>> WELCOME TO THE 24th ANNUAL ASTUTE CLINICIAN LECTURE. I'M DR. JIM GILLMAN OF THE CLINICAL CENTER. THE SPECIAL LECTURE IS AN NIH DIRECTOR'S WEDNESDAY AFTERNOON SERIES HOSTED BY THE CLINICAL CENTER. FRANCIS COLLINS NOT ABLE TO JOIN US DUE TO OTHER COMMITMENTS. THE ASTUTE LECTURESHIP WAS ESTABLISHED BY THE LATE DR. ROBERT MILLER AND HIS WIFE, HARUKO AND OBSERVED A SCIENTIST WHO OBSERVED A NEW AVENUE OF RESEARCH. TODAY WE WELCOME DR. BRIGG ITE WIDEMANN ON NEUROFIBROMATOSIS AND THEN GRADUATED FROM THE NATIONAL CANCER INSTITUTE. SHE'S THE CHIEF OF THE PEDIATRIC ONCOLOGY BRANCH. IS THE TRAINED AS A PEDIATRIC ONCOLOGIST WITH EXPERTISE IN DRUG DEVELOPMENT AND EARLY CLINICAL TRIALS FOR CHILDREN WITH REFRACTORY CANCERS. SHE APPLIED HER EXPERTISE TO STUDY GENETIC TUMOR PREDISPOSITION SYNDROMES IN PARTICULAR NEUROFIBROMATOSIS TYPE 1 AND PEDIATRIC AND ADULT SOLID TUMORS. THESE EFFORTS RESULTED IN THE UNDERSTANDING OF THE NATURAL HISTORY AND BIOLOGY OF NEUROFIBROMATOSIS TYPE 1 RELATED TUMORS AND OTHER SOLID TUMORS AND NOVEL END POINTS AND MEASURES AND BASED ON HER CLINICAL TRIALS IN 2020 THE FDA APPROVED THE FIRST MEDICAL THERAPY THE MEK INHIBITER SELUMETINIB AND HAS WORKED WITH OTHER RESEARCHERS AND PARTNERS. SHE IS AN ELECTED MEMBER OF THE ASSOCIATION OF AMERICAN PHYSICIANS AND RECIPIENT OF THE 2021 AACR AWARD FOR OUTSTANDING ACHIEVEMENT IN CLINICAL CANCER RESEARCH AND NOW DR. WIDEMANN. >> THANK YOU FOR THE INTRODUCTION. I'M VERY HUMBLED TO BE RECEIVING THIS AWARD AND GIVING THIS LECTURE TODAY IN HONOR OF DR. ROBERT MILLER, WHO LOOKING BACK AT HIS ACHIEVEMENTS, WAS INDEED AN EXCEPTIONAL PEDIATRICIAN AND SCIENTIST AND EPIDEMIOLOGIST. THANK YOU FOR GIVING ME THIS HONOR TODAY. I WILL TALK ABOUT THE JOURNEY TO ADVANCING THERAPIES FOR NEUROFIBROMATOSIS TYPE 1 OR NF1 AND FOCUS ON LESSONS LEARNED FROM EVERY PATIENT. I HAVE NO DISCLOSURES BUT WILL TALK ABOUT CLINICAL TRIALS WITH INVESTIGATIONAL AGENTS. I CAME TO NIH IN 1992 UNDER THE LEADERSHIP OF P -- DR. PIZO TO GET TRAINED IN ONCOLOGY AND WHAT ATTRACTED ME WAS WORLD CLASS AND THE CLOSENESS OF THE BENCH TO THE BEDSIDE AND HOW THIS COULD LEAD TO INNOVATIVE TREATMENT FOR PATIENTS WITH UNMET NEED. AFTER COMPLETING THE FIRST YEAR OF CLINICAL TRAINING I JOINED THE PHARMACOLOGY SECTION DIRECTED BY DR. BAYLESS AND DR. PETER ADAMSON WAS MY DIRECT MENTOR AND AFTER LEAVING NCI BECAME THE CHAIR OF THE CHILDREN'S ONCOLOGY GROUP. I LEARNED A LOT THAT PREPARED ME FOR DOING CLINICAL TRIALS IN NF1 DURING THIS TIME AND EARLY REVIEW OF CLINICAL TRIALS WE CONDUCTED AT NCI FOR CHILDREN WITH SOLID TUMORS AND REVIEWED BY DR. KIM A FELLOW IN THE BRANCH AS WELL. WE ENROLLED PREDOMINANTLY BRAIN TUMORS AND NEUROBLASTOMA AND OTHERS AND THE FOCUS WAS ON PHASE 1 TRIALS. 90% OF THE PATIENTS HAD TOLERATED DOSE AND RATE OF DOSE LIMITING TOXICITIES WAS LOW AT 17%. ONLY ONE PATIENT HAD A POSSIBLY DRUG RELATED ISSUE A PATIENT WITH A BRAIN TUMOR. YOU SEE THE RESPONSE RATE WAS VERY LOW AND A WANT TO POINT OUT IN PHASE 1 TRIALS IT WAS NOT THE OBJECTIVE BUT THE MEDIAN OVERALL SURVIVAL FROM ENROLLMENT WAS ONLY FIVE MONTHS. DOING THESE CLINICAL TRIALS WAS NOT EASY AND A WANT TO THANK PETER FOR TEACHING ME HOW TO BE HONEST WITH PATIENTS WHILE AT THE SAME TIME NEVER GIVING UP OR TAKING HOPE AWAY FROM THEM. IT PREPARED ME IN NOT BEING AFRAID OF TAKING ON A NEW DISEASE. WE WERE USED TO FAILURE IN THE SENSE OF DRUGS NOT WORKING AND I WAS NOT AFRAID THIS WOULD TAKE ANYTHING AWAY WHEN WE STARTED WORKING ON NF1 IT BECAME MY PROJECT AND GOT ME TENURE IN 2009 AND THE PROTOTYPE RESULTING IN ACTIVATION OF THE RAS PATHWAY. BY CHARACTERIZED BY MOLECULES AND SKIN TUMORS AND AXILLARRY AND I LOOKED AT TUMORS AND VERY IMPORTANTLY THERE WAS NO EFFECT OF MEDICAL THERAPY FOR THE TUMORS BUT THERE WERE MANY AGENTS IN DEVELOPMENT FOR CANCER CANCERS THAT EMBARK ON THE PATHWAY AND WHY WE STUDY THE NEUROFIBROMATOSIS TYPE 1 AND THE GENE PRODUCT FUNCTIONS AS AN ACTIVATOR PROTEIN AND TURNS ATP RAS TO INACTIVE ATP BOUND RAS. WHEN NEUROFIBE ROMIN IS DEFICIENT THERE'S THE RAF PATHWAY AND OTHER PATHWAYS. AT THE END OF AROUND 1998, TRANSFERRASE WERE STUDIED AND THIS WAS THE FIRST CLINICAL TRIAL I TOOK FORWARD