEPTIDE, AND I WON'T MAKE YOU RAISE YOUR HANDS. EVERYBODY, I'M SURE, HAS TRIED PRILOSEC, OTC. TEASE ARE THE PROTON PUMP INHIBITORS AND THEY ARE USED FOR ACID REFLUX AND HEARTBURN. AND I'M A GASTROINTERROLOGIST. THIS IS ONE OF THE MOST PRESCRIBED DRUGS, BILLION DOLLAR BUSINESS. SO WHAT DO THE P.P.I.'S DO? THIS IS NORMAL PHYSIOLOGY. GASTRON GETS INTO THE CIRCULATION AND ACTS ON THE CCK RECEPTOR ON BOTH THE CHROMATIN CELLS AND MAYBE ON THE PARIETAL CELLS AND CAUSES THE RELEASE OF ACID. IF YOU BLOCK THE PROTON PUMP HERE WITH ANY OF THOSE DRUGS, YOU COMPLETELY BLOCK THE ACID RELEASE, WHICH IS GOOD. IT HELPS CONTROL HEARTBURN BUT WHAT HAPPENS IS,. RUSSELL TEIBERT RUSSELL TEIBERT TRIES. THIS FEEDBACK LOOK. SO THE FEEDBACK CELLS, THERE'S NO ACID. HAVE I TO MAKE MORE GASTRIN AND THEY KEEP TRYING TO MAKE MORE GASTRIC. WHEN THEY MAKE MORE GASTRIC, IT'S NOT ABLE TO INCREASE THE ASPIRIN BECAUSE YOU'RE ON A PROTON PUMP. BUT WHAT IT D IT CAUSES STIMULATION OF GROWTH OF THESE CHROMO FIN LIKE CELLS. ITS THIS IS WHY I DO AN END OF COURSE PEE. THEY GROW THESE POLYPS IN THEIR STOMACH AND THESE POLYPS ARE BECAUSE GHASTRIN IS STIMULATING THE GROWTH. WE SEE THIS ALL THE TIME. IN ANIMAL MODELS, IT CAN CAUSE CARS NOTICED TUMORS -- CARCINOID TUMOR. THERE'S A QUESTION ALSO, OF WHETHER IT CAUSES CANCER. SO THIS WAS A PAPER THAT WAS PUBLISHED. WE USE THESE PROTON PUMP INHIBITORS WHO HAVE HEARTBURN. AND WE USE THEM IN PEOPLE WHO HAVE [INDISCERNIBLE] ESOPHAGUS, WHICH IS A PRECANCEROUS CONDITION. WE USE THESE PROTON PUMP INHIBITORS TO TREAT HEARTBURN AND EVERYTHING, BACK HERE IN THE ACHES OR SO. AND EVER SINCE WE STARTED USING THE PPI'S, INSTEAD OF THE INS KENTS OF CANCER ESOPHAGEAL CANCER GOING DOWN, IT'S GOING UP. AND THE OTHER DRUG, THE OTHER DISEASE THEY SHOWED YOU BEFORE THAT'S GOING UP IS SINCE WE STARTED USING PROTON PUMP INHIBITORS, PANCREATIC CANCER HAS BEEN INCREASING. BOTH OF THESE DISEASES ARE DRIVEN BY GASTRIN WHICH IS THE PROTEIN OR THE PEPTIDE THAT GOES UP WHEN YOU TAKE CHRONIC PPI'S. NOW, THE PHARMACEUTICAL INDUSTRY DOES NOT WANT TO HEAR THIS BECAUSE IT'S A BILLION DOLLAR BUSINESS. BUT NOBODYNESS YET INCIDENTS OF ESOPHAGEAL CANSER AND PANCREATIC CANCER IS GOING UP, AND SOME OF IT MAY BE OBESITY, BUT THIS IS KIND OF A COINCIDENCE. SO WE LOOKED AT THIS, AND WE ACTUALLY, IF YOU KNOW EMBROILING, GASTRIN IS ACTUALLY PRESENT IN THE FETAL PANCREAS AND IT HAS A ROLE THAT IT HELPS WITH DIFFERENTIATION, AND DEVELOPMENT OF THE PANCREAS, BUT IT'S SHUT OFF AT WEEK 14 AND IT'S NOT IN THE NORMAL PANCREAS. HOWEVER, IT BECOMES REEXPRESSED IN THE PANCREAS DURING PANCREATIC CANCER AND STIMULATES THE GROWTH OF PANCREATIC CANCER JUST LIKE CCK. SO GASTRIN ACT AT THE SAME CCK RECEPTOR, AND ARE HORMONES F YOU TAKE CANCER CELLS IN CULTURE AND GIVE THEM CCK OR GASTRIN, YOU'LL STIMULATE THE GROWTH THROUGHOUT CCK RECEPTOR. BUT SOMETHING HAPPENS WHEN YOU'RE DEVELOPING PANCREATIC CANCER. WHEN IT SEES CCK OR GATRIN FLOATING AROUND. THE NORMAL FUNCTION IS TO MAKE DIGESTIVE ENZYMES. BUT (CRITIC CANCER OVER EMPHASIZES -- IF YOU STIMULATE THE RECEPTOR, IT CAUSES PROLIFERATION. IT STARTS MAKING IT'S OWN GASTRIN TO STIMULATE ITS OWN GROWTH. SO PANCREATIC CANCER OVER EXPRESSES THIS RECEPTOR. IT MAKES ITS OWN GASTRIN TO SIMULATE ITS GROWTH. IN CANTSER, TESTIMONIES FROM THE CANCER ITSELF. GASTRIN STIMULATES THE GROWTH OF PANCREATIC CANCER. DURING CARCINOGENESIS, AS PANCREATIC CANS SORRY DEVELOPING, IT GOES THROUGHOUT IF ANY OF YOU ARE DOING PROSTATE CANCER, IT GOES THROUGHOUT DEVELOPMENT OF PAN TYPE LESIONS. AND GOES THROUGH THESE PAN 1, 2, AND 3 LESIONS BEFORE IT BECOMES PANCREATIC CANCER. GASTRIN IN THE CCKB RECEPTOR GET TURNED OEARLY ON DURING PANCREATIC CARS INO GENESIS. THE OTHER THING GOING ON, AND WEAN THIS FROM OUR KRAS MOUSE MODELS WE USE TO STUDY THIS IS THAT THEY HAVE THIS INCREASED FIBROSIS THAT GOES ON, AND THE IMMUNE CELLS CHANGE. SO IF YOU LOOK AT THE T REGULATORY CELLS, THE CD8 CELLS ARE VERY LOW IN THE PANCREATIC CANCER AND THE T REGULATORY CELLS ARE HIGH. AND THOSE ARE IMMUNE SUPPRESSIVE CELLS. SO WE LOOKED AT OUR MOUSE, PANCREAS AND THIS IS WHY YOUR MOUSE