>> WELCOME TO THE NEXT TO THE LAST SESSION OF THE 21st YEAR OF THE DEMYSTIFYING MEDICINE COURSE AT THE NATIONAL INSTITUTES OF HEALTH. WE HAVE ORGANIZED THIS PROGRAM FOR YOU. IT HAS THE GOAL OF BRIDGING EXCITING DEVELOPMENTS IN BIOLOGY AND ENGINEERING WITH MEDICINE, BRIDGING THE GAP. NOW, THIS IS A COURSE IN BRIDGE BUILDING. DURING THE YEAR WE HAVE BRIDGED EXTRAORDINARY GAPS TO SPACE, TO BIO TECHNOLOGY, TO A GREAT VARIETY OF AREAS INCLUDING LANGUAGE BUT THE PRINCIPLE OF THE MAIN ACTIVITY IN DEMYSTIFYING MEDICINE BASICALLY REPLICATED TO WHAT WE REFER TO AS OLD FASHIONED GRAND MEDICAL GROUNDS. A PATIENT WITH THEIR DISEASE AND SOMEONE PUTS A HUMAN FACE ON THE DISEASE. THEN A PHYSICIAN SCIENTIST DESCRIBES WHAT THE DISEASE IS AND WHAT THEY'RE DOING ABOUT IT AND THEN A BASIC SCIENTIST TELLS US MORE OR LESS WHAT WE KNOW, WHAT WE NEED TO KNOW AND THAT'S FOLLOWED BY A ROBUST QUESTION AND ANSWER AND DISCUSSION. SO THESE TWO GENTLEMEN ON THE BRIDGE ARE DISCUSSING WHAT IS IT ABOUT THE BENIGN TUMORS OF CHILDREN, SOME OF THEM. SOME OF THEM TURN MALIGNANT, SOME ARE INHERITED. SOME PRODUCE LOCAL AFFECT THAT REQUIRE TREATMENT, MORE OFTEN THAN NOT SURGERY AND SOME PRESENT PROBLEMS THAT CANNOT BE ADDRESSED BY SURGERY AND WHAT IF ANYTHING CAN WE DO ABOUT THEM AND ARE THEY PRECURSERS OF MALIGNANT DISEASE. THE WORD FOR TUMOR IS OMA. WE HAVE FIBROMAS AND TODAY WE'RE DISCUSSING FIBROMATOSIS AND SOME ARE INHERITED AND SOME ARE MAN MANIFESTED IN CHILDREN AND YOUNG ADULTS. THEY'VE BEEN DESCRIBED CLINICALLY AND PATH OWE LOGICALLY AND ASIDE FROM SURGERY, VERY LITTLE HAS BEEN POSSIBLE IN THE WAY OF EFFECTIVE THERAPY UNTIL TODAY. AND SO TODAY'S SPEAKERS ARE RESPONSIBLE FOR TREMENDOUS ADVANCES IN UNDERSTANDING THE MOLECULAR BASIS OF NEUROFIBROMATOSIS TYPE-1 AND OTHER SUCH TUMORS IN CHILDREN. SOME CHARACTERISTICS ON THIS SLIDE WILL BE DISCUSSED IN MUCH GREATER DETAIL SO I'M GOING TO SKIP OVER IT THE FIRST IS BRIGITTE WIDEMAN WHERE SHE GRADUATED IN GERMANY AND CAME TO THE NIH AS A FELLOW IN HEMATOLOGY AND ONCOLOGY. WE'RE ALL DELIGHTED THE STAYED HERE EVER SINCE. SHE ACHIEVED TENURE IN 2009 AND CURRENTLY IS THE NCI HEAD OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTIC SECTION. SHE'S THE CHIEF OF PEDIATRIC ONCOLOGY BRANCH AND A CLINICAL DEPUTY DIRECTOR. SHE WAS INVOLVED IN EARLY TRIALS IN CHILDREN WITH ADULTS WITH REFACTORY CANCERS AND TUMOR PREDISPOSITION SYNDROME SUCH AS THE ONE TO BE DISCUSSED TODAY, NEUROFIBROMATOSIS TYPE-1. WITHIN THE PAST YEAR OR TWO HER WORK AND WITH HER COLLEAGUES HAS ATTRACTED ENORMOUS AND APPRECIATION. THEY'RE RESPONSIBLE FOR THE FIRST FDA APPROVED TREATMENT FOR NEUROFIBROMATOSIS TYPE-1. AND RECEIVED AN AWARD WITHIN THE TOP 10 CLINICAL RESEARCH AWARDS FROM THE CLINICAL RESEARCH FORUM. THIS IS A BIG DEAL. SHE WAS ELECTED TO THE ASSOCIATION OF AMERICAN PHYSICIANS AND GAVE AN OUTSTANDING LECTURE AT THE NIH. SHE HAS PLAYED A PART IN DEVELOPING MULTIPLE CLINICAL TRIALS OF NEW INVESTIGATIONAL AGENTS. IN PEDIATRIC REFRACTORY CANCERS AS WELL AS NEUROFIBROMATOSIS TYPE-1. THE SECOND SPEAKER IS JACK SHERN WHO GRADUATE FROM THE MEDICAL COLLEGE OF GEORGIA. TOOK HIS PEDIATRIC RESIDENCY AT THE UNIVERSITY OF CHICAGO, CHILDREN'S HOSPITAL AND THEN TRAINED IN PEDIATRIC HEMATOLOGY AND ONCOLOGY AT NIH AT THE NCI. HE'S IN THE CANCER RESEARCH GENETICS BRANCH WHERE HIS MAIN ACTIVITY IS THE DEVELOPMENT AND APPLICATION OF NEXT-GENERATION SEQUENCING TO PROFILE SOME ADDED CHANGES DRIVING MULTIPLE TYPES OF PEDIATRIC SOLID TUMORS AND IN 2018, HE BECAME AN NIH LASKER INVESTIGATOR IN THE PEDIATRIC ONCOLOGY BRANCH. WELL, LET US GET ON TO THIS EXCITING TOPIC WHICH I WOULD POINT OUT IF YOU LOOK IN BOOKS AS RECENTLY AS PERHAPS ONLY SEVEN, EIGHT OR NINE YEARS AGO, THESE DISEASES ARE MENTIONED AND DESCRIBED BUT USUALLY HAVE THE ADDITIONAL STATEMENT THAT ASIDE FROM SURGERY IN SOME CASES, NOT MUCH CAN BE DONE ABOUT THEM. WE'RE LIVING IN A DIFFERENT WORLD THANKS TO RESEARCH AND CLINICAL STUDIES THAT YOU'LL HEAR ABOUT NOW. SO, BRIGITTE, PLEASE. >> THANK YOU, DR. ARIAS. JACK AND I BOTH APPRECIATE THE OPPORTUNITY TO SPEAK TODAY. I WANT TO UP FRONT THANK MY PATIENT HEATHER AND ALL OF THE PATIENTS WHO HAVE PARTICIPATED IN THE RESEARCH THAT WE'RE PRESENTING TODAY BECAUSE WITHOUT THEM NO PROGRESS WOULD HAVE BEEN MADE. THE TOPIC WILL BE ON NEUROFIBROMATOSIS TYPE-1. WE HAVE NO FINANCIAL DISCLOSURES, DR. SHERN AND I BUT I WILL SPEAK OF INVESTIGATIONAL APPROACHES AND WE'LL TALK ABOUT THE NATURAL HISTORY OF TUMORS THAT DEVELOP IN NF 1 AND TALK ABOUT THE DEVELOPMENT OF EFFECTIVE TREATMENTS FOR NEUROFIBROMATOSIS OR NF 1 RELATED TUMORS AND WE'LL TALK ABOUT THE TUMOR MICROENVIRONMENT AND ITS IMPORTANCE IN NF 1 AND TOOLS HE'S USING TO DEFINE TUMOR HETEROGENEITY TO MALIGNANT AND THE STRATEGIES WE'RE DEVELOPING TO MANAGE NF 1 PATIENTS AT RISK FOR MALIGNANT TRANSFORMATION. WE'RE THRILLED TO BE WORKING AT THE NIH CLINICAL CENTER AND AT THE NCI. IN MY MIND IT'S THE BEST PLACE EVER TO CONDUCT CLINICAL RESEARCH AND I DO WANT TO THANK EVERYONE WHO PROVIDES THE AMAZING RESOURCES AT THE NIH BUT ALSO WITHIN THE NCI AND YOU SEE THE PEDIATRIC ONCOLOGY BRANCH. WE'RE A HIGHLY COLLABORATIVE GROUP AND A WANT TO THANK ALL OF OUR MEMBERS IN THE PEDIATRIC ONCOLOGY BRANCH FOR THEIR COMMITMENT. I'M STARTING WITH AN OVERVIEW OF NF 1. IT'S A FAIRLY COMMON SINGLE-GENE DISORDER CAUSED BY A MUTATION IN THE NF 1 GENE AND OCCURS IN ABOUT 1 IN 5,000 PEOPLE AND INHERITED IN AN AUTOSOMIC DOMINANT FASHION. IT MEANS IF YOU HAVE A MOM OR DAD AND INHERIT IT THE CHANCES YOU'LL HAVE IT IS ABOUT 50%. THE NF 1 GENE PRODUCT NEURAL FIBROMIN CAN CONTROL THE RAS PATHWAY. IT'S MUTATED IN MANY TYPES OF CANCERS. I'LL TALK MORE ABOUT THIS BUT WHEN NF 1 MANIFESTS IT LEADS TO UPREGULATION AND IT'S VERY CHARACTERISTIC CUTANEOUS FINDINGS SUCH AS COFFEE-COLORED SPOTS ON THE SKIN. CUTANEOUS NEURAL FIBROMAS YOU'LL SEE ON THE RIGHT SIDE AND A FRECKLING IN THE AUXILLA AND MY EFFORTS HAVE BEEN FOCUSSING ON TUMORS WITH NF 1 DEVELOPED AND MY FOCUS HAS BEEN ON TUMORS AS DR. ARIAS ALLUDED TO THAT ARISE IN NERVES, ATYPICAL TUMORS IN SHORT AND NPNST. WHEN I START THE WORK A LONG TIME THERE WERE NO EFFECTIVE MEDICAL TREATMENTS FOR MOST THE TUMORS. NF 1 CAN BE CLINICALLY DIAGNOSED IN THE VAST MAJORITY OF PATIENTS BY THE AGE OF SIX YEARS. THE TYPICAL FINDINGS ARE FRECKLING, NEURAL FIBROMAS AND THE DIAGNOSTIC CRITERIA DEVELOP DEPENDING ON WHETHER HAVE YOU A PARENT WITH NF 1 OR DON'T. IF YOU HAVE A PARENT WITH NF 1 YOU ONLY HAVE TO MEET ONE OF THE OTHER CRITERIA LISTED HERE. IF YOU DON'T HAVE A PARENT WITH NF 1 YOU'LL HAVE TO MEET TWO CRITERIA. THE MOST TYPICAL ONES ARE THE CAFE AU LAIT MATCHES. IT'S INTERESTING THERE'S VERY FEW PHENOTYPE, GENOTYPE MUTATIONS AND PREDICTS FOR THE CLINICAL BEHAVIOR. IN A FAMILY THE CLINICAL MANIFESTATIONS CAN BE HIGHLY VARIABLE. THERE'S ONE IMPORTANT GENOTYPE/PHENOTYPE CORRELATION WHEN HAVE YOU A LARGE DELETION OF THE NF 1 GENE THESE PATIENTS ARE AT INCREASED RISK FOR DEVELOPMENT OF AGGRESSIVE TUMORS CALLED MPNTS OR PERIPHERAL PERIPHERAL TUMORS. THEY DEVELOP OVER TIME AND IT'S IMPORTANT FROM A PATIENT PERSPECTIVE. IT DOESN'T MANIFEST AT ONE TIME POINT BUT THROUGHOUT LIFE AND THE RED ARROWS SOME MANIFESTATIONS DEVELOP EARLY SUCH AS THE CAFE AU LAIT NODULES AND MALIGNANT TUMORS BUT THERE ARE A FEW MANIFESTATIONS WE THINK ONLY DEVELOP DURING A SHORT PERIOD OF PEOPLE SUCH AS THE PLEXI FORM FIBROMAS OR THE CHANGE THAT WE DON'T BELIEVE HAPPEN LATER IN LIFE. WHAT