FOR PATIENTS WITH NF1. IT WAS NOT SUCCESSFUL BECAUSE SUBSEQUENTLY I AND OTHERS EVALUATED A NUMBER OF ADDITIONAL AGENTS WITHOUT CLINICAL SUCCESS UNTIL WE STUDIED MEK INHIBITOR. WHEN WE BEGAN STUDYING NF1 WE KNEW PATIENTS DEVELOP SKIN TUMORS IN EARLY ADOLESCENTS OR EARLY ADULTHOOD AND THE TUMOR I WAS FOCUSSED ON WAS FLEXIFORM FIBROMA WE BELIEVE ARE CONGENITAL AND WHILE HISTOLOGICALLY COMBINED AND CAN TURN INTO AGGRESSIVE CANCERS WITH SURGERY AND THROUGH STUDYING THESE TUMORS WE BEGAN TO LEARN MORE ABOUT A TYPE OF TUMOR WHICH IS A PRECURSOR TO MALIGNANT TUMORS AND I'LL TALK ABOUT IT DURING THE TALK AND THE GENOMIC CHARACTERISTICS OF THE TUMORS THAT HELP US UNDERSTAND THE MALIGNANT TRANSFORMATION BETTER. WHEN WE MEASURED THEM THIS WAS USED FOR EVERY PATIENT AS METRIC MEASUREMENTS AND WHEN WE START THE WORK WE HAD NO IDEA ABOUT THE NATURAL HISTORY OF THE TUMORS. MANY OF US THOUGHT THEY WERE ERRATICALLY GROWING AND WE HAVE NOW CHARACTERIZED THE NATURAL HISTORY. WHEN WE STARTED THERE WERE FEW CLINICAL TRIALS AND NO MEANINGFUL OUTCOME MEASURES AND NOW WE HAVE MEANINGFUL OUTCOME MEASURES AND PATIENT-REPORTED OUTCOMES AND A MEDICAL THERAPY APPROVED FOR THE TUMORS FOR THE FIRST TIME. NEUROFIBROMAS WERE CHARACTERIZED BY PATHOLOGIC CHANGES AND NOW CHARACTERIZED THEM AS MALIGNANT TUMORS AND WE HAVE INITIATE THE FIRST CLINICAL TRIAL TARGETING THESE TUMORS AND AS IT RELATES TO OTHER TUMORS WHILE THERE'S NO EFFECTIVE THERAPY TODAY WE ARE WORKING ON A STRATEGY TO PREVENT THESE TUMORS AND OVER THE YEARS PRECLINICAL MODELS HAVE BEEN DEVELOPED FOR THE THREE TUMORS AND IT'S VALIDATED. STARTING WITH THE PLEXIFORM FIBROMAS, WE KNEW THEY WERE DEVELOPING IN VERY YOUNG PATIENTS AND KNEW THEY CAN CAUSE DISFIGUREMENT AND CAN GROW QUICKLY IN YOUNG PATIENTS AND THE TUMORS ARE BRIGHT ON MRI COMPARED TO THE SURROUNDING TISSUE. ONE ASPECT WAS DIFFICULT TO MEASURE THE TUMORS AND I'M SHOWING THIS IN A PLEXIFORM NEUROFIBROMA THIS IS A TUMOR OF A PATIENT IN 2007 AND YOU SEE IT IN 2008 AND 2009 AND IN 2012 AND WHILE I DO THINK YOU CAN SEE THERE HAS BEEN SOME INCREASE OVER TIME, MOST OF THE RADIOLOGY REPORTS WOULD TELL US THERE'S NO CHANGE BECAUSE WE USUALLY LOOK A MAXIMUM OF FEW MONTHS BUT NOT FOR A YEAR. THESE TUMORS GROW MORE SLOWLY OVER TIME COMPARED TO CANCER TUMORS. SO DR. SOLMAN CAPTURED THE IMAGE WITH THE AREA AND WE CAN CALCULATE THE TUMOR VOLUME. AND SUBSEQUENTLY WE USED THIS METHOD IN THE NATURAL HISTORY STUDIES WE CONDUCTED AND IN CLINICAL TRIALS AND IT WAS A VERY CRITICAL STEP TO MAKING PROGRESS IN NF1 TUMORS. YOU CAN NOW SEE WITHIN A YEAR, THE TUMOR HAD INCREASE IN VOLUME OF 28% AND THAT BY THE TIME THERE WERE FIVE OR SIX YEARS THE TUMOR VOLUME HAD MORE THAN DOUBLED. OUR APPROACH WAS TO USE THE MORE SENSITIVE AND REPRODUCIBLE METHOD IN PARALLEL IN NATURAL HISTORY STUDY BUT AT THE SAME TIME WE DIDN'T WANT TO WAIT WITH CLINICAL TRIALS EVALUATING THE POTENTIAL BENEFIT OF AGENTS AND THE PROGRESSION WAS DEFINED BY A 20% INCREASE IN VOLUME AND DR. DOUMI HAD RESPONSE EVALUATIONS ON MANY NATIONAL CLINICAL TRIALS. THIS IS ANOTHER QUICK EXAMPLE TO SHOW YOU HOW MUCH FURTHER THE VOLUMETRIC METHOD IS AND SEE A PATIENT WITH A NECK PLEXIFORM NEUROOWE -- NEU FIBROMA AND WE STARTED EMBARKING ON NATURAL HISTORY STUDIES AND THE NIH CENTER IS THE PLACE TO CONDUCT THESE STUDIES. A GENETICISTS AND NEUROLOGIST STARTED THE FIRST NATURAL HISTORY STUDY IN 2001 AND WE PARTICIPATED IN IT. THE STUDY USED OVER THREE YEARS VOLUMETRIC ANALYSIS AND AND WE HAVE VOLUMETRIC MEASURES OVER 20 YEARS AND OUR STUDY FOCUSSED ON UNDERSTANDING THE PLEXI FORM NEUROFIBROMA AND WERE FORTUNATE TO HAVE MANY INVESTIGATORS HELPING US UNDERSTAND OTHER ASPECTS OF NF1 SUCH AS SOCIAL/EMOTIONAL FUNCTION AND MOTOR FUNCTION AND HEARING AND ENDOCRINE MANIFESTATIONS. A VERY ESTEEMED COLLEAGUE OF MINE AFTER A FEW YEARS IN THE NATURAL HISTORY STUDY SAID WHEN ARE YOU GOING TO STOP. THIS IS A VERY RESEARCH INTENSIVE STUDY AND I THINK IT'S A RELEVANT QUESTION BECAUSE WE WANT TO ALWAYS THINK ABOUT WHEN CAN WE STOP AND START AND EMBARK ON SOMETHING NEW. WE DIDN'T STOP THE NATURAL HISTORY STUDY AND I THINK IT WAS A GOOD DECISION. MORE THAN 25 MANUSCRIPTS