>> 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.