RESEARCH IS ALL IMPORTANT. AND THE NORMAL MOUSE PANCREAS DOESN'T HAVE CCKB-RECEPTORS BUT AS THEY DEVELOP THESE FAN AND LESIONS, THEY BEGIN TO EXPRESS THE CCKB RECEPTOR. SO WE THOUGHT OH. MAYBE IF WE BLOCK THE CCK RECEPTOR, WE CAN PREVENT PANCREATIC CANCER. SO WE DID A STUDY AND WE TOOK THIS SAME DRUG AND PUT IT IN OUR MOUSE'S DRINKING WATER, AND THIS IS WHAT THE DRUG LOOKS LIKE. THIS IS A MOUSE THAT HAD REGULAR WATER AND THIS IS A MOUSE WHOSE PANCREAS WHO HAD THE PROVLIMIDEIN THE WATER. THIS IS A PANIN LESION. SO THERE WERE SIGNIFICANT DECREASE IN THE NUMBER OF THESE PRECANCEROUS LESIONS IF WE BLOCK GASTRIN'S INTERACTION AT THE RECEPTOR. NOT ONLY ARE THOSE RECEPTORS ON THE PANINS, BUT THEY ARE ALSO PRESENT IN THESE CELLS WHICH ARE FIBER GLASS, THAT CAUSES THE FIBROSIS ASSOCIATED WITH CANCER M NOT JUST PANCREATIC CANCER BUT OTHER CANCERS TOO THE SURVIVAL IS ONLY 11 MONTHS. ONE OF THE THOUGHT SYSTEM BECAUSE OF ALL THIS FIBROSIS HERE, PARTICULAR DRUGS THAT WE'RE USING, CAN'T GET INTO THE CANCER CELLS TO KILL T. SO IF YOU CAN DISRUPT THIS FIBROSIS OR CHANGE THE IMMUNE ENVIRONMENT, YOU MIGHT MAKE IT SO THAT IT WILL RESPOND BETTER TO THERAPY. SO WE HAVE DONE SOME STUDIES AND FOR YEARS, WE HAVE ALWAYS USED THE NUDE MOUSE TO LOOK AT HUMAN CANCER, BUT YOU CAN'T DO IMMUNE STUDIES, BECAUSE THEY DON'T HAVE T CELLS. SO IF YOU'RE INTERESTED IN LOOK AT IMMUNE RESPONSES, HAVE YOU TO USE A SIN JEN AIC MOUSE MODEL. WE USE KRAS TRANSGENIC MOUSE MOD TOLL LOOK AT IMMUNE RESPONSE. SO TO MAKE A LONG STORY SHORT, WE GAVE SOME OF OUR MICE, ASNINGENAIC -- A LOW DOSE OF AN IMMUNE CHECKPOINT ANTIBODY, A PD1. ANYBODY WORKING WITH IMMUNE CHECK POINTS? SO WE TREATED THEM WITH THAT. IF WE COMBINE OUR CCK ANTAGONIST W IMMUNE CHECKPOINT, THE TUMORS DIDN'T GROW. WE FOUND THAT THAT CAUSED CD8 CELLS TO GO UP, AND ACTUALLY, THE T REGULATORY CELLS GO DOWN WITH THE COMBINATION TREATMENT. SO WE'RE THINKING ABOUT DOING A CLINICAL TRIAL TO TRY TO IMPROVE THERAPY FOR PATIENTS WITH PANCREATIC CANCER BY USING THE CCK RECEPTOR ANTAGONIST, WITH AN IMMUNE CHECKPOINT BLOCKADE. CURRENTLY, CHEMOTHERAPY DOESN'T WORK IN PANCREATIC CANCER. IMMUNE THERAPY DOESN'T WORK IN PANCREATIC CANCER. BUT IF WE CAN DISRUPT THE ENVIRONMENT OF THE ISSUE, SO THERE'S LESS FIBROSIS, AND THE IMMUNE SIGNATURE CHANGES IN THE TUMORS, WE MIGHT BE ABLE TO IMPROVE THERAPY. SO WE HAVE ALREADY SUBMITTED OUR IND NUMBER. WE HAVE AN INDUSTRY PARTNER. WE HAVE GOTTEN SOME FUNDING FOR THIS, AND WE HAVE INTELLECTUAL PROPERTIES SECURED. SO THOSE ARE THE STEPS YOU NEED TO GO THROUGH WANT SO WE WOULD LIKE TO TAKE THIS TO A CLINICAL TRIAL IN PANCREATIC CANCER PATIENTS AND TEST THIS COMBINATION TREATMENT. WE SAID THAT THE CHEMOTHERAPY, NOT ONLY DOESN'T WORK. BUT IT'S TOXIC. AND PATIENT'S HAIR FALL OUT, THEY HAVE A LOT OF TOXICITY WITH TEMPERATURIT. THERE'S NO GOOD DIAGNOSTIC TEST TO PICK UP PANCREATIC CANCER IN THE EARLY STAGES. EVEN OUR CAT SCANS, AND PET SCANS DON'T PICK IT UP WHEN IT'S DETECTABLE. SO WE'RE DEVELOPING A NON-O PARTICLE WHERE WE CAN TARGET THE CCK RECEPTOR, AND IT'S CALLED AN PHER -- THERIAN OFTIC COMPOUND. IT DOES THERAPY AND WE CAN USE IT FOR DIAGNOSIS. WHAT A NANOPARTICLE OR NANOTECHNOLOGY? A NANOMEET NEVER SIZE, BETWEEN A HUNDRED AND 1 NANOMETERS IN SIZE SO WE HAVE DESIGNED A NANOPARTICLE THAT WILL BIND TO THE CCK RECEPTOR ON PANCREATIC CANCER CELLS AND IT CAN DELIVER SIR TO KNOCKOUT GASTRIN. YOU KNOW THE ONLY WE YOU CAN DELIVER SN IS IF YOU USE -- USING TECHNIQUES IN VIVO OR LIKE, IMPOSSIBLE. SO PEOPLE OF COURSE TRYING TO FIND GOOD DRUG DELIVERY SYSTEMS TO DELIVER GENE THERAPY TO KNOCK DOWN TARGET PROTEINS. SO THE FIRST ONES WE TRIED WERE NANOLIPOSOMES AND WE HAVE MADE IT SO THEY BIND TO CCK RECEPTOR AND WE TRIED TO NANOPARTICLES THAT WE COULD TRY TO PUT DIFFERENT SINRA'S AND WE'VE BEEN THROUGH A SERIES OF DIFFERENT NANOPARTICLES. IN ORDER TO MAKE OUR NANOPARTICLE SO THAT IT SELECTIVELY TARGETS THE CCK RECEPTOR WITHOUT ACTIVATING THE RECEPTOR. WE DO NOT WANT IT TO STIMULATE GROWTH. WE DESIGNED A DNA APTIMER, THAT WILL SELECTIVELY BIND TO THE RECEPTOR. BUT IT DOESN'T STIMULATE GROWTH OR CAUSE