HAVE COME FROM THIS AND SOME ARE VERY IMPORTANT AND I WANT TO HIGHLIGHT A FEW OF THEM. THE CHARACTERIZATION OF THE PLEXIFORM NEUROFIBROMA SERVED AS CRITICAL TO FDA APPROVAL AND CHARACTERIZING THE TUMORS CAREFULLY LED TO THE IDENTIFICATION OF THE TUMORS. IT'S BEEN USED FOR THE PAIN SCALE AS A PRIMARY END POINT AND THE NATURAL HISTORY STUDY HAS CHARACTERIZATION OF THE TUMORS. SHOWN HERE ARE THE KEY FINDINGS FROM THE NATURAL HISTORY STUDY FOR THE GROWTH OF PLEXIFORM NEUROFIBROMAS AND YOUNG CHILDREN HAVE THE MOST RAPIDLY GROWING TUMORS WHICH IS WHY WE WERE SO INTERESTED IN FOCUSSING ON DRUG DEVELOPMENT EFFORTS ON YOUNG CHILDREN AND NOT ADULTS WHERE WE DON'T SEE TUMORS GROWING. THERE GROSS DID AN ANALYSIS OF THE COMORBIDITY THAT COMES FROM THE TUMORS AND COULD SHOW MOST OF THE PATIENTS FROM THE FIRST TIME THEY CAME TO THE NIH CLINICAL CENTER ALREADY HAD SUBSTANTIAL MORBIDITY AND ONCE PRESENT IT DIDN'T RESERVE. AND WE DID A PHASE 2 TRIAL AND AN IT WAS ONE OF THE MOST STUDIES DONE TO DATE ON NF1. IT HAPPENED AT A TIME WHEN THERE WAS A PLACEBO CROSSOVER DESIGN AND THE STUDY TAUGHT US A LOT. DPN A VERY ESTEEMED COLLEAGUE I'M VERY FRIEND HI WITH EVEN TODAY SAID IS THERE A STOPPING ROUTE TO YOUR TRIAL BECAUSE THIS INVESTIGATOR DID ANTICIPATE THE TRANSFERASE INFIBT INHIBITOR WAS NOT GOING TO WORK AND YOU SEE HERE FOR THE PLACEBO INDEPENDENT IF THE PATIENT STARTED ON THE FIRST OR SECOND PHASE THERE'S AN OVERLAY HOWEVER, WHAT THIS STUDY TAUGHT US FOR THE FIRST TIME WE HAD NATURAL HISTORY DATA ON THE FORMATION OF PLEXIFORM NEUROFIBROMATOSISES USING AS THE BENCHMARK FOR CLINICAL TRIAL AND THE USE OF MRI ANALYSIS WAS THE ONLY METHOD HOW WE COULD WITHIN A REASONABLE TIME PERIOD COMPLETE THESE STUDIES. THE REASON TIPIFARNIB DID NOT WORK IS THE RAS CAN INSERT IN THE PLASMA MEMBRANE. CLEARLY IT WAS NOT EFFECTIVE FOR THE TUMORS. ANOTHER THING WE OBSERVED IN THE PATIENTS ON THE TIPIFARNIB STUDY WAS TUMORS GROW FASTER IN KIDS. YOU SEE THE 3-YEAR-OLD AND IF YOU LOOK AT THE LOWER PANEL WE ENROLLED A PATIENT A 14-YEAR-OLD AND THEY HAD A NODULE LESION THAT GREW AND AFTER SIX MONTHS ON STUDY HE CAME OFF THE TREATMENT FOR PROGRESSIVE DISEASE. THIS WAS THE FIRST TIME WE IDENTIFIED A DISTINCT NODULE AT THE TIME WE DIDN'T KNOW IT WAS A MALIGNANT PRECURSOR LESION BUT AFTER THE PATIENT WAS REMOVED THE STUDY IT THEY UNFORTUNATELY DECIDE FROM A DISEASE. WITH THE BENCHMARK STUDY OF THE TIPIFARBNIB STUDY WE LOOKED IF WE CAN IMPROVE THE PROGRESSION FREE SURVIVAL. YOU SEE AN ANTI-FIBROTIC AGENT HAD NO EFFECT AND THE ALPHA 2B DID RESULT IN THE DOUBLING OF THE TIME TO PROGRESSION AND 2 OF 175 PATIENTS HAT A CONFIRMED RESPONSE. AND HERE IN A YOUNG BOY, 3 YEARS OLD WE SAW HIM FOR THE FIRST TIME WITH THE HEAD AN NECK AND PLEXIFORM NEUROFIBROMA AND BY THE TIME HE WAS 16 HIS TUMOR MORE THAN TRIPLED AND HAD DEVELOPED BOWEL INCONTINENCE AND CLEARLY MAD TO MAKE PROGRESS IN THE TUMORS AND HAD TO WANTED TO SEE IF WE MADE PROGRESS IN THE PLEXIFORM NEUROFIBROMA AND WE DID A TRIAL BUT PRECLINICAL DATA BECAUSE WHEN WE STARTED THERE WERE NO PRECLINICAL MODELS AND WE SAW IN ALMOST EVERY PATIENT A VOLUMETRIC REGRESSION SHOWING THIS WAS IMPORTANT FOR PLEXIFORM NEUROFIBROMAS AND 17 OF THE PATIENTS HAD A POSITIVE RESPONSE AND THE RESPONSES WERE OBSERVED AT 60% OF THE ADULT RECOMMENDED DOSE. PRIOR TO STARTING THE STUDY IT WAS ALMOST IMPOSSIBLE TO GET A PHARMACEUTICAL PARTNER TO AGREE TO DO THE STUDY BECAUSE WE WANTED TO TREAT CHILDREN AND MEK INHIBITERS WERE NOT TESTED IN CHILDREN AND A WANT TO THANK AUSTIN DOYLE FOR ALLOWING US TO DO THIS TRIAL WITHOUT THE SUPPORT FROM CTEP I DON'T KNOW WE WOULD HAVE AN APPROVED AGENT AT THIS POINT IN TIME. ON THE CLINICAL PHASE I TRIAL WE ALSO OBSERVED A BENEFIT AND YOU SEE HERE THE LARGE FIBROMA THAT WAS PROGRESSIVELY GROWING AND DEMONSTRATED SHRINKAGE ON WHEN WE APPROACHED THE FDA TO SEE IF WE COULD GET THE BREAKTHROUGH THERAPY DESIGNATION, THE FDA TOLD US NO. YOU HAVE NOT LOOKED AT THIS PROSPECTIVELY AND KIND OF LOST THE OPPORTUNITY. YOU SHOULD HAVE INCLUDED PATIENT-RECORDED OUTCOMES OR SOMETHING TO MEASURE THE BENEFIT IN YOUR PHASE I CLINICAL TRIAL AND THIS IS AN IMPORTANT LESSON FOR ANYONE DOING TUMOR IF YOU HAVE SOMETHING YOU ANTICIPATE MAY BE WORKING EVEN IN EARLY TRIALS SUCH AS PHASE 1 AND INCORPORATING PATIENT BENEFIT IS A GOOD IDEA. WE CREATED A TRIAL FOR CHILDREN WITH NEUROFIBROMAS AND THERE WERE A HOST OF FUNCTIONAL END-PATIENT REPORTED OUTCOMES MEASURES TO SEE IF THE PATIENTS WITH SYMPTOMATIC TUMORS COULD MEASURE CLINICAL BENEFIT. YOU SEE THE PLOT OF RESPONSE MIRRORS THAT FROM THE PHASE 1 STUDY. 