THIS MEANS FOR A PATIENT WITH NF 1 IS THEY HAVE TO BE PREPARED TO SEE CHANGES THROUGHOUT THEIR LIFE AND NEED TO BE SEEN BY EXPERT DOCTORS FOR THIS REASON. I'M NOW FOCUSSING ON THE PERIPHERAL NERVE SHEATH TUMORS THIS INCLUDES CUTANEOUS TUMORS YOU SEE ON THE PICTURE AND HERE ON AN MRI. THE TUMORS ARE CHARACTERIZED BY LOSS OF THE SECOND NF 1 ALLELES THEY TYPICALLY DEVELOP DURING PUBERTY AND NOT BABIES OR YOUNG CHILDREN AND THERE'S PLEXI FORM NEUROFIBROMAS. THEY CAN BE LARGE AND TRAVEL ALONG NERVES AND BRANCHES AND CAN OCCUR ANYWHERE IN THE BODY AND CHARACTERIZED BY NF 1 AND THE WORSE IS THE MPNTS TUMORS THAT ARE VERY AGGRESSIVE TUMORS THAT ARE CHARACTERIZED BY ADDITIONAL GENOMIC CHANGES AND DR. SHERN WILL TALK ABOUT THIS. THESE TUMORS REQUIRE SURGICAL RESECTION, COMPLETE RESURGICAL RESECTION FOR CURE AND RECENTLY WE AND OTHERS HAVE DESCRIBED TUMORS THAT ARE BORDERLINE IN THEIR BIOLOGY CALLED ATYPICAL NEURAL FIBROMAS THAT HAVE THE CHARACTERISTIC APPEARANCE THAT HAVE ATYPICAL CELLS AND CHARACTERIZED BY AN ADDITIONAL CHANGE OF A GENE AND I'M NOW SWITCHING TO MY, HEATHER, WHO ACTUALLY HAS HAD ALL OF THESE TUMORS AT VARIOUS STAGES AND IT'S WONDERFUL HEATHER AGREED TO PARTICIPATE. I'LL UNSHARE MY SCREEN SO WE CAN SEE HEATHER AND I WILL ACTUALLY ASK HEATHER A FEW QUESTIONS ABOUT THE NEUROFIBROMATOSIS. HEATHER, THANK YOU VERY MUCH FOR JOINING TODAY. >> SURE. >> I KNOW YOU'RE BUSY AND WE REALLY DO APPRECIATE IT. PEOPLE WILL REMEMBER YOU AS DR. ARIAS SAID AND WHATEVER YOU SAY THEY WILL REMEMBER. MAYBE I CAN ASK IF YOU CAN TELL US HOW OLD YOU WERE WHEN YOU WERE DIAGNOSED AND DO YOU REMEMBER WHAT THE FINDINGS WERE WHEN YOU WERE DIAGNOSED? CAN YOU TALK ABOUT THAT A LITTLE BIT? >> SO I WAS FIRST DIAGNOSED WITH NEUROFIBROMATOSIS WHEN I WAS 9 MONTHS OLD. I DON'T REMEMBER A WHOLE LOT OBVIOUSLY ABOUT THAT BECAUSE BASED OFF MY AGE BUT I DO HAVE SOME MEMORIES OF REMEMBERING WHEN I WAS ABOUT 6 YEARS OLD IS WHEN I STARTED HAVING THE ACTUAL NEUROFIBROMA NODULES OR LUMPS OR WHATEVER YOU WANT TO CALL THEM. AT THAT POINT THEY THOUGHT POSSIBLY I HAD LEUKEMIA WHEN THEY FIRST STARTED APPEARING. THAT HAVE SOME MEMORIES OF THAT WHEN I WAS AROUND 6. >> AND HEATHER, WHAT HAS BEEN YOUR EXPERIENCE GROWING UP WITH NF 1? I KNOW YOU'VE HAD QUITE A NUMBER OF COMPLICATIONS AND EVENTS. I DON'T FLOW IF YOU WANT TO TALK A LITTLE BIT ABOUT THIS BECAUSE IT'S ACTUALLY QUITE IMPRESSIVE. >> SO WHEN I WAS ABOUT 14 YEARS OLD I WOULD HAVE BEEN DIAGNOSED WITH MY FIRST MALIGNANT TUMOR AND THAT WAS IN MY CALF. I WAS 14 AND WAS IN NINTH GRADE AND HAVING A LOT OF PAIN IN MY FOOT AND ONE EVENING MY MOM WAS WITH ME AND COULD SEE AND LIKE SAW THERE WAS A LUMP THAT HAD CHANGED. AT THAT POINT SHE HAD GOTTEN IN CONTACT WITH ONE OF MY DOCTORS AND AT THAT TIME I WASN'T A PATIENT AT THE NIH YET. SO THAT ONE WOULD HAVE BEEN REMOVED AND I HAD RADIATION TO THAT AREA. THEN I WOULD HAVE BEEN DIAGNOSED WITH MY SECOND MALIGNANCY IN 2005. AT THAT POINT MY DOCTORS WHO WERE LOCAL TO THE AREA THAT I LIVE IN REFERRED ME TO THE NIH. SO FROM THAT POINT ON I HAVE BEEN A PATIENT OF DR. WIDEMANN. SO IN 2005 I HAD THE SECOND MALIGNANCY AND I WOULD HAVE HAD BOTH RADIATION AND CHEMO AND THEN ALSO THAT WOULD HAVE BEEN SURGICALLY REMOVED AS WELL. AND THEN I'VE HAD SEVERAL OTHER ATYPICAL NEUROFIBROMAS REMOVED OVER THE YEARS. I GET SCANS REGULARLY AT THE NIH. AND SO AS THEY GROW AND CHANGE, DIFFERENT ONES ARE RECOMMENDED TO BE REMOVED AND THEN I RECENTLY HAD ONE -- ANOTHER ONE REMOVED LIKE A WEEK AND A HALF AGO AND WE JUST FOUND OUT THAT ONE IS MALIGNANT AS WELL. SO THEY WERE ABLE TO REMOVE THE WHOLE TUMOR. AND RADIATION IS WHAT'S GOING TO BE THE NEXT COURSE FOR THAT ONE. >> HEATHER, THIS IS REALLY VERY REMARKABLE OF A STORY. I FEEL WE'VE BEEN WALKING TOGETHER MORE OR LESS. WHAT CAN TELL US ABOUT WHAT IT MEANS TO GROW UP WITH SOMETHING YOU CAN HAVE SOMETHING ALL THE TIME. HOW DO YOU ADJUST AND GET ON WITH YOUR LIFE? I KNOW YOU'RE GOING ON WITH YOUR LIFE. MANY THINGS HAVE CHANGED FOR YOU OVER THE LAST FEW YEARS. I THINK SOMETHING FOR ME I'VE ALWAYS LEARNED TO DEAL WITH BECAUSE IT'S SOMETHING I'VE GROWN UP WITH AND SOMETHING I'VE ALWAYS HAD. I KNOW THERE'S THINGS TO BE WATCHFUL OF BUT SOMETHING I'VE ALWAYS LEARNED TO LIVE WITH AND NOT LET IT SLOW ME DOWN OR STOP ME. I HAVE A WONDERFUL SUPPORTIVE FAMILY TOO AND THAT'S BEEN HUGE. WE'RE PART OF A WONDERFUL SUPPORTIVE CHURCH AS WELL AND THAT'S BEEN HUGE TOO. >> I WOULD SAY YOU'VE BEEN A FANTASTIC JOB IN ALWAYS BEING AVAILABLE WHEN WE SAID WE NEED TO SCAN YOU AGAIN. I HAVE A SLIDE THAT SHOWS YOU'VE HAD QUITE A FEW. >> FOR SURE. >> HEATHER, WHAT IS SOMETHING YOU THINK WE SHOULD FOCUS ON AS RESEARCHERS? >> IT WOULD BE WONDERFUL IF THERE WAS A CURE FOR THESE MALIGNANT TUMORS THAT COULD KEEP THEM FROM TURNING MALIGNANT OR STOP THEM FROM GROWING. STOP THEM FROM OCCURRING IN THE FIRST PLACE. >> I HAVE TO SAY IF WE COULD MAKE ONE THING HAPPEN THAT'S THE TOP ON OUR LIST. WE WILL NOT STOP WORKING, I PROMISE THAT, HEATHER, FOR SURE. I ALSO KNOW YOU'VE HAD SOME RECENT CHANGES IN YOUR LIFE AND TO ME THAT IS INSPIRING. I WAS WONDERING IF YOU WOULD BE WILLING TO SHARE -- >> MY HUSBAND AND I HAVE BECOME FOSTER PARENTS TWO AND A HALF YEARS AGO WE STARTED THE JOURNEY TO BECOMING FOSTER PARENTS AND WERE BLESSED TO HAVE A 4-MONTH-OLD LITTLE BOY PLACED IN OUR HOME. WE GOT HIM RIGHT BEFORE EVERYTHING WITH COVID STARTED AND THEN WE ARE IN THE PROCESS OF ADOPTING HIM. SO NEXT WEEK WE WILL BE ADOPTING HIM SO WE'RE REALLY EXCITED FOR THAT. HE'S BEEN A JOY AND A BLESSING AND KEEPS US BUSY. >> CONGRATULATIONS, HEATHER. WHATEVER WE DO WE'LL TRY TO MAKE SURE THAT YOU CAN GO ABOUT YOUR LIFE AS MUCH AS YOU CAN BUT WE'LL BE ON YOUR SIDE AIMING TO HELP WITH WHATEVER WE CAN TO KEEP THINGS UNDER CONTROL AND I WONDER IF THERE IS TIME NOW FOR SOME QUESTIONS IN THE AUDIENCE? >> YES, LET'S SEE. HEATHER, LISTEN, THANK YOU FIRST OF ALL, ENORMOUSLY FOR TAKING THE TIME AND PARTICULARLY WHEN YOU HAVE AN INFANT YOU HAVE TO TAKE CARE OF. BUT ARE THERE OTHER PEOPLE IN YOUR FAMILY WHO HAVE DISEASES LIKE THIS? >> SO MY DAD -- WE WOULD HAVE FOUND OUT SIX MONTHS BEFORE HE PASSED AWAY THAT HE AS WELL HAD NEUROFIBROMATOSIS. WHEN I FIRST WOULD HAVE BEEN DIAGNOSED MY PARENTS WOULD HAVE HAD SOME AMOUNT OF TESTING OR LOOKED INTO SOME EXTENT IF EITHER HAD IT AND AT THAT TIME THEY WERE TOLD THEY WERE BOTH FINE. SO I HAVE AN OLDER SISTER WHO DOESN'T HAVE NEUROFIBROMATOSIS AND THEN IT WOULD BE ME AND MY NEXT BROTHER DOESN'T HAVE IT EITHER BUT MY YOUNGER BROTHER NEUROFIBROMATOSIS AND HE HAS PASSED AWAY TOO. WHETHER IT WAS UNCLEAR HIS MALIGNANCY WAS RELATED TO THE NEUROFIBROMA OR RELATED TO SOMETHING DIFFERENT, EVERYTHING WENT VERY QUICKLY WITH MY BROTHER AND HIS SICKNESS AND PASSING. SO BOTH FAMILY MEMBERS THAT HAD NEUROFIBROMATOSIS HAVE PASSED AWAY. MY DAD'S WASN'T RELATED AND MY BROTHER'S MAY OR MAY NOT HAVE BEEN. >> ONE OF OUR ATTENDEES WAS CURIOUS WHETHER YOUR DISEASE HAS BEEN ASSOCIATED WITH PAIN AND IF SO IS PAIN MANAGEMENT BEEN EFFECTIVE FOR YOU? >> SO TYPICALLY FOR ME THE ONLY TIME I'VE HAD AT LEAST ANY CONSISTENT PAIN HAS BEEN WITH THE MALIGNANCIES. AND THE THIRD ONE THEY REMOVED I WOULDN'T SAY I'VE HAD A GREAT DEAL OF PAIN WITH THAT ONE. NOT ANYTHING CONSISTENT SO WITH THE MALIGNANCIES I'VE HAD PAIN BUT OTHER THAN THAT I HAVEN'T. >> AND THERE'S ANOTHER QUESTION IN WHICH -- HOW DID IT HAPPEN THAT THE DIAGNOSIS -- WHEN WAS IT MADE AND WAS IT A PEDIATRICIAN