SIGNALING AND THAT WAS A WHOLE PROCESS, BUT WE CAN NOW TAKE THIS AND BIND IT ONTO OUR NANOPARTICLES, AND IT WILL GO RIGHT TO THE CCK RE RECEPTOR. THIS IS A MOUSE THAT HAS A PANCREATIC CANCER GROWING ORANGE COUNTY TOPICALLY AND WE INJECT TODAY MOUSE WITH SOME NANOPARTICLES THAT WERE LOADED WITH A FLUORO -- TO TELL IF IT'S GOING TO THE CANCER OR NOT. THE MOUSE OVER HERE, GOT NANOPARTICLES THAT WERE NOT TARGETING THE CCK RECEPTOR. AND THIS SELECTIVELY TARGETED THE RECEPTOR. YOU CAN Z I THINK AFTER 7 HOURS AND 24 HOURS, THERE'S REALLY NO SELECTIVE BINDING WANT IT WAS NOT TARGET SPECIFIC. BUT IF WE TAKE OUR NANOPARTICLES, AND WE HAVE WHERE WE CAN SEE WHERE THE PARTICLES GO. THEY ALL TO THE PANCREAS AND THEY'RE STILL THERE 24 HOURS LATER. SO WE CAN USE THESE TWO IMAGE THE PANCREATIC CANSER AND DELIVER GENE THERAPY. WAIT WE'RE NOW MOVING ON TO DELIVER THE GENE THERAPY, WE HAVE MODIFIED OUR NANOPARTICLE. WE HAVE USED THIS SPECIAL POLE PLEX THAT ACTUALLY IS A POLYLI SEEM TAIL TO BIND NEGATIVELY CHARGED DNA AND IT FORM ACE MY CELL AND THE MY CELL PROTECTS, SO IT'S NOT DEGRADED IN THE BLOOD AND WE CAN PUT ANY SORT OF TARGETING OUT HERE. SO IT'LL GO RIGHT TO THE RECEPTOR AND WE CAN PUT CHLOROFORES ON THERE SO WE CAN FOLLOW WHERE IT GOES. THIS SHOWS OUR SARNA LABELED WITH PSI THREE SO WE CAN SHOW, IT MADE IT INTO THE TUMOR. AND THEN WHAT WE DID, WE TOOK OUT THE TUMORS AND DID IMMUNOHISTOCHEMISTRY AND SHOWED THIS IS GASTRIN EXPRESSION YOU'RE -- ACTUALLY, GASTRIN PROTEIN. OUR TARGETED PARTICLES CARRYING THE SIRNA WAS THE ONLY ONE THAT SELECTIVELY KNOCKED DOWN GASTRIN IN THE TUMORS WE HAD OTHER ANIMALS TREATED WITH UNTARGETTED PARTICLE BUS IT DIDN'T GET TO THE CANCER. THESE ONCE WENT TO THE CANCER. THIS ONE WAS CARRYING A SCRAMBLED CONTROL. AND THE TUMORS IN THE MICE, HAD SMALLER TUMORS AND NONE OF THESE MICE GOT METASTASES, COMPARED TO ALL THE OTHER TREATMENT GROUPS. SO WHAT ARE THE OBSTACLES FOR TRANSLATIONAL RESEARCH TODAY, WELL , TAB OF COURSE, MONEY. MONEY'S THE PROBLEM. LACK OF FUNDS, MISUSE OF FUNDS, DISPARITY OF FUNDS, WHATEVER. I'M A CLINICIAN, THERE'S MORE EMPHASIS FOR ME TO SEE PATIENTS AND BRING IN MONEY CLINICALLY, THAN THERE IS TO SIT AT BENCH AND DO RESEARCH WANT SO CLINICIANS DON'T ALWAYS GET PROTECTED RESEARCH TIME. YOU HAVE TO ALL PARTNER TOGETHER, BECAUSE YOU NEED AN INDUSTRY PARTNER TO TAKE YOUR DRUG OUT THERE. THERE'S ALWAYS PROBLEMS TO GET PATIENTS TO RESEARCH IN PARTICIPATION. THEY THINK THEY'RE BEING GUINEA PIGS BUT THERE'S NOT. THERE'S NO ONE MAN BAND. YOU CAN'T DO THIS BY YOURSELF. MD'S HAVE TO WORK WITH PHK'S -- PH.D.'S, WE WORK WITH STUDY ACCORD FATE RNATORS AND IT'S A TEAM APPROACH. IT IS IMPORTANT TO WORK TOGETHER. THEY REALIZED HOW IMPORTANT RESEARCH WAS. THE PATIENT HERE, HAD FAILED CHEMOTHERAPY AND ONE OF OUR EXPERIMENTAL DRUGS, AND LIVED MUCH LONGER THAN EXPECTED, OVER THREE YEARS WITH PANCREATIC CANCER AND THE SAME WITH H. SO ANYWAY, WHO IS THE POTENTIAL SIDE EFFECT OF USING A CCK RECEPTOR BLOCK BLOCKADE? WELL , TAB THE ONLY BAD THING I CAN THINK ABOUT, THIS IS THE HEARTBURN GUY THAT'S ON TELEVISION. YOU MIGHT NOT GET HEARTBURN ANYMORE. IF YOU CAN GET THE GASTRIN EFFECT. SO THAT COULD BE A POTENTIAL SIDE EFFECT. AND THIS IS JUST SOME OF THE PEOPLE WORKING IN MY LAB, AND I THANK YOU FOR YOUR ATTENTION. [APPLAUSE] ARE THERE OTHER QUESTIONS? >> SO I'VE GONE THROUGH THREE DIFFERENT FACES. THE FIST WAS A CAT IONIC NANOPARTICLE, WHICH IS POSITIVELY CHARGED. THAT'S NICE BECAUSE IT TAKES UP THE SANRNA. IT'S TOXIC TO THE LIVER. THE OTHER ONE IS ACTUALLY, WE'RE STILL DOING RESEARCH WITH THAT. I WORKED WITH BIOMATERIAL SCIENCE ENGINEER THAT ONE WORKS REAL WELL FOR CARRYING THE FLORESSENT PROBES AND DRUGS AND STUFF, BUT WE COULDN'T GET IT TO TAKE UP THE GENE THERAPY. THE LAST ONE I'M WORKING WITH. I'M COLLABORATE WITHING STEVE STERN UP AT NCI NATIONAL CHARACTERISTICKIZATION LAB AT FREDERICK. I WENT TO HIM WITH MY IDEA AND HE HELPED ME DESIGN THE POLYFLEX. AND SO WE'RE COLLABORATE WITHING THEM AND THEY'RE MAKING THE NANOPARTICLES FOR US AND THEY SHIP THEM DOWN TO GEORGETOWN AND WE TEST THEM WITH THE ANIMALS AND