34 OF 50 PATIENTS HAD A CONFIRMED RESPONSE AND WE ALSO IN THIS STUDY WERE ABLE TO DEMONSTRATE BENEFIT WITH IMPROVEMENT IN PAIN AND FUNCTION. HERE YOU SEE AN IMPROVEMENT IN DISFIGUREMENT WITH A PATIENT WITH A NECK TUMOR AND THEN LOOKING AT GLOBAL IMPRESSION OF CHANGE IN TUMOR-MORBIDITIES AND THERE WAS A GLOBAL CHANGE AND IMPROVEMENT AND VERY FEW PATIENTS REPORTED WORSENING. DOCTORS AND WALTERS AND MARTIN LOOK AT THE PAIN SCALE FROM 0 TO 10 AND SHOWED AN OVERALL DECREASE IN TUMOR PAIN INTENSITY OVER TREATMENT CYCLES AND ONE CYCLE IS FOUR WEEKS. THEY COULD SHOW FROM BASELINE TO PRE-CYCLE 12 APPROXIMATELY ONE YEAR THERE WAS AN AVERAGE DECREASE IN PAIN POINTS BY TWO OR MORE WHICH IS CLINICALLY SIGNIFICANT AND NOT JUST STATISTICALLY SIGNIFICANT. THIS DATA WAS REALLY IMPORTANT FOR THE FDA APPROVAL AND I CANNOT THANK OUR TEAM ENOUGH FOR THE HARD WORK THEY HAVE DONE AND FOR THIS CLINICAL TRIAL. WE ALSO PRESENTED INDIVIDUAL CASES OF IMPROVEMENT FOR EVERY PATIENT TO THE FDA AND I WANT TO SHOW AN EXAMPLE HERE OF THE PATIENT WITH A NECK PLEXIFORM NEUROFIBROMA WITH A TRACHEOTOMY DUE TO AIRWAY BLOCKAGE. AFTER A YEAR THE TUMOR SHRANK ENOUGH SHE COULD BE DECANULATED AND THAT'S A CLEAR SUCCESS FOR THIS INDIVIDUAL PATIENT. I'LL SHOW YOU ANOTHER PATIENT WHEN WE DIDN'T HAVE AN EFFECTIVE MEDICINE. TO SHOW THIS PATIENT HERE. I'VE KNOWN HIM MANY YEARS SINCE HE WAS YEARS OLD AND PARTICIPATED IN SIX PRIOR TREATMENTS BEFORE WE START SELUMETINIB AND THE PATIENT RECOVERED CARDIAC FUNCTION AND WE STARTED SELUMETINIB AND HE CONTINUES WITH A STABLE TUMOR. THESE ARE THE PATIENTS WE HAVE TO THANK. WITHOUT THEM WE WOULD NOT HAVE LEARNED WHAT WE KNOW TODAY AND AN IMPORTANT LESSON IS WE NEED CONTINUED SELUMETINIB EXPOSURE FOR RESPONSES. AND WE USED THE NATURAL HISTORY TODAY FOR THIS AND IN BLUE YOU SEE PATIENTS ENROLLED IN THE NATURAL HISTORY AND IN RED PATIENTS ENROLLED IN THE TRIAL. YOU CAN SEE THERE'S A CLEAR DIFFERENCE IN THE NATURAL HISTORY BY THE ADMINISTRATION OF SELUMETINIB. AND 84% OF PATIENT FREE OF PROGRESSION AND 15% OF PATIENTS ON THE NATURAL HISTORY ARM. AND HERE YOU SEE THE COMPARISON TO THE PRIOR CLINICAL TRIALS. IT'S CERTAINLY BE AN ADVANCE. IT TOOK 30 YEARS THE IDENTIFICATION OF THE NF1 GENE BY OTHERS LINKING IT HAVING AN FDA APPROVED AGENT. SINCE 2020 WHEN SELUMETINIB WAS APPROVED IT WAS APPROVED IN OTHER COUNTRIES AND THEY HAVE WORKED HARD TO GET THE DATA TO THE DIFFERENT REGULATORY AGENCIES IN COLLABORATION WITH ASTRAZENECA. IT'S REALLY A MARATHON AND NOT A SPRINT AND I'LL TALK LATER HOW WE HOPE TO ACCESS RAIL THIS PROCESS. I WANT TO ALSO QUICKLY MENTION WE HAVE AN ADULT STUDY OF SELUMETINIB WITH THE SUCCESS IN CHILDREN AND THIS TRIAL IS NEARLY COMPLETED ENROLLMENT AND WE HAVE OBSERVED PARTIAL RESPONSE RATES SIMILAR TO THE CHILDREN IMPROVEMENT IN PAIN INTENSITY AND PAIN INTERFERENCE AND PROUD TO SAY THE INTERVENTION RADIOLOGY DEPARTMENT HAS BEEN FANTASTIC IN OBTAINING SERIAL BIOPSIES FROM THE PATIENTS NEVER SHOWN BEFORE AND HAVE SHOWN TARGET ENGAGEMENT WITH ADDITIONAL ANALYSES. ENROLLMENT IS NEARLY COMPLETE AND I WILL TALK MORE WHERE WE'RE TAKING TO PLEXI FORM NEUROFIBROMA'S LATER BUT I MENTIONED EARLIER WE WERE ABLE TO IDENTIFY LESIONS THAT WE CALL DISTINCT NODULE LESIONS. THE ABILITY TO DO WHOLE BODY AT THE MRI AT THE NIH CENTER WITHOUT CHARGING ANYONE HAS BEEN A MAJOR ADVANCE. ON THE LEFT YOU SEE A PATIENT WITH A TYPICAL LARGE PLEXIFORM NEUROFIBROMA AND ANOTHER PATIENT BUT WITH THREE DISTINCT NODULE LESIONS. AFTER WE IDENTIFIED THEM WE SAW THEM IN A NUMBER OF PATIENTS AND OUTSIDE OF PLEXIFORM NEUROFIBROMAS. WHEN WE LOOKED AT PET SCANNING WE SAW THESE TUMORS WERE IN CONTRAST TO THE SURROUNDING PLEXIFORM NEUROFIBROMA AND THEY WELL DEVELOPED AND DEVELOPED OVER TIME. THIS