WHO MADE THE DIAGNOSIS WERE YOU CHASING AROUND TRYING TO FIGURE IT OUT AND HOW DID IT UNFOLD? >> THE DIAGNOSIS WAS MADE AT 9 MONTHS OLD AND MY MOM STARTED TO NOTICING DIFFERENT CHANGES ON MY SKIN AND HAD TAKEN ME TO THE DOCTORATE THAT POINT AND FROM THERE WE WERE SENT TO A SPECIALIST AT A LOCAL CHILDREN'S HOSPITAL. >> I DON'T SEE ANY MORE QUESTIONS SO THANK YOU VERY MUCH FOR TAKING THE TIME TO DO THIS AND WE WISH YOU AND YOUR FAMILY THE VERY BEST. WE'RE GLAD YOU'RE IN SUCH GOOD HANDS. >> THANK YOU. >> THANK YOU, HEATHER. THANKS A LOT. I'LL SHARE MY SCREEN AGAIN. AND LET ME KNOW IF YOU SEE THE SLIDES OKAY, I HOPE. SO FROM HERE I'LL MOVE ON TO TALK A LITTLE BIT ABOUT HEATHER AND NOW A 35-YEAR-OLD. AS HEATHER MENTIONED THIS IS INTERESTING, HER DAD HAD NF 1 BUT NOT DIAGNOSED UNTIL LATER. WE HAVE SEEN THIS BEFORE BECAUSE MANIFESTATIONS CAN BE FAIRLY SUBTLE AND WHEN YOU LOOK AT HEATHER YOU WOULDN'T NECESSARILY THINK AT ALL HEATHER HAS NEUROFIBROMATOSIS TYPE-1 WITH HER SITTING THERE BUT HER FATHER HAT ULCERATIVE COLITIS AND SO DOES HEATHER WHICH IS AN INTRIGUING FINDING AND HER BROTHER DEVELOPED AN AGGRESSIVE MALIGNANCY THAT WAS A RARE SARCOMA TYPE OF TUMOR WE COULD NOT CHARACTERIZE VERY CLEARLY. HEATHER WAS DIAGNOSED BECAUSE OF THE SKIN FINDINGS AND SOMETHING FOR PEDIATRICIANS TO LOOK OUT FOR AND HAD HER FIRST LOW-GRADE MALIGNANCY IN 2001. SHE HAD A COLECTOMY AND IF PATIENTS HAVE NEW PAIN, PAIN THAT WAKES THEM UP AT NIGHT, PAIN THAT IS SEVERE, WE ARE ARE ALWAYS CONCERNED IT MAY BE A MALIGNANT TUMOR THOUGH OTHER TYPES OF TUMORS CAN CAUSE PAIN. AND THEN HEATHER CAME TO THE NIH TO ENROLL IN OUR NF 1 NATURAL HISTORY STUDY AND UNDERWENT RECESSIONS THREE TIMES OF DIFFERENT TYPES OF TUMORS WE WERE CONCERNED ABOUT. KNOWLEDGE OF THE TUMORS WERE CANCER TUMORS BUT VERY RECENTLY AS HEATHER MENTIONED JUST A FEW WEEKS AGO THERE WAS A LESION WE FOUND THAT WAS CONCERNING AND FOUND TO BE AN MPNST. >> CAN YOU SWITCH TO PRESENTATION MODE? WE CAN SEE YOUR ADDITIONAL SLIDES. >> OKAY, OF COURSE. IS THIS BETTER? DOES THIS WORK? >> ONE SECOND. CAN YOU SELECT IT AGAIN, PLEASE? >> I SWAPPED THE SCREEN. CAN YOU SEE THE SLIDES OKAY NOW OR IS THIS BETTER? WE'RE SEEING MULTIPLE SLIDES. PLEASE STOP SHARING AND COME BACK. >> OKAY. IS THIS BETTER? SELECT THE PRESENTATION MODE AGAIN. IS THIS BETTER? SORRY ABOUT THAT. I'M SHOWING YOU HERE A PET SCAN WHICH IS A NUCLEAR MEDICINE TEST WHERE LABELLED SUGAR IS INJECTED INTO THE VEIN AND THEY GO ANYWHERE IN THE BODY WHERE NUTRITION IS NEEDED THAT INCLUDES INFECTIONS, FOR EXAMPLE, OR TUMORS AND HIGHLIGHTING HERE IN RED ARROW AN AREA THAT IS DARK WHICH MEANS THE SUGAR OR DYE IS ACCUMULATING IN THE PELVIC AREA. THIS IS THE TORSO AND RIGHT LEG AND LEFT LEG. THEN YOU SEE ON THE SCREEN THE PELVIS AND YOU SEE THE RIGHT LEG AND LEFT LEG. IN WHITE YOU SEE NEUROFIBROMAS IN HEATHER'S BODY AND A ROUND APPEARING TUMOR LESION THAT RESPONDS TO THE DARK AREA ON THE PET SCAN WHICH MEANS AN AREA OF CONCERN FOR US AND THIS WAS ACTUALLY HER FIRST MALIGNANT TUMOR AND DO YOU SEE MY ARROW OKAY? YOU SEE THE TUMOR ON THE AXIAL IMAGE. IN ADDITION YOU SEE OTHER AREAS ON THE PET SCAN CIRCLED IN BLACK, WHICH ARE AREAS OF INCREASE UPTAKE BUT NOT NEARLY AS MUCH AS WE SAW IN THE MALIGNANT PERIPHERAL TUMOR. HEATHER THEN JOINED US FOR THE NATURAL HISTORY STUDY. ON THE RIGHT YOU SEE HER AGE AND YOU SEE THE VOLUME OF EACH OF THE INDIVIDUAL TUMORS ON THE Y AXIS. ESSENTIALLY EVERY DARK SPOT IS AN MRI FROM THE NIH CLINICAL CENTER. YOU CAN SEE ON THE RIGHT MOST HER TUMORS GREW OVER TIME. THERE'S ONLY ONE IN LIGHT GREEN THAT ACTUALLY HAD SOME DECREASE IN VOLUME OVER TIME. ON THE PET SCAN ON THE LEFT YOU SEE A NUMBER OF AREAS OF INCREASED UPTAKE. THESE ARE THE LESIONS WE MONITOR FOR GROWTH, FOR PAIN AND FOR UPTAKE ON THE PET SCAN TO MAKE SURE THAT WE CAPTURE THEM BEFORE THEY BECOME MALIGNANT AND THEN IN THE MIDDLE YOU SEE AN MRI PICTURE WE CALL IT A CORONAL PLANE AND ARM, BODY AND LEGS AND THEN YOU SEE THE NODULE LESION THIS IS AGAIN ONE OF THE TUMORS THAT WE RESECTED AND WAS NOT MALIGNANT. HERE YOU SEE THE MOST RECENT EVOLVEMENT IN HEATHER WHERE ON THE LOWER PANEL YOU SEE IMAGING STUDIES FROM 2019 AND ON THE UPPER PANEL YOU SEE IMAGING STUDIES FROM 2022 AND THE LEFT PANEL YOU SEE WITH RED ARROW A SMALL LESION JUST IN THE AREA OF WHETHER THE CAPULA ON THE LEFT AND IN 2019 WHEN YOU GO TO THE UPPER PANEL IT'S CLEARLY INCREASED IN SIZE. AND IF YOU LOOK ON THE RIGHT PANEL AND THIS IS THE PET SCAN WHERE AGAIN IN 2019 YOU SEE A SMALLER LESION THAT'S BRIGHT. THIS HAS INCREASED QUITE A BIT ON THE MOST RECENT IMAGING STUDIES AND WHAT RAISED THE CONCERN FOR US THAT THIS MIGHT BE A MALIGNANT TUMOR AND WE PERFORM BIOPSIES AND IT WAS A PERIPHERAL TUMOR AND HEATHER WILL UNDER GO ADDITIONAL TREATMENT WITH IMAGING AND LIKELY RADIATION TREATMENT. THIS IS WHAT WE WANT TO PREVENT FROM HAPPENING AND I'LL TALK ABOUT THIS MORE DURING THE TALK. ONE THING THAT BROUGHT ME IN TALKING ABOUT THE TREATMENTS WE'RE DEVELOPING INTO THE PERIOD AS A PEDIATRIC ONCOLOGIST WAS THE FACT THE RAS PATHWAY IS ACTIVATED IN NF 1 AND PHARMACEUTICAL COMPANIES HAVE BEEN DEVELOPING DRUGS TO BLOCK THIS ACTIVATION FOR CANCERS PREDOMINANTLY FOR MANY YEARS. WHEN I STARTED IN THE FIELD AND WE KNOW THAT THROUGH THE MUTATION OF THE NF IS GENE WE HAVE SURVIVAL SIGNALS YOU COULD TARGET, I THOUGHT, EASILY, WITH MEDICAL INTERVENTIONS SUCH AS WITH TRANSFERASE INHIBITORS OR BY SIGNALLING DOWN STREAM OF RAS YOU SEE ON THE LEFT SIDE. BUT DISAPPOINTINGLY NONE OF THIS REALLY WORKED UNTIL WE IDENTIFIED THE MEK INHIBITERS AND THE KINASE PATHWAY WERE THE FIRST TO SHOW ACTIVITY IN THESE TUMORS AND I TALK ABOUT THIS IN THE FOLLOWING. THIS HOLDS TRUE FOR THE BENIGN HISTOLOGICALLY BENIGN PLEXIFORM FIB FIB FIB FIBROHISTOMA AND YOU CAN SEE THE PHOTOGRAPHS IN THE BOTTOM AND RIGHT AND YOU SEE THEY'RE NOT BENIGN TUMORS. AND OUR GOAL SEE IF WE COULD UNDERSTAND THE GROWTH OF THE TUMORS AND DEVELOP EFFECTIVE TREATMENT AND WHAT WE DO IN CANCER CLINICAL TRIALS WE DO ONE DIMENSIONAL MEASUREMENTS MEANING THE LONGEST DIAMETER OR THE LONGEST PERPENDICULAR DIAMETERS AND WE SEE PROGRESSION OR SHRINKAGE QUICKLY BUT FOR NF 1 TUMORS THE PLEXI FORM FIBROMAS THAT NEEDED A METHOD AND WE HAVE THIS HERE IN THE ORBITAL TUMOR AND YOU SEE THE AXIAL PLANE HOW THIS PUTS A NICE ORDER AROUND EACH SLICE AND THIS ALLOWS US TO MEASURE THE TUMORS AND IDENTIFY SHRINKAGE OR GROWTH MORE QUICKLY. SO WE USED THE METHOD IN TWO WAYS. ONE IS IN THE NATURAL HISTORY STUDY AND TWO IS IN CLINICAL TRIALS AN THIS WORK WAS DONE IN WHICH YOU CAN SEE ON THE PANEL ON THE RIGHT IS THE AGE AT THE INITIAL MRI ON OUR NATURAL HISTORY STUDY AND EVERY DOT IS A PATIENT AND ON THE Y AXIS YOU SEE THE PERCENT GROWTH OR SHRINKAGE OF THE TUMOR PER YEAR TO SEE THE YOUNGEST PATIENTS HAD THE MOST RAPIDLY GROWING TUMORS WHEREAS LITTLE GROWTH IN OLDER PATIENTS. THAT WAS AN IMPORTANT OBSERVATION FOR US AND WHY WE TARGETED WITH OUR TREATMENT TRIALS YOUNG PATIENTS WHO WE HOPE TO GET THE MOST BENEFIT FROM THIS. IN ADDITION, DR. GROSS DOCUMENTS AT A YOUNG AGE WHEN THE PATIENTS CAME FROM THE FIRST TIME TO THE NIH TUMORS WOULD ALREADY HAVE CAUSED MORBIDITY SUCH AS VISION LOSS, PAIN, DISFIGUREMENT AND RARELY REVERSAL. THIS IS THE FIRST BIG CLINICAL TRIAL I CONDUCTED AND THIS WAS A DOUBLE-BLINDED PLACEBO-CONTROLLED WITH KIDS WITH GROWING NEUROFIBROMATOSIS WITH A FLIP OF A COIN DECIDED IF THEY GOT SELUMETINIB OR A PLACEBO. WE DIDN'T KNOW WHAT