WE'RE WORKING ON A PROJECT NOW, WE JUST SUBMITTED ANOTHER GRANT, TO USE THESE PARTICLES TO DO EARLY IMAGES AND HOPEFULLY, THERAPY, TOO. THOSE PARTICLES CAN DELIVER OUR GENE. WE CAN FLORESSENTLY LABEL THEM. SO OVER THE YEARS, WE HAVE KIND OF COME UP WITH A BETTER PRODUCT AND I'M SURE WE MAY COSOME MORE REFINING WHERE WE G. BUT THAT'S KIND OF WHERE IT CAME FROM. HAD A QUESTION? SO ACID REFLUX IS A VERY COMMON CONDITION. BUT ACID REFLUX, ONLY IF IT CAUSES ESOPHAGITIS, WHICH IS INFLAMMATION IN THE ESOPHAGUS, COULD IT INCREASE THE RISK FOR MAYBE ESOPHAGEAL CANCER. ANY TYPE OF CHRONIC INFLAMMATION CAN CAUSE INCREASED RISK OF CANCER, WHETHER IT'S CHRONIC HEPATITIS, CHRONIC COLIT IS. BUT MOST PEOPLE WHO HAVE ACID REFLUX, DO NOT HAVE EROWSIVE ESOPHAGITIS. SO WITH THAT POPULATION ANOTHER BETTER TO TAKE A PERIODIC -- I'M GIVING YOU MY G.I. ADVICE. A PERIODIC HISTAMINE BLOCKER, PEPSID AC. ZANTAX OR OVER THE COUNTER, YOU KNOW, SOME ANTI-ACID IF IT'S JUST A PERIODIC ONE. HOWEVER I DO SCOPES JUST TO MAKE SURE THEY DON'T HAVE THE EROWSIVE ESOPHAGITIS OR BARRETTES ESOPHAGUS. IT CHANGES THE MUCOSAL LINING FROM! OUS TO MUCOSA AND THAT -- IF THEY HAVE BARRETTES ESOPHAGUS, WE USUALLY KEEP THEM ON PPI'S, BUT THERE MAY BE A CATCH 22 WITH THAT. WE DON'T KNOW. SO THAT'S THE RECOMMENDATION. REPURPOSING OLD DRUGS FOR NEW INDICATIONS. IF YOU ARE CHANGING GOING FROM THE APPROVED INDICATION OR THE APPROVED DOSE. YOU CAN DO FAST TRACK IF IT'S A PRIOR APPROVED DRUG AND IT'S A 301B2 WHERE REPURPOSING OLD DRUGS, CAN YOU EPE INDICT IT. NEXT LECTURER IS SONIA JAKOWLEW SHE DID A POST DOCTORAL POSITION IN FRANCE. SHE CAME BACK TO NCI, AND WAS WORKING WITH MICHAEL SPORAN HERE AT NCI ON TRANSFORMING GROWTH. DR. BET A SHE'S NOW IN THE CANCER TRAINING BRANCH CENTER FOR CANCER TRAINING AT NCI. HER TITLE, TRANSFORMING LUNG CANCER BETA AND TUMOR GENESIS. WHY LUNG CANCER? OVER THE PAST YEARS, LUNG CANCER HAS BECOME THE MOST COMMON CORE CAUSE OF CANCER DEATHS, AMONG BOTH MEN AND WOMEN IN THE U.S. THE AMERICAN CANCER SOCIETY SAID OVER THIS YEAR, THERE WILL BE OVER 234 CASES OF LUNG CANCER, AMONG BOTH MEN AND WOMEN. AND MORE THAN 154,000 DEATHS WILL OCCUR. THE 5 YEAR SURVIVAL RATE IS STILL LESS THAN 15%. THE NUMBER OF DIAGNOSED CASES, AND THE NUMBER OF DEATHS HAS BEEN DECREASES OVER THE DECADES IN THIS C. THE BAD NEWS IS, W THE INVENTION OF E-CIGARETTES AND TEENS CATCHING ON TO SMOKE WITHING THESE NEW GADGETS. IT'S EXPECTED THAT THE CASES OF LUNG CANCER WILL INCREASE BECAUSE THESE E-CIGARETTES CONTAIN NICOTINE, JUST AS TOBACCO DOES. AND WE ALL KNOW THAT THE INCIDENCE OF LUNG CANCER IS DECREASING IN THIS COUNTRY, AND IN EUROPE AND ASIA, IT IS INCREASING BY LEAPS AND BOUNDS, SO THIS IS A VERY DANGEROUS DISEASE. [INDISCERNIBLE] SAY MOSTLY FUNCTIONAL REL LATER OF CELL GROWTH. IT HAS BEEN SHOWN TO BE A POTENT INHIBITOR OF A PROLIFERATION OF MOST EPITHELIAL CELLS AND CULT. IT SHOWS WIDESPREAD TISSUE EXPRESSION IN HOW MANY HUMANS, AND HAS BEEN SHOWN A PIVOTAL ROLE IN EPITHELIAL HOMEOSAYS IS. IT'S ANYONE ASSOCIATED WITH VARIOUS TYPES OF CANCER, INCLUDING LUNG CANCER, AND IT SHOWS THE CONTEXT DEPENDENT INHIBITION OR ASSIMILATION OF CELL PROLIFERATION AND NEO PLASTIC TRANSFORMATION FORMATION. WHEN YOU PUT THIS ALTOGETHER. IT IS APPARENTLY, AN ATTRACTIVE CANDIDATE FOR NEW THERAPEUTIC INTERVENTION APPROACHES. SO TO UNDERSTAND SARCOMA GROWTH FACTOR IS A POLYPEPCIDE SECRETED BY [INDISCERNIBLE] THAT IS ABLE TO STIMULATE THESE NORMAL [INDISCERNIBLE]. THIS IS ESSENTIALLY THE TRANSFORMATION ASSAY THAT WAS USED WHEN REPORTED IN THE LATE 70'S. >> THE [PLEASE STAND BY] [INDISCERNIBLE] WAS CONTEMPLATED PERFORMED, AND IN 1983, THREE PAPERS CAME OUT BY THREE DIFFERENT AUTHORS ALL AT THE NCI, FROM HUMAN PLATELETS, HUMAN PLACENTA AND BOVINE KIDNEY. TO GIVE YOU SOME IDEA OF THE PURIFICATION THAT WAS INVOLVED IN PURIFYING BETA 1, A HUNDRED GRAMS OF BOVINE KIDNEY WAS [INDISCERNIBLE] FROM THE SLAUGHTER HOUSE, DIRECTED WITH [INDISCERNIBLE] DURING THE DAY. REMOVAL OF THE GUNK AND THEN THE LIQUID WITH A MIXTURE OF ETHANOL OF THE TUNE OF ABOUT 50 LITERS OVERNIGHT IN A COLDRUM. THE NEXT MORNING, WAS