WAS A 15-YEAR-OLD AND HER MOTHER BECAUSE SHE SAID YOU ARE THE EXPERTS AND A STUDY WITH A FIBROMA WITH A DISTINCT NODULE AND AT THAT TIME THE BIOPSY SHOWED A NEUROFIBROMA AND THE LESION PERSISTS BUT DIDN'T GROW IN VOLUME AND WHEN IT HAD A PET SCAN OF 10.8 WE DID ANOTHER BYPASS AND IT WAS AN ATYPICAL NEUROFIBROMA. THEY SAID DON'T WORRY BECAUSE THESE DON'T METASTASIZE AND THAT IS VERY TRUE HOWEVER, AFTER WE FOLLOWED THE PATIENT FOR SOME TIME WITHIN SIX MONTHS THIS TUMOR DID NOT METASTASIZE BUT TRANSFORMED TO A HIGHLY AGGRESSIVE NPNST AND HAD SURGERY AND DIED IN QUITE A BIT OF INTOLERABLE PAIN AND MANY TIMES I WONDERED IF I WOULD HAVE KNOWN THIS WOULD HAVE HAPPENED WOULD WE HAVE EMBARKED IN THIS PROCEDURE THOUGH IT WAS IN A DIFFICULT PLACE. IT'S A PATIENT IL WILL NEVER FORGET. TAKING FORWARD WE HAVE A PATIENT WITH A SIMILAR SITUATION AND KNEW WE HAD TO STUDY THIS MORE. THE NCI AND A FOUNDATION WANTS US TO HAVE A STATE OF THE SCIENCE MEETING TO LOOK AT HOW TO MAKE PROGRESS IN NF1 IN TUMORS AND WE IDENTIFIED THESE PATIENTS WHO DEVELOP THESE NODULE LESIONS AS YOU CAN SEE ON A PANEL OVER TIME, MANY TIMES HAVE CDK AND 2A LOSS AND A CHARACTERISTIC OF THESE FIBROMAS AND WHEN WE LOOKED AT THE GROWTH CHARACTERISTICS OF DOMINANT FIBROMAS THAT DO NOT GROW IN ADULTS OR VERY LITTLE THE IT DISTINCT NODULAR LESIONS AND WE HAVE IDENTIFIED A LESION THAT IS A NEOPLASM OF UNCERTAIN BIOLOGIC POTENTIAL AS TUMOR THAT MAY BE AT GREATER RISK FOR MALIGNANT TRANSFORMATION AND HAVING THE BO PATHOLOGIST HERE AT NCI WAS AMAZING AND WE IDENTIFIED THE NEED TO CHARACTERIZE THE LESIONS AND ANDS AND WE STUDIED THE PATIENTS OUT OF BELGIUM AND ENGLAND AND AT THE NCI WITH ATYPICAL NEURO FIB FIBROMA AND THERE WERE 63 PATIENTS WITH TYPICAL NEUROFIBROMAS AND THE MEDIAN AGE OF DIAGNOSIS WAS 27 YEARS. PAIN WAS THE MOST FREQUENT PRESENTING FEATURE. HOWEVER, 13 ATYPICAL NEURO NEUROFIBROMAS AN 17% HAD NO SIGNS OF SYMPTOMS AND 21 OF 63 PATIENTS HAVE A HISTORY OF AN MPNST AFTER THE DEVELOPMENT OF A TYPICAL FIBROMA. THE PROPORTION OF THE DISEASE WITH MANIFESTATIONS THE ATYPICALS OR THE MPNST AND THE MEDIAN WAS 51 YEARS. ALLOWED US TO DETERMINE THEY DO NOT DEVELOP AS PREVIOUSLY THOUGHT BUT LIKELY MANY DEVELOP THROUGH THE STAGE OF AN ATYPICAL NEUROFIBROMA CHARACTERIZED BY CDK AND ADDITIONAL MUTATIONS WIN DEVELOPMENT OF AN MPNST AND WE LOOKED AT STRATEGIES TO PREVENT AN MPNST AND AN IMPORTANT TREATMENT MODALITY WAS RESECTION OF FIBROMAS AND A NEW SURGEON AT NINDS HAS BEEN OUR KEY COLLABORATOR AND CONDUCTED SURGERIES IN MORE THAN 40 PATIENTS AT THE NIH AT THIS POINT IN TIME WHICH HAVE BEEN SAFE AND FEASIBLE AND RARE REOCCURRENCE RATE UNLIKE AGGRESSIVE NMPNST -- MPNST AND THEY CAN DO IT WITHOUT LACK OF DEVELOPMENT OF MOBILITY BECAUSE A NODULE THAT ENLARGED AND REMOVING THEM DOESN'T INJURE AND MOST THE PATIENTS HAVE FUNCTION SIMILAR TO PRESURGERY. WE TALKED ABOUT IMAGING AND HOW WE DETECT THE TUMORS AND A TENURE TRACK INVESTIGATOR IN THE PEDIATRIC ONCOLOGY BRANCH LOOKED AT THIS BY SAYING CAN WE USE BLOOD SAMPLES TO DETECT SOMETHING THAT WILL TELL US THAT A TUMOR HAS BECOME MALIGNANT. THEY'VE DEVELOPED A NICE ASSAY FOR DETECTION OF MPNST AND ALL THE TUMOR SAMPLES UNDER GO GENOMIC DISSECTION AND MANY UNDER GO SINGLE CELL SEQUENCING TO UNDERSTAND THE MALIGNANT TRANSFORMATION BETTER. WITH US CHARACTERIZING A TYPICAL NEUROFIBROMAS WE TARGETED CLINICAL TRIALS AND DR. GROSS IS LEADING A PHASE 1 TRIAL OF A RATIONAL TREATMENT FOR PATIENTS THAT HAVE CDK LOSS. THE TRIAL HAS THE PRIMARY OBJECTIVE TO LOOK AT TUMOR SHRINKAGE BUT HAVE CORRELATIVE STUDIES TO INFORM US MORE ABOUT THE TUMORS. FINALLY, OVER THE PAST TWO YEARS, TWO NEW MOUSE MODELS HAVE BEEN DESCRIBED TO TRANSCRIBE FROM THE TUMORS AND WE CAN EMBARK IN COLLABORATION WITH OTHER CLINICAL TRIALS. THIS SHOWS THE NICE WORK THAT WAS A COLLABORATIVE EFFORT BETWEEN THE NCI AND WASHINGTON UNIVERSITY WHERE THEY TOOK HEALTHY VOLUNTEER SAMPLES AND MPNTS SAMPLES AND PERFORMED ULTRA LOW WHOLE GENOME SEQUENCING AND THEN USED THE FRAGMENT LENGTHS AND COPY NUMBER OF VARIATIONS TO DISTINGUISH TUMOR FROM NON-TUMOR AND PLASMA CELL FREE DNA WAS ABLE TO DISTINGUISH THE DIFFERENCE WITH AN ACCURACY