WELCOME, EVERYBODY, TO THE ANITA
ROBERTS LECTURE, SPONSORED BY
THE WOMEN'S SCIENTIST ADVISER
COMMITTEE AT THE NIH.
I'M DORIS WU, INVESTIGATOR, THE
MODERATOR.
THIS EVENT IS TO HONOR DR. ANITA
ROBERTS, BY CELEBRATING
DISTINGUISHED WOMEN SCIENTISTS
AT THE NIH.
AND THIS YEAR WE ARE SHOWCASING
THE WORK OF DR. BRIGITTE
WIDEMANN FROM NCI.
I WANT TO POINT OUT THERE'S A
LIVE FEEDBACK BUTTON ON YOUR
SCREEN THAT IF YOU HAVE
QUESTIONS, ENTER THEM DURING THE
SEMINAR, THE QUESTIONS WILL BE
ADDRESSED AT THE END OF THE
SEMINAR.
NOW WITH THAT I WOULD LIKE TO
INVITE YOU TO MEET OUR NEWLY
ELECTED CHAIR, DR. MARY KEARNEY
FROM NCI, TO SAY A FEW WORDS
ABOUT THE WSA.
DR. KIERNEY?
>>THANK YOU, DR. WU.
SO, BEFORE WE BEGIN, I'D LIKE TO
JUST GIVE A LITTLE BIT OF
BACKGROUND ABOUT THE NIH WOMEN
SCIENTIST ADVISORS FOR WSA, THIS
MEETING WAS FORMED IN RESPONSE
TO TASK FORCE RECOMMENDATIONS IN
1993 THAT WOMEN WERE
UNDERREPRESENTED, THAT REMAINS
TRUE TODAY.
EACH INSTITUTE HAS ELECTED
REPRESENTATIVES, REGULARLY MEET
TO WORK TO A EQUAL STATUS,
IDENTIFY BARRIERS AND PROMOTE
WOMEN IN SCIENCE.
THIS HIGHLIGHTS THE LEGACY OF AN
OUTSTANDING SCIENTIST AND
AMAZING ACCOMPLISHMENTS.
A FEW WORDS ABOUT ANITA ROBERTS,
BORN IN PITTSBURGH, ATTENDED
OBER LAND COLLEGE, DOCTORATE
FROM UNIVERSITY OF WISCONSIN IN
1968 IN BIOCHEMISTRY.
AFTER POSTDOC AT HARVARD JOINED
NIH IN 1976, BECAME THE CHIEF OF
THE LABORATORY OF CELL
REGULATION AND CARCINOGENESIS IN
1995.
SHE IS WELL KNOWN FOR PIONEERING
WORK ON TRANSFORMING GROWTH
FACTOR BETA AND ITS ROLE IN
WOUND HEALING, CARCINOGENESIS,
AUTOIMMUNE DISEASE, PUBLISHED
WORK HAS BEEN INCLUDED AMONG THE
TOP 50 MOST CITED RESEARCH
PAPERS, THE THIRD MOST CITED
FEMALE SCIENTIST IN THE WORLD.
DR. ROBERTS WAS RECIPIENT OF THE
FAS EXCELLENCE AWARD FOR
DISTINGUISHED SCIENCE.
DR. ROBERTS WAS NOT ONLY A
HIGHLY ACCOMPLISHED SCIENTIST
BUT OUTSTANDING MENTOR,
PROVIDING A WONDERFUL EXAMPLE OF
HOW TO BALANCE FAMILY AND WORK
LIFE AND WAS UNFAILINGLY WARM,
CARING, ENTHUSIASTIC,
SUPPORTIVE.
I DIDN'T KNOW DR. ROBERTS
PERSONALLY BUT THOSE WHO DID
INDICATE SHE WAS NOT ONLY A
TREMENDOUS SCIENTIST BUT A
WONDERFUL HUMAN BEING WHO IS
DEEPLY MISSED.
AND IN THE END, I THINK THAT
SAYS IT ALL, THAT'S WHY WE HONOR
HER TODAY.
I THANK THE PEOPLE WHO HELPED
PUT THIS LECTURE TOGETHER, THE
INTRAMURAL PROGRAM SPECIALIST
WHO ORGANIZED WSA ACTIVITIES,
DR. DORIS WU, MODERATOR, AND
COORDINATED THIS LECTURE.