REDISSOLVED IN TWO LITERS OF ACID. -- THESE WERE REDEVELOPED FOR FURTHER VERIFICATION, AND FINALLY YIELDED ABOUT 6 MICROGRAMS FROM A HUNDRED GRAMS OF TISSUE. SO TO GIVE YOU SOME IDEA, USED TO DO THIS, THIS IS BIOJELL 60 COLUMNS, AND SHOWN IN THE GALLON DRUM USED TO COLLECT WASTE. INCLUDED THE GROWTH OF KIDNEY CELLS, AND CASE CELLS. SO THE ASSAY CONDUCTED WAS USING A PLATING ON A BASE AND A MIXTURE OF MEDIA SERUM AND CASE CELLS, EDF, WHICH WAS THE GROWTH FACTOR AND A PORTION OF THE SAMPLE. THE COLONY, WITH A NORMAL COUNT IMAGE AND SYSTEM, SHOWN AT THE BOTTOM. IF BETA IS FRONT IN THE SAMPLE, THEN COLONIES SHOULD GROW, AND WE COUNTED IF THERE ARE AT A CERTAIN SIZE OR GREATER. SO THE FINAL LIQUID (INAUDIBLE) PURIFICATION WAS CONDUCTED, AND THIS SLIDE SHOWS A ABOUT 25,000 MOLECULAR WEIGHT, [PLEASE STAND BY] IT CONTAINED A SINGLE PEPTIDE WHAT IS CALLED THE LACENCEY ASSOCIATED IN THE MIDDLE. AND AT END, BETA OF 112 AMINO ACID. NOW, SHOWN ON THE UPPER RIGHT PANEL, IS A CARTOON OF THE AMINO ACID. SEQUENCE OF HUMAN PDF BETA ONE. AND SHOWN IN BLACK ARE THE NON-CHARACTERISTIC SISTINE RESIDUES FOLLOWING THE PURE IF I PURIFICATION. SO TJ BETA 2, EXISTING AS TWO -- THERE ARE 5 DIFFERENT ISOFORMS OF TJ BETA 1, 2 AND 3 ARE FOUND IN MAMMALS. 4 IS FOUND IN BIRDS. AND IN ADDITION TO TJPHETA -- THIS IS THE BONE PROTEINS, GROSS DIFFERENTIATION FACT OSHOWN IN THE MIDDLE AND THERE ARE QUITE A FEW, AS WELL AS THE ACTIVE INHUB TAINTS. STRUCTURALLY, THEY BEAR A LOT OF RESEMBLANCE TO THE TJ BET A PER SE, BUT THEY ARE UNIQUE PROTEINS THEMSELVES. SO TO PUT ALL OF THIS TOGETHER, TJ BETA EXISTS AS A 25 UPON BONDED HOMO DIMEER. 300 HOMOLOGOUS ISOFORMS OF COURSE IDENTIFIED IN HUMANS AND MAMMALS. PRINCIPLE SOURCES OF MAMMALIAN TJ BETA INCLUDING PLATELETS, SPLEEN, MOST CELLS ARE ABLE TO EXPRESS TJ BETA. MOST NORMAL CELLS ARE ABLE TO EXPRESS TJ BETA IN ITS RECEPTOR AND TJ AT THE TIMA IS SECRETED IN THE ACTIVE FORM, THAT HAS TO BE ACTIVATED, IN ORDER. IF THERE'S ANY QUESTIONS, PLEASE DON'T HESITATE. NOW WHEN, TJ BETA SUPER FAMILY WAS IDENTIFIED AND THERE WERE SO MANY PEOPLE WORKING ON THIS, THIS PROJECT IT WAS READILY OBSERVED THAT THERE ARE MANY BIOLOGICAL PROCESSES THAT ARE CONTROLLED BY THIS SUPER FAMILY, INCLUDING SUCH IMPORTANT PROCESSES AS DEVELOPMENT, IMMUNE SYSTEM FUNCTION, REPRODUCTION, ANGIOGENESIS, AGING TISSUE REPAIR METABOLIC REGULATION AND PROLIFERATION. SO THERE ARE A WHOLE A LOT THINGS CONTROLLED BY THIS SUPER FAMILY AND A WHOLE A LOT OF PEOPLE INTERESTED IN WORKING ON IT, AND FINDING OUT HOW THIS PROCEEDS. NOW, THERE ARE MANY MAJOR BIOLOGICAL RESPONSES THAT CAN BE REGULATED. AND THIS DEPENDS, REALLY, ON THE CELL TYPE. IN CERTAIN CELL TYPES, IT CAN INHIBIT PROLIFERATION. IT CAN ALSO REGULATE IT CAN STIMULATE THE ACCUMULATION OF CELL MATRIX, UNDER CERTAIN CIRCUMSTANCES AND CAN ALSO PROMOTE HEMOTASIS. GAIN, DEPENDING ON THE CELL:TYPE. MODEL 4, FOR THE TJ BETA PATHWAY WAS CONSTRUCTED WITH INPUT FROM SEVERAL LABORATORIES. I'LL START AT THE UPPER LEFT HAND SIDE, THE BLUE REPRESENTS THE TJ BETA LIGAN. AND THIS COULD BE TJ BETA PER SE. THE LIGANS TO BIND TO THE TYPE 2TJ BETA RECEPTOR, SHOWN IN PINK, WHICH IS CONSISTENTLY PHOSPHORYLATED. ONCE ITS COMPLEX STARTS TO FORM THE TYPE 2 RECEPTOR, THEN RECRUITS THE TYPE 1 RECEPTOR AND IS ABLE TO PHOSPHORYLATE THE RECEPTOR. WHEN THIS HAPPENS, AND COMPLEX IS ABLE TO INTERACT WITH THE REGULATORY RECEPTOR AND THIS IS A LITTLE BIT COMPLICATED BECAUSE THE REGULATORY RECEPTOR DEPEND ON BINDING TO THIS, DEPENDENT ON WHICH TYPE OF LIGAND YOU'RE TALKING ABOUT. SO IF YOU'RE TALKING ABOUT ACT VIN OR TGF, WE TALK ABOUT THE SNAG1 AND 3. AGAIN, IT DEPENDS ON THE CELL TYPE THAT'S INVOLVED ONCE THE LIGAN COMPLEX IS ABLE TO INTERACT WITH THE RECEPTOR. REGULATED ONCE IT BINDS TO INTERACT WITH 4 PROTEIN, THEN A TABLE TO CROSSES INTO THE NUCLEUS AND IT AFFECTS TRANSSCRIPTION. THE WHOLE THING CAN BE SIR COME VENTED BY WHAT WE QUALITY INHIBITOR SMAZ. 6 OR 7 WHICH CAN SHORT KIRKITY THE WHOLE PROCESS, INCLUDING INHIBITION OF GROWTH. PEOPLE WILL BE INVESTIGATED AGAIN, AND BECOME INTERESTED IN THE CLINIC. IT WAS SHOWN TO BE A CONSUMER