OF 8 6% AND CORRELATED WITH TUMOR SIZE ON IMAGING. THIS MAY BE SOMETHING WE CAN USE IN FUTURE CLINICAL TRIALS TO PREDICT RESPONSE POTENTIALLY EARLIER THAN WHAT WE CAN DO WITH IMAGING STUDIES AND TO LOOK TO THE DEVELOPMENT OF MAG MALIGNANT TRANSFORMATION. THIS IS SOMETHING THAT WILL BE APPLICABLE TO OTHER TUMOR SYNDROMES AS WELL. I'M SHOWING YOU ON THE NEXT SLIDE EXCITING DATA OF HUMAN NF1 TUMORS. WHAT YOU SEE HERE SINGLE CELL SEQUENCING WHERE EACH DOT REPRESENTS AN INDIVIDUAL CELL AND THERE WERE 600,000 INDIVIDUAL CELLS REPRESENTED IN THE ANALYSIS. THIS IS FOR TUMORS AT DIFFERENT STAGES. DOWN YOU SEE THE SCHWAN'S CELLS AND HIGHER UP THE TUMORS THAT HAVE BECOME AGGRESSIVE MALIGNANT TUMORS. IN THIS WORK COLLEAGUES ARE ABLE TO CATALOG THE CELLULAR HETEROGENEITY PRESENT AND HAVING A DETAILED TRANSCRIPTOMIC MAP WE HOPE OFFER THE COURSE OF TIME WILL HELP UNDERSTAND THE CELL POPULATIONS AND BE A STRATEGY TO DEVELOP BETTER TREATMENTS FOR THE TUMORS. I WANT TO THANK THOSE WHO HAVE DIDN'T THE WORK. I WANT TO THANK THOSE WHO PROVIDED THEIR EXPERTISE AND EVERY PATIENT ENROLLED IN HER OMICS PROTOCOL AND I WANT TO THANK MICKY WHO DID MULTIPLE TRIPS TO THE O.R. TO GET THE TUMORS IN THE FASHION IT'S NEEDED. IT'S TEAM WORK TO GET TO THIS. I WANT TO PROVIDE ANOTHER PATIENT PICTURE ANY 11-YEAR-OLD FEMALE WITH NF1 AND WHOLE GENE DELETION. SHE DEVELOPED AN PMPST AND YOU SEE THE PRIMARY TUMOR AND THEN FOR THE METASTATIC LESION AND -- MPNST AND WE CAN LOOK AT THE LYMPHOCYTES TO PROVIDE MORE DETAIL AND THE BIOLOGY OF THE TUMORS. WE TALKED ABOUT THE NATURAL HISTORY STUDY AND WHEN TO STOP THE NATURAL HISTORY STUDY AND I'M HERE TO SAY WE'LL BE CLOSING OUR NATURAL HISTORY STUDY BUT ONLY TO BE OPENING A NEW NATURAL HISTORY STUDY THAT WILL HAVE A DEDICATED FOCUS ON STUDYING PATIENTS THAT HAVE INCREASED RISK FOR MPNST. OUR PRIMARY GOAL IS TO CHARACTERIZE THE GOAL OF ATYPICAL AND MALIGNANT REASONS WE CAN IDENTIFY USING AN ALGORITHM WE HAVE WORKED ON FOR SOME TIME. PATIENTS WITH NF1 AND ONE OF THE RISK FACTORS IDENTIFIED HERE WILL BE ELIGIBLE TO UNDER GO CLINICAL INVESTIGATION AND DIFFUSION WEIGHTED IMAGING AND PET WITH MRI AS CONTRAST AS INDICATED AND WE'LL FOLLOW THE PATIENTS FOR SIGHT SOW KINES AND OTHER -- CYTOKINES AND OTHER BIOMARKERS AND LOOKING AT RISK FACTORS AND WILL DETERMINE THE MANAGEMENT USING OUR ALGORITHM WITH BIOPSY OR RECEPTION. THIS IS A HUGE COLLABORATIVE EFFORT. I WANT TO THANK THOSE WHO PROVIDED STATISTICAL GUIDANCE FOR ALL OF OUR NF1 AND MANY OF OUR SOLID TUMOR TRIALS. WITH THAT THANK YOU VERY MUCH FOR BEING THERE FOR US. I'D LIKE TO QUICKLY HIGHLIGHT AN IMPORTANT ASPECT OF OUR WORK, INTRAMURAL, EXTRAMURAL COLLABORATION AND WHERE THEY FURTHER ENHANCE HOW THE NIH CLINICAL CENTER IS AT THE HEART OF THIS. I HAVE NO MOUSE MODELS AND FOR PLEXIFORM NEUROFIBROMA AND THE LAB IN CINCINNATI AND IN INDIANA DEVELOP PRE-CLINICAL AND TRANSGENIC MOUSE MODELS OF NF1 AND EXCITINGLY, THEY FIRST DEMONSTRATED THE SELL-- SELUMETINIB WORKS AND IT WORKS IN THE MOUSE AND PEOPLE. THIS IS A VALIDATED MOUSE MODEL AND ALL WILL GO THROUGH ONE OF THOSE MOUSE MODELS GOING FURTHER. AND AND THE KINASE INHIBITOR SHRINKS TUMORS. THE NF1 CLINICAL TRIAL CONSORTIUM DEPARTMENT OF DEFENSE FUNDED CONDUCTED A CLINICAL TRIAL OF CABODANTINIB. BECAUSE IT CAN CAUSE A NUMBER OF TOXICITIES THEY LIMITED IT TO PATIENTS 16 YEARS AND OLDER AND THE RESPONSE RATE WAS 42%. IT SHOWED THE PRE-CLINICAL MODELS CAN PREDICT FOR RESPONSE. AND THE CONSORTIUM HAS BECOME VERY IMPORTANT TO CONDUCTING CLINICAL TRIALS AT MULTIPLE SITES. THIS STUDY I'M PRESENTING YOU HERE IS VERY IMPORTANT EFFORT, I BELIEVE. IT WILL BE LED BY DR. ANDREA GROSS AND SELUMETINIB SHRINK TUMORS BUT CAN IT PREVENT THE DEVELOPMENT OF MORBIDITY? IMAGINE THIS YOUNG KID HERE IF WE CAN TREAT HER AT 11 MONTHS OR 17 MONTHS OPPOSED TO 3 YEARS WHEN SHE HAS A DISFIGURING TUMOR. THIS WILL BE THE QUESTION DR. GROSS WILL ADDRESS AND GLAD WE HAVE COLLABORATION BECAUSE WE WOULDN'T BE ABLE TO AT THE NIH CENTER AND ONE QUESTION IS ONCE WE IDENTIFY ASYMPTOMATIC PLEXIFORM NEUROFIBROMAS IN HIGH RISK LOCATIONS AND TREAT AND OBSERVE WILL WE SHOW WE PREVENT THE DEVELOPMENT OF MORBIDITY AND