THE KIDS WERE RECEIVING. THE KIDS DIDN'T KNOW AND THE PARENTS DIDN'T KNOW WHAT THEY WERE RECEIVING. WE WOULD FOLLOW THE PATIENTS WITH THE MRI UNTIL THE TUMOR WAS SHOWN TO BE GROWING AND CHANGED THEIR RECEIVING STATUS AND THIS DID NOT RESULT IN THE DESIRED GROWING OF THE GROWTH. WE HAVE A SURVIVAL PERCENTAGE AND IDEALLY WE'D LIKE TO SEE 100% SURVIVAL AND YOU CAN SEE MOST THE PATIENTS DEVELOPED TUMOR GROWTH AND THERE WAS REALLY NO DIFFERENCE BETWEEN PLACEBO AND THIS PHARMACEUTICAL AND WE CONDUCTED CLINICAL TRIALS WITH THE GOAL IMPROVE ON THIS AND YOU SEE THE CURVE FOR THE OTHER CLINICAL TRIAL AND THE BEST DRUG WAS AN IMMUNE MODULATORY AGENT WHERE WE INCREASED THE TIME TO PROGRESS OF 29 MONTHS COMPARED TO THE PLACEBO. HOWEVER WE HAD TUMOR SHRINKAGE IN ONLY FEW PATIENTS AND WHEN YOU HAVE A CHRONIC CONDITION LIKE NF 1 IT WASN'T ENCOURAGING AND I WASN'T READY TO GIVE UP BUT IT WAS SOBERING WE HAD PATIENTS THAT HAD GONE ON CLINICAL TRIALS NOT SEEING CLEAR TUMOR SHRINKAGE BUT PROGRESSION OF THE TUMOR AS WE SEE IN THE 3 AND 4-YEAR-OLD. NOT ONLY MORE VISIBLE DIG FIGURATIVE BUT THE BOY UNDERWENT ADDITIONAL SURGERIES AND PAIN MEDICATIONS AND DEVELOPED BOWEL INCONTINENCE SO WE FELT WE NEEDED TO MAKE PROGRESS FOR THE PATIENTS. THEN WE CONDUCTED A CLINICAL TRIAL WITH A MEK INHIBITOR BLOCKING THE MEK KINASE. THIS TRIAL SHOWED SUBSTANTIAL PROMISE IN THAT EVERY PATIENT HAD AT LEAST SOME TUMOR SHRINKAGE AND THE TUMOR VOLUME SHOWN IN EVERYTHING NEGATIVE MEANING THE BLACK BAR HAS A DOWNWARD TREND MEANS TUMOR SHRINKAGE. WE HAD NEVER SEEN THIS BEFORE AND WE ALSO SAW SOME CLINIC IMPROVEMENT WITH IMPROVEMENT IN DISFIGUREMENT WE TALKED BIG THE FDA BECAUSE WE'RE EXCITED ABOUT THE FINDING AND ASK IF THEY WOULD GIVE YOU WILLS WHAT THEY CALL BREAKTHROUGH THERAPY DESIGNATION BUT THEY SAID YOU'RE SHRINKING THE TUMORS BUT YOU NEED TO SHOW US PATIENTS HAVE TRUE CLINICAL BENEFIT FROM THIS. YOU NEED TO GO BACK TO THE DRAWING BOARD AND SO WE DESIGNED A LARGER STUDY FOR PATIENTS WHO HAD SOME SYMPTOMS WHEN THEY ENROLLED ON THIS STUDY. WE USED THE TUMOR MEASUREMENTS AS THE PRIMARY END POINT. YOU CAN SEE OB THIS WATER FALL PLOT WHEN YOU LOOK AT ZERO ALMOST ALL THE BARS WENT DOWN AND THE RID DOTTED LINE SHOWS THROUGH THE NUMBER OF PATIENTS WHO HAD MORE THAN 20% TUMOR SHRINKAGE BY VOLUME. WE WERE ABLE TO SHOW WITH METICULOUS DOCUMENTATION WE SAW SIGNIFICANT DISFIGUREMENT TO CYCLE 37 THERE'S CONTINUOUS IMPROVEMENT AND WE LOOKED AT PATIENT-REPORTED AND PARENT-REPORTED OUTCOMES THEY SELF-REPORTED AND THERE WAS AN OVERALL IMPROVEMENT IN MORBIDITIES RELATED TO THEIR PLEXIFORM NEUROFIBROMA AND THEN LOOKED AT PATIENT-REPORTED OUTCOME MEASURES OF PAIN INTENSITY. THIS WAS WORK DONE BY DR. WALTERS AND DR. MARTIN WHO SHOWED THAT COMPARING BASELINE TO PREPSY CYCLE THERE WAS A REDUCTION CLINICALLY MEANINGFUL AND IN TUMOR INTENSITY AND IN INTERFERENCE. THESE FINDINGS WERE VERY IMPORTANT FOR THE SUBSEQUENT FDA APPROVAL BECAUSE THEY WERE ABLE TO DOCUMENT NOT ONLY THE TUMOR SHRANK BUT IT WAS CLINICALLY MEANINGFUL. I WANT TO SHOW ONE MORE EXAMPLE OF AN 8-YEAR-OLD GIRL WITH A TUMOR THAT OBSTRUCT THE AIRWAY AND HAD A TRACHEOSTOMY TO HELP HER BREATHE. YOU SEE AN MRI AND THE BLUE ARROWS POINT TO THE AIRWAY WHILE THE TUMOR ONLY SHRANK BY 25% OR SO THE AIRWAY DID OPEN UP, THE PATIENT COULD BE DECANNULATED AND CONTINUES ON TREATMENT TO DATE WITHOUT THE NEED FOR AN ARTIFICIAL HELP. THAT WAS A MAJOR ADVANCEMENT FOR THE SPECIFIC PATIENT. I WANT TO DRIVE ONE OTHER POINT HERE. THIS IS ONE OF THE BOYS, WYATT, STARTING AT 5 YEARS OLD AND HIS TUMOR GREW RELENTLESS. WE THEN STARTED THE MEK INHIBITOR AND HAD TUMOR SHRINKAGE AND HAD TO STOP TEMPORARILY BECAUSE OF THE LEFT VENTRICULAR CARDIAC FUNCTION THIS IS OBVIOUSLY IMPORTANT. WE STOPPED THE TREATMENT THE TUMOR STARTED AND STARTED AT A REDUCED DOSE AND THEY CONTINUE ON TREATMENT TO DATE BUT IT SHOWS IT'S NOT A CURE IT HAPPENS AND PATIENTS NEED TO BE ON IT LIKE ON BLOOD PRESSURE MEDICINE TO MAKE SURE WE HAVE A CONTINUOUS POSITIVE EFFECT. FOR THE MOST PART IT'S WELL TOLERATED AND THE MOST FREQUENT ARE NAUSEA AND VOMITING AND SOMETHING WHICH IS AN INFLAMMATION AROUND THE NAIL BED WHICH CAN LOOK QUITE AGGRESSIVE AS YOU CAN SEE BUT WE DEVELOPED GOOD TREATMENT APPROACHES. SO MOST PATIENTS CAN THIS SHOWS CHILDREN TREATED ON THE TRIAL AND MOST PATIENTS HAD A VOLUME REDUCTION AND THEN YOU SEE AN AGE-MATCHED CONTROL COMPARISON FOR PATIENTS ON THE NATURAL HISTORY STUDY WHO DID NOT RECEIVE THE MEC INHIBITOR AND HAD GROWTH IN TUMORS AND I'M COMING BACK TO THE KAPLAN MEIER CURVE AND KIDS ON THE NATURAL HISTORY STUDY HAD PROGRESSIVE TUMORS WITH A MEDIAN REGRESSION-FREE SURVIVAL OF 1.3 YEARS COMPARED TO KIDS WHO RECEIVE SELUMETINIB WHERE 84% WERE PROGRESSION FREE IN YEARS. THIS IS IMPORTANT TOWARDS THE NAD APREEFL -- AND HERE YOU SEE IT COMPARED TO OTHER CLINICAL TRIALS. ALL THIS DATA WAS SUBMITTED TO THE FDA AND DR. AREA ASKED THE NF 1 GENE WAS DISCOVERED BY DR. COLLINS AND DR. RAY WHITE. IT TOOK 30 YEARS TO FOR APPROVAL FOR KIDS WITH SYMPTOMATIC AND PLEXIFORM NEUROFIBROMAS. BASED ON THE TRIAL THERE'S APPROVAL IN MORE THAN 13 COUNTRIES AND MORE COMING. THIS MARATHON HAS PAID OFF BUT I THINK THERE'S MORE TO DO. THERE'S A TRIAL BROSE WILL BE LEADING LOOKING AT NOT ONLY CAN WE REDUCE MORBIDITY AND TREATMENTS TUMORS BUT PREVENT THEM FROM BECOMING SYSTEMATIC AND YOU CAN SEE OVER TIME THIS LITTLE GIRL DEVELOPED A DISFIGURING FACIAL TUMOR AND WHAT DR. BROSE WANTS DO IS START THE INHIBITOR IN THE CHILD WHEN IT'S AN ASYMPTOMATIC PLEXIFORM NEUROFIBROMA AND WANT TO SHOW WE CAN PREVENT THESE FROM HAPPENING. A TRIAL IS AMBITIOUS AND WE LOOK AT THE INCIDENTS AND USE WHOLE BODY MRI. IN THE SECOND PART WE'LL HAVE A RANDOMIZED COMPARISON OF ASYMPTOMATIC TUMORS TREAT AND OBSERVED AND IN THE THIRD PART THEY'LL LOOK AT THE DIFFERENT SCHEDULE LOOKING AT A DIFFERENT SCHEDULE AND LOWER DOSE TO SEE IF WE CAN SUSTAIN THE BENEFIT. I'LL KNOW TALK IN LESS DURATION BECAUSE WE HAVE LESS DATA ABOUT THE MALIGNANT TUMORS THAT DEVELOP IN UP TO 16% OF PEOPLE WITH NF 1 AND OUR EFFORTS TO PREVENT THE DEVELOPMENT OF MPNST BY FOCUSSING ON THE ATYPICAL NEUROFIBROMAS. THE TUMORS ARE AGGRESSIVE SUBTISSUE SARCOMAS. AND COMPLETE SURGICAL RESECTION WITH NEGATIVE MARGINS MEANING THERE'S NO TUMOR CELL LEFT IS REQUIRED. IN PATIENTS WHERE THIS CANNOT BE ACHURD WE HAVE DONE A NUMBER OF CLINICAL TRIALS AND MOST ARE PHASE 2 TRIALS AND WANTED TO KNOW IF WE REDUCED TUMORS OR SLOWED PROGRESSION. UNFORTUNATELY WE'VE NOT BEEN SUCCESSFUL. THE TILES WERE FEASIBLE BUT WE HAVE NOT SEEN MAJOR SHRINKAGE OR DELAYING IN THE TIME TO PROGRESSION. WITH THAT IN MIND WE FOCUSSED AT LOOKING AT PRE MALIGNANT TUMORS USING WHOLE BODY MRI. ON THE LEFT YOU SEE THE CRONAL MRI AND LARGE TUMOR WITH A PRE MALIGNANT LESION. ON THE RIGHT YOU SEE ANOTHER MRI WHERE I HOPE YOU CAN DETECT THE NODULES AND THOSE WE BELIEVE ARE PRE MALIGNANT. WE IDENTIFIED IN PATIENTS WITHIN PLEXIFORM NEUROFIBROMAZ AN AS THE ARROWS INDICATE MANY LESIONS APPEAR AS DISTINCT NODULES. THEY'RE BRIGHT IN COMPARE TO NO SIGNAL IN PLEXIFORM PLEXIFORM AND DEVELOP LATER IN LIFE NOT IN YOUNG PATIENTS. YOU CAN SEE THIS NICELY IN THE UPPER PANEL WHERE YOU SEE A 90 YEARS WITH A PLEXIFORM FIBROMA OF THE NECK. WHEN SHE'S 15 AND LOOK AT THE RED ARROW, THERE'S A DISTINCT NODULE NOT THERE AT 9 YEARS OF AGE AND GREW RAPIDLY. WHEN IT WAS IN THE PROCESS OF TRANSFORMING TO BECOME MALIGNANT. YOU SEE AND THE LOWER PANEL COMPARED