HAVE ASSUMER SUPPRESSIVE PROPERTY. WERE SHOWN FOR EMILIO PREDISPOSITION CANCER. AND THIS HAS BEEN SHOWN JUVENILE (INAUDIBLE). SECONDLY, THE TJ BETA PATHWAY COMPONENTS, WERE SHOWN TO BE ABLE TO BE SOMATICALLY MUETATTED OR DELETED IN SOME HUMAN CANCERS CANCERS. -- [INDISCERNIBLE] SHOWN TO BE ASSOCIATE WITH THE DISEASE PROGRESSION. THIS INVOLVES THE TYPE 2 RECEPTOR, AS WELL AS TYPE 1 AND ALSO, A INTERACTING PROTEIN, THAT OFTEN INTERACTS WITH BETA THIS HAPPENS TO BE A PROS AT THE TIMIC CARCINOMA, FOR BETA 1, AND YOU SEE THE BROWN TYPE OF STAINING, THAT IS INDICATIVE OF BETA 1. AND TGF BETA HERE IS IN A POSITION TO SIT AT THE INTERFACE, BETWEEN THE TUMOR AND THE MICRO ENVIRONMENT. CALL IT A HERO OR A VILLAIN. TURNS OUT, IT CAN BE BOTH. FGF BETA CAN BE A PROXIMATE PROXIMAL EFFECT ORS OF BETA TYPE. AND A GROWTH INHIBITOR TUMOR SUPPRESSOR, DEPENDING ON CELL TYPE AND THE CONDITION THAT IT IS PUT UNDER, AND IT COULD BE A PRO METASTATIC FACTOR AS WELL. SO HOW DOES IT DO THIS? AGAIN, AFTER MANY YEARS OF WORK HOW DOES IT DO THIS? WELL, IN NORMAL EPITHELIUM, THE TUMOR SUPPRESSOR PREDOMINATE OVER THE PRO ORANGEOGENIC ACTIVITIES AND YOU GET DECREASE IN CELL GROWTH. YOU HAVE TUMOR GENESIS, AND CHANGE UP IN EPIGENIC CONTEXT WANT SO THAT WHEN YOU BEGIN TO LOSE RESPONSIVENESS TO TJ BETA AND SAY., YOU GET EITHER AN INCREASE IN EXPRESSION OR ACTIVATION OF TJ BETA AND THEN YOU SEE THAT THE PRO ONCOGENIC ACTIVITIES, BEGIN TO DOMINATE OVER THE TUMOR SUPPRESSOR ACTIVITIES, THIS BEGINS TO ACCUMULATE AS THE TUMOR BECOMES METASTATIC. PATHWAYS TAINVOLVED GASWAY, GROW, AND PROTEIN [INDISCERNIBLE] AS FOR EXAMPLE, NOW, WE WERE PARTICULARLY, INTERESTED IN THE RAS KIND PATHWAY BECAUSE CAN MODULATE BETA SIGNALING, AND THE NUMBER CELL LINE. AND IN FUTURE STUDIES HAVE SHOWN THAT BETA DOMINATES OVER THE -- ACTIVATED RAS CAN OVERRIDE THE [INDISCERNIBLE] BETA ONE UNDER CERTAIN CONSCIENCE. SO HOW DOES THIS HAPPEN? WHERE THE TUMOR SUPPRESSOR PROPERTIES OF BETA CAN BE LOST, AND TOMB TUMOR PROMOTER EFFECTS BECOME ENHANCED. WELL, ON THE LEFT, ON THE LEFT SIDE, YOU SEE A NORMAL TJ BETA PATH IF ONE HAS A CASE OF DECREASED EXPRESSION OF THE TYPE 2 RECEPTOR THAT CAN RESULT IN TUMOR PROMOTION. LIKE WISE, HYPER ACTIVATION OF THE MACRAS PATHWAY, CAN ALSO LEAD TO TUMOR PROMOTION AS CAN DECREASED LEVELS AND COMPROMISE EFFECTIVE FUNCTIONS IN ANY PART OF THE SUPPRESSOR ARM OF TISSUING J BET A. CAN RESULT IN TUMOR SUPPRESSION. SO WE WERE PARTICULARLY INTERESTED IN -- DEVELOPMENT AND MALIGNANT TRANSFORMATION OF EPITHELIAL CELLS. DETERMINE THE EARLY EVENTS AND DEVELOPMENT OF LUNG LESIONS, AND HAVE A PROGRESSED, AND THEN TO IDENTIFY POTENTIAL SIGNALING TRANS-- PATHWAYS. TO CARRY OUT THIS WORK. WE USED MOUSE MODELS, WHICH ARE VERY GOOD FOR ASSESSING MECHANISM. WE USED 4 MASS MODELS. THE AJ MOUSE, C57. BETA ONE. -- FOR THIS ONE, I'LL JUST CALL THE IT MODEL MOUSE. FOR SAKE OF TIME. SO WE ASK TWO QUESTIONS. FIRST QUESTION, DOES TUMOR GENESIS EFFECT THE SHALLING PATHWAYS PATHWAYS, AND DOES IT AFFECT LUNG TUMOR JEN SAY. L THIS MOUSE MODEL HAS BEEN SHOWN TO BE VERY SUSCEPTIBLE TO CHEMICALLY INDUCED LUNG TUMOR. AND THE TUMOR'S DEVELOP IN A TIME-DEPEND MANNER, SUCH THAT PROGRESSES THROUGH THE CARS NOMES THAT FOREIGN, ARE HISTOLOGICALLY SIMILAR. REMEMBER, WE WANTED TO PARLAY THIS INTO RELEVANCE TO HUMANS AND THE SAME MOLECULAR MUTATIONS OCCUR THIS BOTH HUMANS AND TUMORS, FOR EXAMPLE, SO TO TURN ON THIS LAST TUMOR GENESIS, WE USE CARBON MATE. CAN BE ON METABOLIZED IN TWO DIFFERENT PATHWAYS. THERE'S A DETOXICITYIFICATION PATHWAY, SHOWN ON THE LEFT. WHERE, IT FORMS SIMPLE ETHANOL CO2 AND AMMONIA. BUT IT CAN ALSO GO THROUGH A BIOACTIVATION PATHWAY WHERE IT FORMS A BIOCONCERN NATE AND A BIOCARBONATE CONSIST KIND OF BAD NEWS BECAUSE THESE CAN BIND TO MACROMOLECULES LIKE DNA. SO WE INJECTED TWO-MONTH-OLD MICE WITHETHYL CARBONATE AND THEN SACRIFICED 20 MICE PER [INDISCERNIBLE] OVER A PERIOD OF 12 MONTHS. WE EXTEPPED TIME TRACTED THE LUNGS, AND PUT THEM IN THE EXAMPLE, AND THEN STAINED FOR BETA 1 LIGAN, AS WELL TG1 -- TO MAKE A LONG STORY SHORT, WHEN YOU LOOK AT THE PANEL ON THE RIGHT SIDE OF THE