IN PATIENTS WHO RESPOND TO MEK INHIBITION, CAN WE SWITCH THE PATIENTS TO AN INTERMITTENT DOSING SCHEDULE WHICH WILL HOPEFULLY HAVE LESS TOXICITY AND SUSTAIN ACTIVITY. DR. GROSS WAS AWARDED A TRIAL AND AS TRA -- ASTRAZENECA IS PROVIDING FUNDS FOR THE MRIs AND THE LAST IS SPEARHEAD ED BY OTHERS AND HAS THREE PRIMARY PROJECTS. ONE IS NF1 PLEXIFORM NEUROFIBROMAS AND A THIRD ON LEUKEMIA THAT OCCURS MORE FREQUENTLY IN COLLABORATION WITH THE SPORE THEY HAVE BLOCKED PROGENITORS AND DO CORRELATES FOR STUDIES AND EVALUATE PRE-CLINICAL AGENTS FOR CLINICAL TRIALS. ONE SOON TO BE STARTING AND CURIOUS WILL BE A PHASE II TRIAL COMBINI COMBINING SELUMETINIB AND OTHERS AND WE ARE LOOKING AT THE RESEARCH AND COLLABORATION AND THERE'S CLINICAL TRIALS WITH US COLLABORATING FOR A NUMBER OF YEARS AND I AM THANK FOR DENISE REINKE'S SUPPORT AND OTHER CLINICAL TRIALS THAT DR. KIM AND I CONDUCTED UNFORTUNATELY WE HAVE NOT SEEN PARTIAL RESPONSES AND THE MEDIAN SURVIVAL RATE HAS TYPICALLY BEEN AROUND TWO MONTHS. IT'S VERY SOBERING AND NEED TO DO BETTER FOR THESE TUMORS. WE ARE COUNTURRENTLY CONDUCTING A TRIAL WHERE WE SAW TUMOR SHRINKAGE IN THE PATIENTS WITH THE PARTICIPATING IN THE TRIAL OF THE NIH CLINICAL CENTER AND USING FDG PET AS A PHARMACO DYNAMIC READOUT AND WE'RE PROCEEDING TO THE SECOND STAGE WHICH MEANS A MINIMUM AMOUNT OF ACTIVITY HAS BEEN DEAN -- SEEN AND THERE'S A TRIAL THAT DEMONSTRATES SUBSTANTIAL TUMOR SHRINKAGE OF AN INHIBITER AND CHECKPOINT INHIBITOR AND I'M VERY MUCH HOPING THIS WILL TRANSLATE IN MORE CLINICAL ACTIVITY THAN WE HAVE SEEN TO DATE. WE HAVE BEEN LIVING WITH VIRTUAL MEETINGS AND WANT TO HIGHLIGHT HOW IMPORTANT IN PERSON MEETINGS ARE AND HOW MUCH THE NF1 COMMUNITY HAS GROWN GOING FROM THE FIRST INTERNATIONAL CONSORTIUM FOR THE MOLECULAR BIOLOGY IN 2000 IN ASPEN, COLORADO TO THE LAST NON-VIRTUAL MEETING IN SAN FRANCISCO AND I CAN ATTEST TO HOW MUCH PERSONAL INTERACTIONS HELP US ADVANCE SCIENCE AND BEING IN BEAUTIFUL SETTINGS WHERE WE CAN THINK ABOUT THINGS DIFFERENTLY. IT TOOK SO LONG TO MAKE PROGRESS IN NF1 I'M THINKING HOW TO MAKE PROGRESS FASTER. THE LAST TWO OR THREE SLIDES I WANT TO MENTION TWO EFFORTS I'M EXCITED ABOUT. THE FDA RECENTLY PROVIDED GUIDANCE IN NATURAL HISTORY GUIDANCE AND THE FIRST EFFORT IS ONE THAT WILL FOCUS ON MAKING PROGRESS IN CHILDREN THAT HAVE TUMORS THAT HAVE EITHER RAS MUTATIONS OR PATHWAY ALTERATIONS OR IN PATIENTS THAT HAVE NF1 WHERE THERE'S A GERM LINE MUTATION THAT RESULTS IN PATHWAY ACTIVATION. THE FACT WE'VE BEEN ABLE TO TREAT PATIENTS WITH NF1 WITH SUCCESS LED TO THIS DEVELOPMENT OF THE EFFORT WHICH AS A PRE-CLINICAL COMPONENT THE NATURAL HISTORY STUDY THAT IS OPEN NOW AND WE PLAN TO BRING OUR FIRST PATIENTS TO THE NIH CLINICAL CENTER IN A PUBLIC HEALTH GENOMICS APPROACH AND IT'S A WONDERFUL COLLABORATION WITH EXTRAMURAL ADVOCACY AND INTRAMURAL CCR AND THE RAS INITIATIVE. I'M SHOWING A LOT OF MORE ABOUT THIS SOON. AND I WANT TO BRIEFLY MENTION TUMOR NETWORK WITH A NATURAL HISTORY STUDY TO STUDY CHILDREN, TEENS AND YOUNG ADULTS WITH RARE SOLID TUMORS. THE NATURAL HISTORY PROTOCOL IS OPEN FOR ENROLLMENT. THERE WAS A HUGE EFFORT BUT WE HAVE A NICE PIPELINE TO COMPREHENSIVELY EVALUATE THE PATIENTS TO PROVIDE GUIDANCE TO THE PATIENTS FOR TREATMENT AND TO LEARN ABOUT THE TUMORS. VERY IMPORTANTLY, ALSO WE CAN ENROLL PATIENTS REMOTELY DURING THE COVID PANDEMIC WHICH HAS MADE IT FEASIBLE FOR PATIENTS TO LEARN MORE ABOUT THE TUMORS THOUGH THEY COULD NOT COME TO THE NIH CLINICAL CENTER. ADVOCACY PARTNERSHIP HAS BEEN HUGELY IMPORTANT AND THIS SHOWS THE NUMBER OF PATIENTS THAT HAVE BEEN ENROLLED SINCE THE START IN 2019. IT'S QUITE IMPRESSIVE AND IT'S REALLY FOR MANY DIFFERENT STATES IN THE UNITED STATES AND COUNTRIES AROUND THE WORLD. I'M HIGHLIGHTING TWO TUMORS. I HAVE LEARNED IT IS TRUE WE NEED CHAMPIONS FOR TUMORS TO MAKE PROGRESS. SOMEBODY HAS TO SAY THIS IS MY TUMOR AND WHAT I FOCUS ON AND SOME ARE FOCUSSING ON A CHORDOMA AND ESTABLISHED A SINGLE CELL SEQUENCING AND DEVELOPMENT OF CLINICAL TRIALS AND OTHERS HAVE TAKEN ON CARDOMA. WE HAVE ONLY 30 PATIENTS WITH PEDIATRIC CHORDOMA AND IN ADVOCATING WE HAD OUR FIRST PEDIATRIC CHORDOMA