TO PLEXIFORM NEUROFIBROMAS THEY DON'T SLOW DOWN AND IN PATIENT THE GROWTH RATE IS IN DEPENDENT OF AGE. AND CERTAIN PATHOLOGIC FEATURES ARE CALLED NEUROPLASMS OF POTENTIAL AND MANY HAVE A CHANGE DR. SHERN WILL TALK ABOUT MOMENTARILY CALLED CDK AND OUR FOCUS IS ON SURGICAL RESECTION OF THE TUMORS PRIOR TO BECOMING MALIGNANT. THERE WAS AN UPPER ARM NEUROFIBROMA AND VOLUMETRIC ANALYSIS SHOWED IT WAS GROWING SLOWLY OVER TIME WITH THE HYPOTHESIS IT WAS A PRECURSOR LESION FOR MPNST. WE COULD NOT PREDICT BUT IT DID TRANSFORM AND YOU CAN SEE IN THE RED LINE IT GREW MORE QUICKLY ALL OF A SUDDEN AND WE'RE STRUGGLING THE RIGHT TIME TO INTERVENE AND HOW CAN WE PREDICT MALIGNANT TRANSFORMATION. WE'RE WORKING ON A NEW STUDY FOCUSSING ON CHARACTERIZING THE MALIGNANT INTERVENTION INCLUDING SURGICAL RESECTION WITH OUR NEUROSURGEON AND THE STUDY IS IN DEVELOPMENT AND HOPEFULLY MAKE PROGRESS. I'M PLEASED DR. SHERN WILL TALK ABOUT THE AMAZING WORK HIS TEAM IS DOING TO UNDERSTAND THE BIOLOGY AND HOPEFULLY MAKE MORE STRIDES IN THE PREVENTION OF MPNST. I'LL STOP SHARING TO HE CAN TAKE OVER. >> THANK YOU, DR. WIDEMANN OR SETTING ME UP TO TELL THE CROWD ABOUT WHAT WE'RE WORK IN THE LABORATORY TO FOLLOW-UP ON SOME OF THESE STUDIES THAT HAVE BEEN SO SUCCESSFUL IN THE CLINICAL. I'M A CLINICIAN SCIENTIST AND WORK IN THE PEDIATRIC ONCOLOGY BRANCH AT THE NCI. I SPENT A LOT OF TIME SEQUENCING TUMORS AND LOOKING FOR THE CHANGES IN TUMORS OVER TIME AND WHEN I STARTED MY LAB I WAS STRUCK BY THIS DISEASE BECAUSE I THINK IT'S A TREMENDOUS TEACHER OF TWO POINTS. THEY'RE RELATED BUT I THINK THEY'RE IMPORTANT AND HOW WE STUDY PATIENTS AND HOW THEY EVOLVE OVER TIME. FIRST IS THERE'S A GENETIC TUMOR PROGRESSION. DR. WIDEMANN LAID OUT THE CLINICAL PROGRESSION. IT HAS TO BE ENCODED IN THE CANCER CELLS THAT ALLOW IT TO PROGRESS OVER TIME. THE SECOND POINT IS THESE ARE MASSIVE TUMORS. THESE BENIGN PLEXIFORM FIBROMAS ARE MASSIVE IN SOME PATIENTS AND YOU CAN IMAGINE THERE'S A LARGE DEGREE OF TUMOR CELLULAR GENEITY AND THERE'S A DIVERSITY OF CANCER AND IMMUNE AND STROMAL CELLS THAT MAKE UP THE TUMOR MICROENVIRONMENT. THIS IS CRITICAL GOING FORWARD AND I'M A CANCER GENETICISTS. THIS IS AN ELEGANT DEMONSTRATION OF HOW TUMORS EVOLVE OVER TIME. THEY HAVE A GERM LINE MUTATION. THEY'RE SET UP LIKE THIS WITH RAS PATHWAY ACTIVATION YOU'VE HEARD THESE WERE FIRST DESCRIBED IN 1990 AND FRANCIS COLLINS WAS ONE THEIR INVESTIGATORS INITIALLY INVOLVED IN THE DISCOVERY OF THESE GENES. THE PLEXIFORM NEUROFIBROMAS TOOK MORE TIME BEFORE WE SAW IT WAS A UNIQUE LOSS OF THE ALLELE THAT CAUSED THE SPECIFIC CHANGE IN THE PATIENTS. AND WITH WE HAD AN EXPLOSION OF INFORMATION AND SEEING TP53 MUTATIONS AN ALTERATIONS IN TWO GENES EED AND SUS 12 INVOLVED IN THE POLY COMER COMPLEXES AND EPIGENETIC COMPLEXES IN THE CELLS AND IT CAN BE QUITE GENETICALLY DIFFERENT THAN THE PLEXIFORM ALTERATIONS AND WE THINK THERE'S AN INTERMEDIATE COUPLE STEPS AND WHAT'S BEEN DISCOVERED IS THE LOSS OF THE TUMOR SUPPRESSER CDKN2A AND USUALLY IT'S ONE ALLELE BUT SOMETIMES TWO. UNDERSTANDING THE GENETIC PROGRESSION PRESENTS MULTIPLE OPPORTUNITIES FOR US IN THE LABORATORY THE FIRST IS YOU CAN START TO BUILD POWERFUL MOUSE MODELS. THE NF 1 MOUSE CAN COPY THIS AND THEY'VE KNOCKED IT OUT AT MULTIPLE TIME POINTS IN DIFFERENT CELLS ACROSS THE MOUSE. DO THEY MATCH WHAT WE SEE IN THE PATIENTS? YOU CAN SEE THERE'S MULTIPLE NF 1 MOUSE MODELS. SOME MAKE PLEXIFORM AND SOME MAKE IT IN CERTAIN PARTS OF THE BODY AND SOME MAKE OTHER TUMOR TYPES. IT'S BEEN A POWERFUL TOOL AND A KEY FINDING IS TO GET THE PLEXIFORM FIBROMAS TO GROW YOU HAVE TO KNOCK THEM OUT AT A SPECIFIC TIME WINDOW. YOU HAVE TO HAVE THE SECOND ALLELE LOST IN THE EMBRYONIC STATE. IT'S A TIMING EFFECT AND PROBABLY HAPPENS PRETTY EARLY IN THE PATIENTS. THIS IS A MODEL USED DEVELOPED BY NANCY RATNER'S GROUP SHE HAD A DEVELOPMENTALLY RESTRICTED GENE DRIVING AND LINKED TO THE LOSS OF NF 1 SO OWN THE SCHWANN CELLS STARTED TO DEVELOP TUMORS AND THEY'RE SIMILAR TO THE HUMAN TUMORS. YOU CAN SEE WHAT THE WILD TYPE SPINAL CORD AND PERATIVAAL -- PERIPHERAL NERVES LOOK LIKE AND YOU SEE THESE BIG BENIGN TUMORS AND SOME HAVE HYPERPIGMENTATION SIMILAR TO THE HUMAN CONDITION. WE DISCOVERED MEK INHIBITORS IMPORTANT AND IF YOU HAVE A MOUSE MODEL YOU CAN RUN THE EXPERIMENTS IN THE MOUSE AND TAKE THEM TO THE CLINICAL TRIAL. YOU CAN SEE IT'S TREATED AND YOU CAN TREAT WITH DIFFERENT DOSES OF THE DRUG. THIS IS A MEK INHIBITOR CALLED PD AND YOU SEE THE PLEXIFORMS CONTINUE TO GROW IN THE MOUSE AND IF YOU HAVE MORE DOSES OF THE MEK INHIBITOR YOU HAVE A SHRINKAGE OF THE TUMORS. THIS IS POWERFUL. NOW YOU CAN IMAGINE ALL THE FAILED CLINICAL TRIALS WHAT IF YOU HAD THE RIGHT MODEL YOU CAN TEST THEM IN THE LABORATORY BEFORE GIVING THEM TO PATIENTS? AND THE TUMOR SUPPRESSER LOSS COMES AFTER THE NF 1 LOSS AND YOU CAN MAKE A MOUSE THAT MODELS THAT. IN THE RIGHT PANEL WE'RE SHOWING SHOWING A MOUSE MODEL AT THE INDIANA UNIVERSITY AND WE'RE MIRRORING SIMILARLY BY KNOWING THE GENETIC HITS IN THE HUMAN ALOUZ US -- ALLOWS US TO BUILD MOUSE MODELS AND IS A POWERFUL TOOL BUT ONLY COME ONLINE RECENTLY. THE PROGRESS MADE IN THE EARLY PLEXIFORM TRIALS WE CAN MAKE ATYPICAL NEUROFIBROMAS. ON THE FAR END OF THE SPECTRUM IS THE BAD MALIGNANT PLAYERS. USING A MOUSE MODEL WITH LOSS OF NF 1 AND TP53 ANOTHER TUMOR SUPPRESSER WE SEE AND YOU CAN TEST DIFFERENT DRUGS OR COMBINATIONS IN THE MODEL THAT MATCHES THE HUMAN CONDITION. THERE'S A MEK INHIBITER AND WHEN YOU COMBINE THOSE THINGS YOU GET SOME SYNERGY. IF YOU USE THE MEK INHIBITOR IN THE MPNST IT DOESN'T REALLY RESPOND AT ALL AND WE SEE THAT IN THE PATIENTS. INTERESTING CORRELATION BETWEEN THE CLINIC AND LABORATORY. IS A CLINICAL TRIAL AND WE WERE A PARTICIPATING SITE AND WERE RECENTLY PUSH THIS THROUGH TO PATIENTS FOLLOWING THE MODEL. AND WE ALWAYS HAVE OUR EYE ON THE NEXT THING AND WHAT IS LIKELY TO WORK AND IT'S USED TO SHOW THIS, THERE'S A COMBINATION OF TWO INHIBITERS A MEK AND BROMO DOMAIN INHIBITOR. IT'S INTERESTING IS THIS UNLEASHED AN IMMUNE RESPONSE WHEN YOU ADDED THIS TO A PD CHECKPOINT INHIBITOR. THIS REALLY WHEN YOU UNLEASH THIS YOU GET THE INHIBITOR AND LET'S TAKE THIS IN THE CLINICAL TRIAL. WHAT THE MOUSE WAS TEACHING US WE CAN TAKE THAT BACK TO THE HUMAN. THAT'S OUR MODEL FOR HOW IT WILL WORK. OUR PATIENT MADE THE POINT, I DON'T WANT TO GET MPNSTAL ALL. IF I CAN GET ONE THING MAYBE IT'S TO STOP THE PROGRESSION. YOU HEARD SOME OF DR. WIDEMANN'S STRATEGIES, LET'S DO SURGERY WHEN WE SEE THEM AND MEDICAL THERAPIES TO TREAT THESE NEUROFIBROMAS BEFORE THEY MAKE THE JUMP. ONE THING WE'VE HAD SUCCESS OVER IN RECENT TIMES AND PREDICT WHEN THE MALIGNANT TRANSFORMATIONS ARE HAPPENING, WOULDN'T THAT BE A USEFUL TOOL? IN SOME WAYS THE TECHNOLOGY HAS ADVANCED TO THE POINT WHERE WE CAN START TO DO THIS. DR. WIDEMANN SHOWED RIGHT NOW WE DIAGNOSIS THESE CLINICALLY. THE PATIENT WILL SAY IT'S ACTUALLY MORE PAINFUL. LET'S TAKE A DEEPER LOOK AT THAT OR SCAN HEAD TO TOE WITH AN MRI EVERY YEAR. YOU CAN IMAGINE IT'S NOT PARTICULARLY SENSITIVE OR SPECIFIC BECAUSE WE THINK THEY'RE DEVELOPING WITHIN THE BIGGER PLEXIFORM FIBROMA AND WE CAN STICK A NEEDLE INTO EVERY AREA WE'RE CONCERNED AND LOOK AT THE TISSUE BUT IT HAS SIGNIFICANT MORBIDITY AS WELL. YOU DON'T WANT TO DO A LOT OF PROCEDURES IN THE LARGE BENIGN TUMORS ESPECIALLY FOR NO REASON. YOU CAN STICK THE NEEDLE TO THE RIGHT OR LEFT AND MISS A DIAGNOSIS. WHAT WE'VE