SCREEN, TYPE 2 RECEPTOR. YOU SEE DECREASE RECEPTION STAINING OF THE TYPE TWO PROTEIN AND DECREASES FROM TWO MONTHS TO FOUR MONTHS. NOW, TO SHOW THIS MORE CONVINCE 'LL ON THE LEFT SIDE OF THE PANEL. YOU'LL SEE A COMPARISON FOR THE TYPE 1 AND TYPE 2 RECEPTOR. COME PARISON WITH THE TYPE 2 RECEPTOR, SHOWS COPPER STAINING IN THE NORMAL SHOWING HIM THE RED ARROW, BUT WHEN WE LOOK AT THE TUMOR, SHOWN BITE PINK ARROWS, YOU SEE THEY ARE APPRECIATIVELY, LOWER STAINING. SO WE SEE DECREASE EXPRESSION OF THE TYPE TWO RECEPTOR. WE'RE SHOWING FIVE DIFFERENT CELL LINES FOR -- PROBE FOR THE RECEPTORS. AND I'D LIKE TO DRAW YOUR ATTENTION TO THE PCC CELL LINE, WHICH WAS A CARBONATE INDUCED TUMOR IN AJ MICE, AND WE SEE HERE, THAT THERE'S A DECREASE EXPRESSION OF THE TYPE 1 RECEPTOR, AND TYPE 2 RECEPTOR, COMPARED TO THE OTHER CELL LINES SO THIS MIRRORS THE DECREASE IN BOTH LEVELS OF THE TYPE 2 RECEPTOR, AS WELL AS MR NETWORK A IN THESE TUMORS. WE ALSO LOOKED AT THE EXPRESSION OF LIGAN, AND TWO RECEPTOR PROTEINS, AND MESSAGES, SHOWN ON THE TOP PART OF THE SCREEN IS, CHEMICAL STAINING FOR -- HERE AGAIN, IN PANEL, SAY ON THE RIGHT, YOU CAN SEE DECREASED EXPRESSION OF TYPE 2 RECEPTOR, COMPARED TO THE OTHER TWO PROTEINS. WE SAW HYBRIDIZATION TO LOOK AT MRNA'S FOR THIS PROTEIN, AGAIN, WE SEE DECREASED EXPRESSION OF OF THE TYPE 2 RECEPTOR -- OFFERING PROTEINS, IN NORMAL BRONCHIAL [INDISCERNIBLE] SO WE'RE SEEING BEHAVIOR BOTH IN THE SO THIS LEADSES TO BELIEVE THAT THE TYPE 2 RECEPTOR IS ONE MECHANISM THAT MAY BE WORKING HERE TO PROMOTE LUNG TUMOR IT BEGINS TO SHOW SIGNS OF NOT DOING SO WELL, AND BY 21 DAYS, THESE MICE ARE ESSENTIALLY DEAD. SO THEY'RE NOT VERY GOOD MODELS FOR TUMOR GENESIS IF ONE WANTS TO CARRY THIS OUT FOR SEVERAL MONTHS. BUT THE HETEROZYGOUS LITTER MATE IS ABLE TO THRIVE AND REPRODUCE SO THIS IS A BETTER MODEL WE'RE LOOKING AT TUMOR GENESIS. SO WHITEFIELD TREATED THESE MICE. SHE'S INTERESTED IN LEVERAGE. TREATE THESE HETEROZYGOUS MICE WITH A LIVER CARS INGENIC. SHE FOUND SHOWN IN THE RED THAT THERE WERE ENHANCED LIVER TUMOR GENESIS AND THESE HAD MICE COMPARED TO THE WILD TYPE LITTER MICE. BUT SURPRISINGLY, SHE FOUND EVEN MORE HUNG TUMORS IN THESE MICE, COMPARED WILD TYPE LITTER MICE. SO WE BEGAN TO COLLABORATE ON THIS. SO SO IN COLLABORATION WITH DR. WHITEFIELD, WE CROSSED THE C57 BLACK FIX HEAD MICE, WITH THE A.J. BETA 1 WILD TYPE MICE THAT WE HAD. WE CAN GET COMMERCIALLY. TO DEVELOP F1 GENERATION OF WHAT WE CALL AJ BLACK 6 -- SO BEFORE WE DID THIS, WE WANTED TO KNOW THAT OUR CROSSES WERE WORKING SO ESSENTIALLY, THE TOP PANELS HERE, THE CHEMISTRY OF WILD TYPE AND HAD MICE, STAINED FOR FGF BETA 1, AND THEN THE MIDDLE PILE, YOU'LL SEE MIDDLE TOP PANEL, YOU'LL SEE, REDUCED STAINING OF THE (INAUDIBLE), COMPARED TO THE WILD TYPE ON THE RIGHT. THIS IS WHAT WE EXPECT, WE HAVE ONLY ONE ALLELE OF TJ BET A. WE EXPECT TO HAVE DECREASED EXPRESSION OF THE PROTEIN. SHOWN ON THE BOTTOM IS ALSO NORTHERN BLOTTING AND COMPETITIVE RPCR AND THIS ALSO SHOWS REDUCE EXPRESSION OF TGF BETA ONE MESSAGE AND THE HEAD MICE, COMPARED TO THE WILD TYPE MICE. THEY HAD A WILD TYPE OVER A PERIOD OF ONE YEAR. SHOWS IN THIS, RATHER COMPLEX, VERY COLORFUL SLIDE, IS ESSENTIALLY IN PANELS A AND B AT THE TOP. YOU SEE, ESSENTIALLY, INCREASED TUMORS, AND MULTIPLICITY OF THE -- IN THE ORANGE BARS, COMPARED TO THE [INDISCERNIBLE] MICE, COMB PAIRED TO THE WILD TYPE MICE SHOWN BITE GREEN BAR. SO YOU SEE INCREASED TUMOR INCIDENTS, AND MULTIPLICITY AND DECREASED LATENCY, AND THE HEAD MICE SHOWN IN ORANGE, COMPARED TO THE WILD TYPE MICE, SHOWN IN GREEN. NOW, THIS IS SHOWN -- THIS HAS SHOWN, VERY EFFECTIVELY IN CALCIUM FOR THE CARS NOPE A. WHILE THE MICE, BEGIN TO SHOW CARCINOMAS, BY FOUR MONTHS, AFTER THE INJECTION OF THE CARS INO JEN, IT TAKES 4 MONTHS BEFORE COMPARABLE TUMORS START APPEARING IN THE WILD TYPE MICE. MICE, COMPARED TO THEIR WILD TYPE (INAUDIBLE). WE LOOKED AT THE LEVELS OF THE TYPE 2MRNA. BECAUSE ESSENTIALLY. DECREASING LEVELS OF THE RECEPTOR, MRNA, WITH DECREASING LUNG TUMOR GENESIS. AS ONE PROCEEDS TO CARCINOMA. FOR THIS WE USED, YET ANOTHER MOUSE MODEL. THE