CLINIC AND THEY'RE LEADING EXCITING CLINICAL TRIAL WITH TWO IMMUNE CHECKPOINT INHIBITERS FOR THE PATIENTS. I'M HOPING HAVING OUR APPROACHES WITH THE NATURAL HISTORY STUDY OF RARE SOLID TUMORS OUR PROGRESS WILL GO MORE QUICKLY. I WANT TO THANK FIRST AND FOREMOST OUR PATIENTS AND FAMILIES. I HOPE I HAVE SHOWN YOU HOW MUCH THEY GO WITH US AND PARTICIPATE AND ARE WILLING TO GO THROUGH CLINICAL TRIALS. I WANT TO THANK THE NIH, NIH CLINICAL CENTER AND NCI. THIS IS A FANTASTIC FACILITY TO CONDUCT RESEARCH. OUR COLLABORATORS AND THE FUNDING AGENCIES AND INDUSTRY PARTNERS AND OUR NF1 TEAM FOR THE HUGE AMOUNT OF WORK THAT WENT INTO GETTING SELUMETINIB APPROVED AND ALL THE COORDINATORS AND SOCIAL WORKERS AND POST-BACS AND PSYCHOLOGISTS TO GET THIS APPROVED. IT'S A TEAM EFFORT. THANK YOU SO MUCH. >> DR. WIDEMANN THANK YOU VERY MUCH FOR THE PRESENTATION. WE HAVE A FEW MINUTES AND I NEED TO REMIND THE AUDIENCE THEY CAN SUBMIT QUESTIONS STILL. WE HAVE A FEW MINUTES TO GO. AND YOU CAN SUBMIT THE QUESTIONS. I'M ALSO SUPPOSED TO REMIND PEOPLE THAT THE CME CODE FOR THE PRESENTATION IS 37924 IF YOU TEXT THAT TO JOHNS HOPKINS AND MAKE SURE YOU GET CREDIT. YOU MENTIONED NF2 AN NICE MEETING IN ASPEN AND I DON'T THINK IT'S AS COMMON AS NF1 BUT ARE THE THINGS YOU LEARNED IN NF1 NOT APPLICABLE? IT'S REALLY GOOD YOU MENTION THIS AND NF2 IS LESS COMMON. ONE IN 30,000 PEOPLE. THERE'S A HUGE UNMET NEED AND A NEUROSURGEON HAS A NATURAL HISTORY STUDY FOR THE TUMORS. THERE IS ACTIVITY OF TREATMENT AND THEY STUDY THE TUMORS AND I'M INTERESTED IN OPENING A CLINICAL TRIAL WITH THE MULTI-TARGETED KINASE INHIBITOR OPEN IN THE CLINICAL TRIAL CONSORTIUM. I'M A LITTLE BIT STRETCHED RIGHT NOW BECAUSE WE WOULD NEED MORE RESEARCH NURSE SUPPORT TO DO THIS BUT IT IS A VERY MUCH UNMET NEED AND I'M GRATEFUL THEY'RE STUDYING THE TUMORS HERE AND I'M HOPEFUL WE CAN DEVELOP CLINICAL TRIALS HERE FOR THE DEVASTATING TUMORS AS WELL. >> WHAT WE HAVE FROM A MEMBER OF THE AUDIENCE IS SINCE THE TUMORS ARE OFTEN STARTING EARLY IN LIFE, IS THERE A DEMONSTRABLE IMPACT OF HORMONAL CHANGES ASSOCIATED WITH PUBERTY ON THE RATE OF TUMOR GROWTH PROGRESSION OR IS THEY FACTOR AT ALL? >> PATIENTS ASKED US THIS ISSAL TE -- THIS ALL THE TIME AND WE'RE CONFIDENT AND WE HAVE ANECDOTAL DATA FIBROMAS CAN GROW RAPIDLY DURING PREGNANCY BUT FOR PLEXIFORM NEUROFIBROMAS WE HAVE NOT SEEN THAT. >> IN THE 30 YEARS YOU'VE SPENT IN THE FIELD WHAT ARE THE MOST IMPORTANT LESSONS THAT ARE APPLICABLE OT STUDY OF CHILDHOOD MALIGNANCIES. THE THING THAT SURPRISED YOU THE MOST OR ANY NEW INVESTIGATOR TO THE FIELD AND YOU DON'T HAVE TO GO THROUGH THIS TO LEARN X, Y OR Z BECAUSE I'LL TELL YOU NOW AFTER 30 YEARS OF EXPERIENCE. >> I THINK ONE OF THE LESSONS IS TO LOOK MORE THAN ASSUME. I HAD A NUMBER OF ASSUMPTIONS THAT ARE NOW WRONG. IF WE PAID MORE ATTENTION TO THE PATIENT AND LISTEN AND OBSERVE THE PATIENT AND TRUTHFULLY HAVING LESS ASSUMPTION AND BEING LESS BIASSED IS GOOD ADVICE. AND FINALLY, I THINK TAKING A RISK. I'M A LITTLE BIT AN INCREMENTALIST I GO STEP BY STEP BUT IF YOU TAKE A RISK, PATIENTS ARE WILLING TO TAKE A RISK AND A PHASE I PATIENT WOULD TELL ME I WANT TO SEE THE TWO DRUGS COMBINED AND I TOLD THEM WE CAN'T DO THIS BECAUSE WE HAVE TO FIRST LEARN IT'S SAFE AND THINKING MORE FROM THE PERSPECTIVE, WHAT DOES THE PATIENT WANT AND CAN WE MAKE IT HAPPEN AND NOT NECESSARILY GO BY THE RULES WE HAVE ESTABLISHED. THAT MAY BE ANOTHER ADVICE. >> DR. WIDEMANN, I WANT TO THANK YOU AGAIN FOR YOUR WONDERFUL TALK AS THE CEO OF THE CLINICAL CENTER AND TELL YOU HOW PROUD WE ARE TO HAVE SPONSORED THIS PRESENTATION AND A YEAR OR SO AGO I ALSO WATCHED YOU THROUGH THE REMEMBRANCE CEREMONY WHERE WE ACKNOWLEDGED THE CONTRIBUTIONS OF OUR PEDIATRIC PATIENTS WHO HAVE DIED IN A FASHION THAT ENABLED US TO LEARN MORE ABOUT DISEASE AND IT'S NICE TO SEE YOUR REACTIONS THEN AND HOW MUCH YOU CARED ABOUT THE PATIENTS WHO WERE INVOLVED IN THIS WORK AND IT'S VERY NICE TO SEE THE KIND OF RESULTS THAT THAT WORK HAS PRODUCED SO CONGRATULATIONS AS THE ASTUTE CLINICIAN FOR 2021 AND THANK YOU TO THE AUDIENCE FOR DIALING IN AND EVERYBODY HAVE A GREAT WEDNESDAY AFTERNOON. >> THANK YOU SO MUCH.