DONE IS SAY WHAT IF WE LOOK AT PLASMA TO SEE EVIDENCE OF THE CHANGES. THIS HAS BEEN LED BY MY GROUP AND IT SEEMS LIKE ANUPLOITY AND IN TUMORS YOU GET GAINS AND LOSSES OF CHROMOSOMES. THE TUMOR CAN ADD DEF AND IF YOU LOOK AT THE MPNST THIS INCREASE EXPONENTIALLY. THEY'RE BECOMING MORE AND MORE A FEATURE OF THE MPNST. SO WE SAID OKAY WE NEED A BLOOD TEST TO DETECT THE ANEUPLOID EVENTS AND TOOK PATIENTS THAT HAD BENIGN AND MALIGNANT TUMORS. AND WE TAKE THE PLASMA AND SPIN IT DOWN AND DO WHOLE GENOME SEQUENCING. WE LOOK AT SHALLOW SEQUENCING ACROSS THE GENOME. IT ALLOWS TO PREDICT THE ANEUPLOIDY CHANGES AND CORRELATE THIS WITH THE FINDINGS AND ANOTHER KEY FEATURE IS THE CELL-FREE DNA FRAGMENT SELECTION I'LL TOUCH ON. THIS IS WHAT THIS LOOKS LIKE AND TO ME IS STRIKE. IF YOU SEQUENCE THE TUMOR DNA, NORMALLY THIS SHOULD BE RIGHT ALONG THE DIPLOID GENOME. HERE'S THE PATIENT'S GERM LINE DNA DOWN HERE. NICE AND FLAT. YOU SEE CHROMOSOME AND 2 AND IF YOU SEQUENCE THE DNA FROM THE PLASMA, SURE ENOUGH YOU CAN SEE THE TUMOR DNA SHED IN THE BLOODSTREAM AND YOU CAN SEE IT NICELY MIRRORS THE CHANGES IF YOU LOOK AT THE TUMOR. NOW WE HAVE A BIOMARKER AND IF YOU GIVE A PATIENT THERAPY AND START TO SHRINK THE TUMOR YOU START TO SEE IT GO AWAY. THAT'S A USEFUL TOOL CLINICALLY BECAUSE NOW YOU CAN FOLLOW THE PATIENT OR FOLLOW THE PATIENT IN THE BENIGN STATE AND LOOK FOR THESE CHANGES AND IF YOU SEE THESE CHANGES YOU MAY WANT TO BE WORRIED IT'S TRANSFORMED SOMEWHERE. A POWERFUL ADJUNCT WITH US THIS DISCOVERY THE SIZE OF THE GENOMIC FRAGMENTS WE WERE FINDING IF IT CAME FROM THE TUMOR, WERE A LITTLE BIT SHORTER. THIS WAS SEEN IN MULTIPLE TUMOR TYPES NOW WHERE THE ASSUMER SEEMS TO SHED SMALLER FRAGMENTS OF DNA AND NOBODY'S QUITE CLEAR WHERE IT HAPPENS BUT IS A RECURRENT FEATURE IN TUMOR TYPES AND WE CAN FILTER THIS AND MAKE IT A BETTER TEST BY JUST LOOKING AT AT AN AREA OF SEQUENCING READ SPECIFIC LENGTH ENRICHED FOR THE TUMOR AND IF YOU STARTED TO LOOK AT THIS COMPARED TO THINGS THAT WE NORMALLY DO IN THE CLINIC LINE ANATOMIC MRI WITH A SPECIFICITY OF 61% WE WERE JUST AS GOOD IF NOT A LITTLE BIT BETTER USING OUR CELL-FREE GENOME SEQUENCES. WE CONTINUE TO REFINE THIS BUT IT'S AN EXCITING WAY YOU CAN IMAGINE INCORPORATING THIS INTO YOUR CLINIC WHERE YOU HAVE MULTIPLE F1 PATIENTS. INSTEAD OF SCANNING THEM HEAD TO TOE YOU WOULD GET A BLOOD TEST AND LOOK FOR CHANGES. THE CELL-FREE DNA ASSAY WAS PICKING THIS UP BEFORE THE IMAGING AND YOU CAN ONLY DO IMAGING SO OFTEN BUT CAN DO A BROOD TEST AND THIS HAS HUGE POTENTIAL IN THE PATIENTS THAT HAVE A GERM LINE PREDISPOSITION WHERE YOU'RE LIKELY TO GET A TUMOR AT SOME POINT IN YOUR LIFE. THIS ASSAY MIRRORED THE TREATMENT COURSE FOR THE PATIENT. IF YOU GAVE A SUCCESSFUL TREATMENT, THE CELL-FREE DNA ASSAY WOULD COME UP AND IF YOU DON'T WAIT FOR THE PATIENT TO BLOW THROUGH WHATEVER THERAPY YOU'RE GIVING THEM YOU CAN FOL THEM AND SEE HOW THEY'RE DOING AND PROGRESSING AND WOULD ALLOW US TO MAYBE TRI TATE THE THERAPY AND THERE'S TUMOR CELLULAR GENEITY -- GEN AITY AND WE WOULD EXTRACT THINGS LIKE THE DNA AND RNA AND THAT WOULD BE AVERAGED OUT. AND THAT'S THE FRUIT SALAD APPROACH TO SEQUENCING AND WE'RE STARTING TO DO SINGLE CELL SEQUENCING AND YOU CAN TEASE OUT POPULATIONS AND STUDY THOSE IN DETAIL. THESE ARE MASSIVE TUMORS AND YOU SEE A PLEXIFORM NEUROFIBROMA BUT WAS COMPLAINING OF PAIN IN THE UPPER PART OF THE TUMOR. YOU CAN SEE THE DISTINCT NOJ -- NODULEAR AREA AND YOU CAN IMAGINE IF YOU DID BIOPSIES IN MULTIPLE PLACES YOU'D GET DIFFERENT ANSWERS. IT'S A BENEFIT OF WORKING AT THE NIH CLINICAL CENTER. WE CAN ENROLL THEM AND STUDY TUMORS IN DEPTH ACROSS THEM. AND WHAT YOU SEE AT EVERY STAGE OF THESE TUMORS THERE ARE DISTINCT POPULATIONS OF CELLS THERE'S IMMUNE CELLS AND TUMOR CELLS AND STROMAL CELLS MAKING THIS THICK PINK MATRIX IN THE SLIDES. THEORY IS EACH CELL POPULATION CONTRIBUTES TO THE TUMOR'S GROWTH. IT'S THE MICROENVIRONMENT THAT ALLOWS THE TUMOR TO AGAIN TO GROW AND YOU CAN IMAGINE EVERY ONE OF THOSE CELL POPULATIONS BECOMES A POTENTIAL THERAPY. AND IMMUNE THERAPY IS BECOMING MORE AND MORE SUCCESSFUL. IMAGINE CHARACTERIZING THE T CELLS WITHIN THE TUMORS BECOMES AN IMMEDIATE THERAPEUTIC POTENTIAL FOR THE MACROPHAGES PRESENT IN THE TUMORS. AND YOU HAVE TO UNDERSTAND THE COMPLEX ENVIRONMENT TO UNDERSTAND WHY YOUR TUMOR IS PROGRESSING. WHY HAS THE MEK INHIBITOR ONLY SHRUNK IT BY 20% AND THOSE ARE KEY QUESTIONS WE'RE STARTING TO ANSWER NOW. YOU CAN SEE IN THE TUMORS THE SMALL IMMUNE CELLS AND THE TUMOR CELLS ARE ELONGATED NUCLEI HERE. AND THE CURRENT BASIC UNDERSTANDING OF THIS IS THERE'S A NEOPLASTIC SCHWANN CELL AND THIS INTERN FEEDS BACK AND DELIVERS GROWTH FACTORS BACK TO THE NEOPLASTIC SCHWANN CELL AND THIS IS KEY FOR THE NEXT SET OF THERAPIES FOR THE PATIENTS AND WHAT WE'VE WORKED ON IN MY LABORATORY LED BY A TALENTED POST-DOC AND THE IDEA IS WE'LL CREATE A SINGLE CELL ATLAS OF ALL THE CELL TYPES WITHIN THE NF 1 NERVE TUMORS. HAVING THE NATURAL HISTORY AND CLINICAL STUDY WE'RE ABLE TO COLLECT PATIENTS SEQUENCE BY SINGLE CELL SEQUENCING AND EVERY DOT REPRESENTS THE GENE EXPRESSION PROFILE OF AN INDIVIDUAL CELL. THIS COMES FROM 56 UNIQUE TUMOR SAMPLES AND 49 INDIVIDUAL TUMORS AND 500,000 SINGLE CELLS. THE REWARDING THING OF THE EXPERIMENTS IS TO START TO DEFINE CELL POPULATIONS BASED ON THE GENE EXPRESSION PROFILING. YOU CAN SEE HERE'S THE MALIGNANT SCHWANN CELL. HERE'S ALL THE LYMPHOID CELLS BEEN THE BIG MAP AND THE FIBROBLAST. YOU CAN START TO SUB CLUSTER WITHIN INDIVIDUAL GROUPS. YOU CAN LOOK AT ALL THE CELLS FROM A PATIENT WITH A PLEXIFORM NEUROFIBROPLA OR MPNST AND SEE THE VERY DIFFERENT PROFILES AND IF YOU SUMMARIZE THIS THE OBVIOUS ONE IS THIS BIG PINK REGION GROUP THE TUMOR CELLS. NOT SURPRISE IING THERE'S TARGETS AND LOOK AT THE CLUSTER ON THE FIBROBLAST SPECIFIC TO THE MPNST. AGAIN THIS OPENS UP NEW IDEAS AND WAYS TO ENGINEER AND IT STRUCK ME HOW SIMILAR IT WAS. YOU GET THE PURPLE GROUP AND THAT'S THE TUMOR CELL POPULATION AND CONTRACTION OF THE MYELOID IMMUNE CELLS. THOSE TWO THE ATYPICAL AND AND I'M A CANCER CELL BIOLOGIST AND I'M INTERESTED IN THE MALIGNANT TRANSFORMATION OF THE CANCER CELLS AND YOU CAN FOLLOW THEM AND LOOK AT THE SINGLE-CELL RESOLUTION LEVEL AND LOOK AT THE GENE EXPRESSION PROFILE AND THOSE DROPPING OUT OF THE TYPICAL LESION AND AS IT BECOMES AN MPNST. ONE THING THAT STRUCK US OUT OF THE GATE IF YOU TOOK THE SCHWANN CELLS REPRESENTS THE GENE EXPRESSION PROFILE. WITH THE EXPERIMENT YOU CAN SEE THERE'S A PLEXIFORM SIDE OF THE SCHWANN AND CELL GROUP AND THAT CHANGE REPRESENTS A BASIC UNDERSTANDING AND THERE'S CDKNTA. THERE'S A FINDING THAT DIDN'T MAKE SENSE OUT OF THE GATE. IN THE PLEXIFORM AND IN THE ATYPICALS, IT'S REALLY HIGHLY EXPRESSED IN FACT'S A BIOMARKER OF THE CELLS. WE EXPECT IT TO BE GONE AND SURE ENOUGH IF YOU LOOK AT THE ATYPICAL ATYPICALS YOU HAVE A LARGE NUMBER OF CELLS AND WHAT'S THE POPULATION? IT COMES DOWN TO THIS EXPERIMENT. THIS IS ANOTHER UNIQUE POINT WHERE THIS RESOLUTION CAN GIVE YOU A TARGET. THIS IS AGAIN WORK DONE IN INDIANA IF YOU TAKE THE SCHWANN CELLS AND CULTURE THEM, WHAT YOU SEE IS NOT SURPRISING, THE CELLS GROW BUT THEY DON'T GROW SUPER RAPIDLY. THEY GROW A BIT BETTER THAN THE WILD TYPE. IF YOU STAIN WITH A MARKER OF CELLULAR SENESCENCE, THE NF 1 KNOCKOUT CELLS HAVE A LOT OF SENESCEN SENESCENCE. YOU SEE THIS AT THE mRNA LEVEL AND YOU CAN SEE THIS AT THE PROTEIN LEVEL AS WELL. THIS IS