TG BETA [INDISCERNIBLE] AND TO GENERATE THESE MICE, IT TOOK A LONG TIME, SO ESSENTIALLY, IT WOULD CROSS TJ AT THE TIMA 1 HEAD MICE AND KRAS ACTIVATABLE MICE. TO GENERATE FOUR DIFFERENT GENOTYPES THE TGF BETA 1, KRAS, ACTIVATABLE MOUSE, I'LL REFER TO IT AS DOUBLE MUTANT. THE BETA 1 WILD TYPE, KRAS ACTIVATED VITALY NINAKOVABLE, I'LL REFEVITALYACTACVITALY NINAKOVED -- AN D THE SINGLE MUTANT AND THE WILD TYPE. SO SHOWN HERE IS A SLIDE OF THE HISTOLOGICAL DISSECTION OF THESE LUNGS THAT I HAVE TO FORM. AND WHITE NODULES ON SHOWN IN A. AS WELL AS A SINGLE [INDISCERNIBLE] IN B. THE OTHER TWO GENOTYPES DO NOT SHOW SIGNIFICANT NODULES, EVEN AFTER SEVERAL MONTHS OF LOOKING. [INDISCERNIBLE] FOUR GENOTYPES, AND CHOSE THAT ESSENTIAL LEAKER I'D LIKE TO DIRECT YOUR ATTENTION TO THE BOX WHICH SHOWS THE DOUBLE MUTANT AND THE KRAS MUTANT, HAVING SIGNIFICANTLY DECREASED LIFE SPANS, COMPARED TO THE WILD TYPE IN THE SINGLE MUTANT. WE SHOW INCREASED HI PER PRAISIA. INCREASED LEVELS OF HYPER PLACIA, AND THE SINGLE MUTANT. MICE SLOAN IN GREEN. BUREAUCRACIED CARCINOMAS, IN THE DOUBLE MUTANT, SHOWN AT THE BOTTOM IN THE ADINOID CARS INONLY A. SEEMS LIKE THERE'S AN ACCELERATEER PRODUCTION, IN THE MICE. REDUCE LEVELS OF EXPRESSION OF A TGF BETA LIGAND, AND DOUBLE MUTANT MICE, SHOWN BITE PINK ARROWS ON THE RIDE. NOW, WE ARE ALSO INTERESTED IN HOW THE SMADS WERE BEHAVING, AND SO WE LOOKED AT EXPRESSION OF THE SMADS OF BOTH THE TYPE 2 RECEPTOR IN THESE DIFFERENT MICE, AND SHOWN AT THE TOP, IS ESSENTIALLY, IN THE DOUBLE MUTANT, WE SHOW ESSENTIALLY, EXPEDITED REDUCTION WANT TYPE 2 RECEPTOR PROTEIN, AND INCREASED PROJECTION OF THE SMADS PROTEIN IN THESE MICE. WE SHOW ESSENTIALLY, NO DIFFERENT NOT THAT OTHER TWO MICE PHENO TYPE. SO PUTTING THIS ALTOGETHER, I WOULDN'T WORRY YOU WITH THIS, BUT IF YOU CONCENTRATE ON THE KRAS AND RAS FORM, WE SHOW, IN THESE MICE, USING REAL TIME REDUCE TYPE TWO RECEPTOR IN THE CARCINOMAS. AS WELL AS EXPEDITED KRAS IN THESE MICE. COMPARE TO THE SINGLE MUTANT. THIS MODEL SHOWS QUITE EFFECTIVELY THAT BY WHICH LONG-TERM PROMOTION CAN BE EXAS PERRATED. NOW, IN THE SEVERAL COMPOUNDS OF COURSE DEVELOPED, AND ARE CURRENTLY IN CLINICAL TRIAL. I CAN'T FORM MUCH. BUT THERE ARE VARIOUS COMPANIES INVOLVED IN THIS, LIKE PFIZER, INDISCUS FARMER AND SO SO THEY ARE WORKING ON A VARIETY OF CANCERS, INCLUDING THE LUNG CANCER, AND WE EXPECT TO HAVE SOME FEEDBACK FROM THIS IN THE COMING MONTHS. SO WE'RE KEEPING OUR FINGERS CROSSED AND WHAT IT CAN AND CANNOT DO. IT CAN BE TRANSLATED INTO HELPING HUMAN PATIENTS WITH IN NEED OF CURES. SO I'D LIKE TO ACKNOWLEDGE THE PEOPLE WHO WORKED ON THIS PROJECT WHO ARE NOW TAKING OFF TO BIGGER AND BETTER ACTIVITIES, JERRY ANDERSON. JOYCE AND I'D I'D LIKE TO IF YOU HAVE ANY Q I'D BE HAPPY TO ENTERTAIN THEM AT THIS POINT. COME ON, I COULDN'T HAVE OVERWHELMED YOU, I KNOW YOU'RE HUNGRY. ONE QUESTION? IT'S TOUGH TO SAY. I THINK THEY ARE ALL IMPORTANT. AND I THINK WHEN YOU LOOK AT LUNG CANCER, YOU REALLY HAVE TO LOOK AT THE STAGE OF LUNG CANCER. IF YOU CAN FIND IT WHEN IT'S MORE EARL STAGE, YOU HAVE DIFFERENT POSSIBILITIES. YOU HAVE MORE POSSIBILITIES. I'M TRYING TO HEAD IN HERE, BECAUSE IT DEPENDS. MORE DIFFICULT IN HUMAN PATIENTS, EASIER IN MOUSE MODELS. NOW, WHEN WE GOT INTO THIS PROJECT, WE WERE WORKING WITH, THE VERY EARLY VERSION OF THE KRAS MOUSE. OUR KRAS MICE GOT TOO MANY TUMORS, THEY DIED TOO QUICKLY. BUT NOW, THEY HAVE ENGINEERED, I BETTER -- WELL, NOT A BETTER, SEVERAL BETTER KRAS MICE THAT YOU CAN TURN ON AT YOUR WILL, AND SO YOUR MICE DON'T DIE PREMATURELY FROM TOO MUCH TUMOR OVERLOAD. THAT WAS OUR PROBLEM. ANYMORE QUESTIONS? COME OIT'S AN EXCITING FIELD, YOU JUST HAVE TO GET INTO IT, YOU KNOW. OKAY. IF YOU GO TO A PHARMACEUTICAL COMPANY, THEY HAVE IT REVVED UP TO A SCIENCE WHERE IT CAN BE PURIFIED. THIS IS LIKE A HOME MADE VERSION OF JUST PUTTING [INDISCERNIBLE] TOGETHER AND THIS IS THE BEST WE CAN DO IN THE USE AT THE NCI. AND WHEN OUR WORK WAS BEING DONE, THEY WERE TRYING SEVERAL DIFFERENT TYPES OF PURE PURIFICATION SYSTEMS, AND THAT ONE TURNED OUT TO BE THE BEST. OKAY. GUYS. GO GET DINNER. [APPLAUSE]