REVOLUTIONIZING HOW TO VIEW THIS AND MAYBE THE MOUSE MODEL SKIPS A STEP AND MAYBE WE'RE MISSING PART OF THE PICTURE HERE. IF YOU FOLLOW THE CDKN2A LEVEL MOVING FROM THE PLEXIFORM OR MPNST IT GOES UP AND THEN DOWN. I THINK THE MOUSE MODEL SKIPS THIS. IF YOU LOSE NF 1 AS A SCHWANN CELL YOU WANT THE CELL TO STOP GROWING. THAT'S WHAT IT'S DOING. I THINK THESE ARE THE ATYPICALS WHERE THEY STOP GROWING AND SIT IN PLACE AND HAVE VERY FEW MITOSIS AND LOSE SOME CELLULAR ARCHITECTURE AND MAY BE NODULAR BUT CDKN2A IS INTACT. WITHIN THAT A CELL WILL HAVE AN EVENT BY THE NUMBER OF CELL DIVISIONS IT WILL HAPPEN. AND THAT'S THE CELL THAT ALLOWS IT TO JUMP OFF THE EDGE AND PROGRESSION TOWARDS THE MALIGNANCY. AGAIN, YOU CAN START TO COME UP WITH ALL DIFFERENT IDEAS AND QUESTIONS ABOUT WHAT CAUSED THE CHANGE AND WHAT'S THE CELL TRYING TO DO? IS IT TRYING TO ARREST OR HAPPENING BECAUSE THE TUMORS ARE CONSTRAINED OR SOME CELLULAR STRESS. COULD WE TRY AND GET RID OF THE CDKN2A HIGH CELLS AND PRUNE THEM BECAUSE THEY'RE AT RISK OF FALLING OFF THE CLIFF AND IS IT TRUE ONE CELL OR MAYBE A HANDFUL OF CELLS WILL LOSE THAT LOCUS AND THAT'S THE PROGRESSION THAT LEADS TO RAPID PROGRESSION DOWN THE MALIGNANCY PATHWAY AND CLINICALLY, CAN WE USE A DRUG TO REVERSE THIS EFFECT AND PUSH THINGS BACK TOWARDS WHERE THINGS ARE A LITTLE BIT LESS LIKELY TO TRANSFORM INTO MALIGNANCY. THAT'S WHAT I THINK TUMOR HETEROGENEITY IS TEACHING US AND THIS RESOLUTION OF SINGLE CELL ALLOWS US TO COME UP WITH IDEAS. WE HAVE TAKE HOME MESSAGES AND NF 1s ARE GREAT CLINICAL TEACHERS AND THEIR CLINICAL TEACHERS. YOU'VE SEEN THAT IN BRIGITTE'S PRESENTATION AND HOPEFULLY MINE AND THE CLINIC CENTER IS A GREAT PLACE TO STUDY THE DISEASES AND NF 1 IS A GREAT TEACHER BECAUSE THE CLINICAL PROGRESSION MIRRORING THE PROGRESSION AND THINK WE'RE MAKING PROGRESS IN TREATING THE BENIGN TUMORS BUT ONCE IT TRANSFERS TO MALIGNANCY THE PROGNOSIS IS POOR. THE TECHNOLOGY IS MOVING RAPIDLY ENOUGH THAT WE SHOULD HAVE THESE THINGS IN THE CLINICS SOON. AND FINALLY PATIENT ENGAGEMENT AND COLLABORATION ARE CRITICAL TO MAKING ADVANCES HERE AND OUR PATIENTS ARE THE ONES THAT TAUGHT US ORIGINALLY AND THEY'RE TEACHING US AGAIN AND AGAIN HOW TO DO THIS BETTER AND THIS IS WHAT WE RAN FOR SOME PATIENTS WHERE WE TAKE THEM OUT TO HAVE A SUMMER CAMP AND IT'S GREAT FUN FOR EVERYBODY AND THIS SAY HUGE TEAM OF PEOPLE THAT HAVE DONE THE WORK AND WE'RE HERE TO DELIVER THE MESSAGE. THERE'S LOTS OF PEOPLE BEHIND THE SCENES WHO HAVE BEEN GREAT COLLABORATORS TO US OVER THE YEARS. I GUESS I'LL STOP THERE AND WE CAN OPEN THE DISCUSSION. >> OKAY. THANK YOU BOTH. EXCITING IS TOO MINIMUM OF A WORD TO ADD TO THE ENORMOUS WORK PRESENTATIONS AND THE DIMENSIONS OF WHAT THE FUTURE MAY HOLD FOR THIS. IT STRUCK ME THAT THIS IS AN INTERESTING EXAMPLE. CLINICAL OBSERVATIONS OF PEOPLE TAKING DRUGS MUCH LATER LED TO THE MECHANISM OF HOW A DRUG ACTS. AND THIS IS MODERN SCIENCE SOMEWHAT IN REVERSE WHERE A CLINICAL TRIAL BASED UPON AN EXPERIMENT EXPERIMENTAL MECHANISM LEADS TO A WHOLE EXPANSION OF SCIENCE AS APPLIED AND THE DRIVING FORCE IS THE CLINICAL TRIAL. I SUSPECT IF THAT HAD NOT HAPPENED YOU'D BE DOING SOMETHING ELSE OR NOT HAVE THE SAME ENTHUSIASM WHICH SEEMS TO BE JUSTIFIABLE. WE HAVE A BUNCH OF QUESTIONS. EACH OF YOU DECIDE HOW YOU WANT TO DEAL WITH IT. WHY DO YOU THINK SOME PATIENTS WITH NF 1 MUTATIONS DON'T RESPOND TO THE MEK INHIBITER AND ARE THEY THE ONES THAT HAVE THE MUTATION OR ARE THERE OTHER MUTATIONS? WHAT DO YOU THINK ABOUT THAT S&P -- THAT? >> THAT'S A GREAT QUESTION AND EXACTLY RIGHT. I WOULD SAY THE PLEXIFORM NEUROFIBROMAS ALMOST ALL RESPONSE. THE MAGNITUDE MAY VARY BUT WE'VE SEEN SHRINKAGE IN ALMOST ALL OF THEM. IF A TUMOR LOST THE CDNK2A THAT QUALITIES AS AN ATYPICAL FIBROMA AND MAY CONTINUE TO GROW. I THINK THAT'S OUR CURRENT THINKING. >> HOW MUCH GETS IN A TUMOR DEPENDS ON HOW DENSE IT IS. IT'S MULTI-FACTORIAL BUT I THINK IF IT'S GOTTEN THE CDNK2A LESION AND THESE WE WANT TO COME UP WITH A NEW THERAPY. >> THERE'S A CERTAIN SPECIFICITY FOR THE TUMOR TO PARTICIPATE IN CELL GROWTH ALL OVER THE BODY. AND MAYBE SOME TOXICITY IS RELATED TO IT BUT SEEMS EXTRAORDINARY THE AFFECT ON THE TUMOR WOULD DOMINANT OVER THE TOXICITY. ARE THERE EFFORTS TO TRY AND TARGET THE MEK INHIBITOR TO THE TUMOR EVEN NANO SYSTEMS? WHAT'S THE THINKING ABOUT THAT? >> IT'S FUNNY YOU BRING THAT UP. IT'S AN INCREDIBLE IDEA AND I THINK WE HAD A MEETING A COUPLE WEEKS BACK WHERE IT WAS WHERE, WE SHOULD WORK ON THIS. I THINK THE DETAILED UNDERSTANDING OF THE MICROENVIRONMENTS AND THE TARGETS THERE WILL HELP DEFINE THE RIGHT STRATEGY TO DELIVER A DRUG IN A BETTER WAY. THAT'S ANOTHER BYPRODUCT OF HAVING THE DETAILED UNDERSTANDING OF THE ENVIRONMENT. YOU CAN IMAGINE IT BECOMES AN ENGINEERING PROBLEM. HOW DO YOU GET MORE DRUG TO THAT REGION? THAT'S WHAT I LOVE YOU UNDERSTAND THE MECHANISM AND THAN CAN ENGINEER YOU'RE WAY TO FIXING IT. >> AN INTERESTING TALK TWO WEEKS AGO THAT THE BIO ENGINEERING DEPARTMENT AT M.I.T. GAVE DEALING IN PART WITH SUCH ISSUES AND STUDIES THEY'VE DONE USING NANO 2 DELIVERIES AND THERE'S A QUESTION ABOUT ENVIRONMENTAL FACTORS AND WHETHER THEY INFLUENCE THE PROGRESSION OF THE TUMOR OR RESPONSIVENESS TO THERAPY SPECIFICALLY THE SUN WAS MENTIONED. IS THERE ENVIRONMENTAL INFORMATION THAT GIVES SOME CLUE ABOUT THAT? >> I'M NOT AWARE OF GOOD CLUES. THERE'S BEEN THOUGHTS ON VITAMIN D AND SUN EXPOSURE AND MANY, FOR EXAMPLE OF THE CUTANEOUS TUMORS ARE ON THE TRUNK BUT THE DENSITY OF THE TUMORS AND THE THOUGHT WAS COULD IT BE RELATED TO LACK OF SUN EXPOSURE BUT I DON'T THINK IT'S A STRONG LINK. WE TRY TO AVOID RADIATION BECAUSE WE THINK RADIATION TO A CELL ALREADY PREDISPOSED TO DEVELOP TUMORS MAYBE AT A GREATER RISK FOR MALIGNANT TRANSFORMATION. WE VERY MUCH TRIED TO AVOID RADIATION IN NF 1 PATIENTS UNLESS CLINICALLY NEEDED AND RADIATION CAN EXACERBATE VASCULOPATHY BUT OUTSIDE OF THAT HORMONAL FACTORS HAVE BEEN DISCUSSED. FOR EXAMPLE WHEN WOMEN ARE PREGNANT SOME DESCRIBE THOUSANDS OF SUB CUTANEOUS TUMORS ERUPT AND MANY TELL ME THEY WERE DIAGNOS DIAGNOSED. >> THERE'S A QUESTION WHETHER THERE ARE I GUESS GEOGRAPHIC HOT SPOTS AND THERE'S MANY RECESSIVELY INHERITED NF 1s AND GRANTED THIS IS A MORE DOMINANT TRANSMISSION BUT ARE THERE HOT SPOTS GEOGRAPHICALLY? >> NOT THAT I'M AWARE OF. I'M PRETTY SURE IT'S NOT BEEN DESCRIBED FOR NF 1. >> AN INTERESTING THING ABOUT THE GENE IS IT'S HUGE. JUST THE SIZE IN SOME PERCENTAGE OF THE POPULATION YOU'LL GET AN ERROR THAT OCCURS IN THAT FASHION. I DON'T KNOW IF ANY GEOGRAPHIC REGION BUT INTERESTING TO THINK IT'S A HUGE GENE WITH A LOT OF OPPORTUNITIES FOR THINGS TO GO WRONG IN MY THINKING. >> YOU MENTIONED THE GTP ACTIVATING PROTEIN. IS IT CIRCULATING IN BLOOD? >> I DON'T KNOW THE ANSWER TO THAT. >> I HAVE TO PASS. I DON'T KNOW. THAT'S A GREAT QUESTION. >> IT'S AN INTRACELLULAR PROTEIN BUT I DON'T KNOW WE'VE LOOKED IN THE SERUM SAMPLES. NEUROFIBROMIN IS SYNTHESISED BY WHAT CELLS? >> IT'S NOT RESTRICTED TO PARTICULAR LINEAGES. >> WOULD IT BE IN HEPATOCYTES FOR EXAMPLE? >> YEAH, IT'S IMPORTANT IN MANY CELLS IN DIFFERENT LINEAGES. >> THERE'S COMMUNICATION BETWEEN THE MEK AND RAS PATHWAY. IS THEY ARE ROLE FOR PI3 KINASE IN THESE RESPONSES? AND THERE ARE NOW VARIOUS KINASE INHIBITERS. IS THAT WORTH INVESTIGATING? >> I CAN SAY THAT THAT PATHWAY IS ACTIVATED PERHAPS IN A DIFFERENT WAY AND THAT WAS THE RATIONALE BETWEEN THE MPNST TRIAL WHERE WE TRIED TO ADD A MEK INHIBITER AND WHEN YOU START TO INHIBIT BOTH THE TOXICITY GOES HIGH. YOU CAN IMAGINE IN A BENIGN CONDITION OF PLEXIFORM NEUROFIBROMAS YOU WOULDN'T TOLERATE MUCH TOXICITY AT ALL AND THAT'S A BENEFIT OF THE SELUMETINIB IS THE TOXICITY PROFILE IS FAIRLY WELL HANDLED. >> THEY LOOK AT THE KINASE INHIBITERS AS WELL AND WOULD BE INTERESTING TO EXPLORE IN COMBINATION WITH THE MEK INHIBITOR BUT JACK HAS A GREAT POINT IN THE PATIENTS WHO HAVE BENIGN TUMORS PARTICULARLY IN YOUNG KIDS THEY'RE NOT AS LIKELY TO TOLERATE AS MUCH TOXICITY AND IT'S TOO MUCH AND PATIENTS ARE MORE LIKELY TO PUT OUT THE TOXICITIES THEY SEE IN HOPES OF BETTER RESPONSE AND SOMETHING TO CONSIDER AS WE DEVELOP MEDICINES FOR THE TUMORS. >> WE HAVE A FEW WHAT I CALL GENERAL CLINICAL RELATED THINGS. DOES THE AMERICAN ACADEMY OF PEDIATRICS REALLY REQUIRE PEDIATRICIANS KNOW SOMETHING ABOUT NF 1 AND ARE YOU CONFIDENT MOST PEDIATRICIANS KNOW ABOUT IT AND IF NOT HOW DO YOU DISSEMINATE THE INFORMATION? >> HAVING BEEN THROUGH PEDIATRIC RESIDENCY THIS IS SOMETHING YOU DO LOOK FOR AS A GENERAL PEDIATRICIAN AND THE SKIN FINDINGS ARE SO STEREOTYPICAL IF YOU SEE MULTIPLE CAFE AU LAIT SPOTS OR THE UNIQUE CLINICAL FINDINGS, IT'S ENGRAINED IN THE PEDIATRICIANS HEAD THIS IS NF 1. >> AND IF THE FDA APPROVES THE USE OF THE INHIBITOR, QUESTION PRACTICAL, IS ITS COVERED BY INSURANCE AND HOW MUCH DOES IT COST? >> IT'S INTERESTING. WE TALK WITH ASTRAZENECA THEY DEVELOP THE SELUMETINIB I STILL CAN'T GIVE A PRECISE ANSWER BUT I DO THINK THERE'S COVERAGE BY ENSURANCE AND THERE'S A NUMBER OF MECHANISMS FOR PATIENTS WHO DON'T HAVE THE MEANS. AND GET ACCESS TO THE MEK INHIBIT INHIBITOR. I WOULD EXPECT IT'S NOT INEXPENSIVE BECAUSE MOST THE DRUGS IN THIS AREA WITH THE KINASE INHIBITOR DEVELOPED ARE QUITE EXPENSIVE. THE INTERESTING ASPECT IN NF 1 IS WE HAVE PATIENTS THAT HAVE BEEN ON IT FOR YEARS AND IT'S AT THE CHRONIC MEDICINE BUT A NUMBER OF THEM HELP PATIENTS GET ACCESS. SORRY I CAN'T ANSWER THE PRECISE QUESTION. >> DO PATIENTS RELAPSE ON THE DRUG >> PATIENTS WHO STOP TAKING THE MEDICINE FOR EXAMPLE ADOLESCENTS MAY STOP TAKING IT THE TUMORS WILL LIKELY GROW WE HAVE FEW PATIENTS WITH BENIGN TUMORS WHO DEVELOP PROGRESSION AND TREATMENT. THERE'S A FEW. WE CERTAINLY HAVE SEEN RELAPSE OF PROGRESSION IN PATIENTS WHO UNDER GO GOES REDUCTION FOR TOXICITY. THE RELATIVELY SMALL NUMBER OF PATIENTS WITH A DOSE REDUCTION SOME OF THEM WILL HAVE GROWTH OF TUMORS BECAUSE THEY DON'T SEEM TO GET THE ADEQUATE DOSE. WE HAVE TO HOLD FOR TOXICITY OF SURGERY OR FOR SOME REASON THE TUMOR WILL REGROW AND IT WILL TYPICALLY RESPOND TO THE MEK INHIBITOR. THOSE ARE INTERESTING OBSERVATIONS. >> THERE'S A LITTLE EVIDENCE FOR THE DEVELOPMENT OF REAL RESISTANCE. >> THAT IS CORRECT. WE HAVE RESPONSES TO SEE THE RESISTANCE AFTERWARDS. >> DO YOU PATIENTS WITH NF 1 BECOME PREGNANT OR DO THEY USUALLY CHOOSE ADOPTION. >> YOU CAN ABSOLUTELY HAVE CHILDREN. WE HAVE A NUMBER OF PATIENTS THAT HAVE OFFSPRING WITH NF 1 AND WITHOUT. YES. >> ARE THEY ALL BY IN VITRO FERTILIZATION. >> YOU HAVE HALF THE PATIENTS WE HAVE A FAMILY HISTORY OF NF 1 WHERE THE MOM OR DAD HAD IT AND THEY KNOW ABOUT IT OR DON'T KNOW ABOUT IT. THE MAJORITY WOULD KNOW THEY HAVE NF 1. AND THE OTHERS HAVE SPONTANEOUS MUTATIONS THAT OCCUR. >> SO IT'S NOT THAT THEY HAVE PRENATAL TESTING LIKE ASSOCIATED WITH IN VITRO FERTILIZATION. >> THE ABILITY TO DO PRENATAL TESTING FOR THE PRESENCE OF NF 1. FOR EXAMPLE, IF YOU HAVE A FAMILY HISTORY AND YOU WANT TO BECOME PREGNANT AND YOU HAVE NF 1 OR YOUR PARTNER HAS NF 1 MANY LEAD TO THE PHENOTYPE CORRELATIONS. WE MAY HAVE THE MOM VERY MULTI-AFFECTED BUT DOESN'T PREDICT THE CHILD WILL BE MILDLY AFFECTED. THERE'S SO LITTLE PREDICTABILITY OF CORRELATIONS. >> >> AMONGST THE MANY OTHER OMAS AND ALL OF THAT, ARE THEY ALL RELATED ONE WAY OR ANOTHER TO NF 1 OR NF 2? >> I WOULD SAY NOT ALL OF THEM. AN NF 1 GLIOMAS WE SEE MORE FREQUENTLY AND IN NF 2 CHROMOSOME 22 A COMPLETELY DIFFERENT GENETIC BASIS WE SEE BILATERAL VESTIBULAR SCHWANNOMAS AND IN SCHWANNOMATOSIS AND SEE OTHERS WITHOUT A GENETIC BASE FOR IT. >> WHEN YOU SAY SPORADIC, IS THAT ACTUALLY BEEN TESTS? COULD THERE BE HETEROZYGOTE FORM OF MUTATION WITH SUSCEPTIBILITY? COULD THEY ALL BE RELATED? >> I'M PRETTY SURE THEY'VE BEEN EXAMINED AN IT'S TRUE SPORADIC AT LEAST NF 1 AND NF 2 AND SCHWANNOOMA TOSE IS HAS BEEN RULED OUT >> THERE'S A LARGE NUMBER OF NF 1 MUTATIONS THAT CAN OCCUR BUT I THINK THE SECOND ONE WOULD BE REALLY THE CONSEQUENCE BECAUSE WE HAVE PEOPLE WITH NF 1 WHO GROW UP AND LIKE OUR PATIENT WHO ARE INTELLIGENT AND SOME ARE SEVERELY AFFECTED. AND THERE'S A SUCH A BROAD SPECTR SPECTRUM. >> WE HAVE A PERSONAL QUESTION FOR YOU. HOW DID YOU BECOME INTERESTED IN THE STUDY? >> IT'S NOT REALLY COOL BUT IT WAS BECAUSE I KNEW THERE WERE DRUGS OUT THAT TARGET RAS AND WE THOUGHT THIS IS GOING TO BE HELPFUL FOR THESE PATIENTS AND WE ENROLLED PATIENTS IN TREATMENT TRIALS. I THOUGHT THIS IS GOING TO BE AN EASY THING. WE HAVE TRANSFERASE INHIBITERS THAT BLOCK ACTIVATION. IT SEEMED SO LOGICAL TO TRY AND THIS REALLY THEN I LEARNED IT'S NOT AS EASY AS I THOUGHT AND THE RELATIONSHIP WE ESTABLISHED WITH OUR PATIENTS HAS HELPED SUSTAIN THIS. THEY STAY WITH US FOR YEARS. I HAVE KIDS THAT WERE 3 YEARS OLD AND NOW 23 YEARS OLD. ONCE YOU GET INTO THE FIELD YOU GET HOOKED. AND NOW DR. SHERNA IS HOOKED TOO BECAUSE HE'LL HOPEFULLY MAKE THE PROGRESS WE FAILED TO MAKE TO DATE. >> THE PROGRESS JACK DESCRIBED IS BREATHTAKING IN ITS POTENTIAL. IF I'D BE SMARTER AND YOUNGER I'D APPLY TO BE A POST-DOC IN HIS LAB. >> I'LL TAKE YOU. >> THIS HAS OPENED UP A PANDORA'S BOX OF POSSIBILITIES AND PATIENTS WHO HAD LITTLE INFORMATION OF THE DISEASE AND TREATMENT, I ASSUME IT'S ALSO A GLOBAL IF NOT NATIONAL EFFORT. MAYBE YOU WOULD EXPLAIN HOW YOU GO FROM BEING SINGLE LAB AND DEALING WITH A RARE DISEASE ALL OVER THE WORLD. HOW DO YOU GO ABOUT MARSHALLING ALL THE OPPORTUNITIES AND TALENTS THAT EXIST AND WHAT ARE THE MECHANISMS USED TO BRING THIS COMMUNITY TOGETHER AND IS THERE SUPPORT FOR IT? >> BRIGITTE IS A MASTER OF COLLABORATIONS AND I SORT OF LEARN FROM HER. I THINK THIS COMMUNITY THERE'S SOMETHING UNIQUE ABOUT THE COMMUNITY. IT ATTRACTS PEOPLE WHO ARE CREATIVE AND COLLABORATIVE AND YOU DON'T FIND THAT IN EVERY DISEASE TYPE BUT THIS PARTICULAR ONE IS A REMARKABLE THING AND THE CONFERENCE THEY STARTED AND THE PEOPLE WHO BLOCKED TO THIS AND IT'S AN INTERNATIONAL COLLABORATION. WE HAVE ANNUAL MEETINGS WHERE PEOPLE FROM ALL OVER THE WORLD COME. IT'S COMPETITIVE FIELD. IT'S GOTTEN MORE COMPETITIVE. OUR ADVANTAGE HERE I THINK AT THE CLINICAL CENTER IS WE INDEED CAN DO WHOLE BODY MRIs THAT COST $10,000 AT THE OUTSET, IT SHOULDN'T BUT DOES AND THE LUXURY WE FOLLOW PATIENTS METICULOUSLY AND HAVE BASIC COLLABORATORS AT THE SAME TIME AND THIS GAVE US THE ADVANTAGE WHEN WE DEVELOPED OUR CLINICAL TRIALS BUT WITHOUT THE PATIENTS BEING COMMITTED TO SAYING YES, I'LL COME FOR THIS MEDICINE I GET EVERY FOUR MONTHS AN MRI AND SLEEP STUDY AND RANGE OF MOTION STUDY AND ALL THE QUESTIONNAIRES WE WOULD NOT HAVE AN FDA APPROVAL FOR TREATMENT. THAT'S WONDERFUL. IT'S VERY EXCITING. ON BEHALF OF I'M SURE A LARGE NUMBER OF PEOPLE WHO ARE TUNED IN AROUND THE WORLD THAT I THINK I'M NOT OUD OF OUT OF LINE TO EXPRESSING OUR GRATITUDE TO YOU YOU AND HEATHER AND ADMIRATION FOR THE TENACITY, CREATIVITY AND HOPE THAT YOU BRING TO THIS FIELD. SO THANK YOU. THANK YOU VERY MUCH.