FELICE HARPER, JOY JACKSON FARAR
AND JONATHAN BENNETT.
PLEASE USE THE "LIVE FEEDBACK"
BUTTON BELOW THE SCREEN IN THE
VIDEOCAST DESCRIPTION BOX TO
ENTER QUESTIONS, CLICK ON THE
ASL ICON BELOW THE FEEDBACK
BUTTON TO VIEW SIGN LANGUAGE
INTERPRETER DURING THE LECTURE.
I'LL TURN IT OVER TO OUR REP,
DR. REBECCA VOGELBY, TO
INTRODUCE THIS YEAR'S SPEAKER.
>>GOOD MORNING.
I AM DELIGHTED TO INTRODUCE YOU
TO THE SPEAKER FOR THE 2022
ANITA B. ROBERTS LECTURE.
DR. WIDEMANN IS A SENIOR
INVESTIGATOR WITH NATIONAL
CANCER INSTITUTE, CHIEF OF THE
PEDIATRIC ONCOLOGY BRANCH.
CAN WE MUTE?
SHE IS A SENIOR INVESTIGATOR
WITHIN THE NATIONAL CANCER
INSTITUTE, CHIEF OF THE
PEDIATRIC ONCOLOGY BRANCH, HEAD
OF THE PHARMACOLOGY AND
EXPERIMENTAL THERAPEUTICS
SECTION, AND SPECIAL ADVISER TO
THE NATIONAL CANCER INSTITUTE'S
DIRECTOR FOR CHILDHOOD CANCER.
DR. WIDEMANN EARNED MEDICAL
DEGREE IN GERMANY, COMPLETED
PEDIATRIC RESIDENCY AT THE
UNIVERSITY CHILDREN'S HOSPITAL
IN COLOGNE, JOINED THE NATIONAL
CANCER INSTITUTE, ORIGINALLY AS
PEDIATRIC HEMATOLOGY AND
ONCOLOGY FELLOW, LATER AS
TENURE-TRACK INVESTIGATOR.
AFTER RECEIVING TENURE DR.
WIDEMANN BECAME THE CHIEF OF THE
PEDIATRIC ONCOLOGY BRANCH IN
2016.
IN THIS POSITION, SHE LEADS A
GROUP OF BASIC TRANSLATIONAL AND
CLINICAL RESEARCHERS WITH JOINT
VISION TO IMPROVE THE SURVIVAL
AND QUALITY OF LIFE OF CHILDREN
AND YOUNG ADULTS WITH REFRACTORY
OR HIGH RISK MALIGNANT TUMORS,
RESEARCH FOCUSED ON DRUG
DEVELOPMENT AND CLINICAL TRIALS
FOR CHILDREN WITH REFRACTORY
SOLID TUMORS OR GENETIC TUMOR
PREDISPOSITION SYNDROMES, IN
PARTICULAR NEUROFIB FIBROMATASI,
SELUMETINIB RESULTED IN APPROVAL
OF THERAPY FOR CHILDREN WITH
NF1, INOPERABLE SYMPTOMATIC
PLEXIFORM NEUROFIBROMA.
DR. WIDEMANN CO-DIRECTS CANCER
MOONSHOT SUPPORTED PROGRAM
CALLED MY PEDIATRIC AND ADULT
RARE TUMOR WORK, AIMS TO ADVANCE
THE KNOWLEDGE OF RARE TUMORS AND
DEVELOP THERAPIES FOR THEM.
DR. WIDEMANN IS A MEMBER OF THE
ASSOCIATION OF AMERICAN
PHYSICIANS, RECIPIENT OF THE
AMERICAN ASSOCIATION FOR CANCER
RESEARCHERS, JOSEPH BIRCHENALL
AWARD, HAS CONDUCTED SEVERAL
LARGE SCALE CLINICAL TRIALS.
HER SCIENTIFIC ACHIEVEMENTS GO
BEYOND THESE MEASURES.
LIKE DR. ROBERTS, DR. WIDEMANN'S
LEGACY EXTENDS TO HER
EXTRAORDINARY SKILLS IN
MENTORING THE NEXT GENERATION OF
CLINICIANS AND SCIENTISTS.
WE REACHED OUT TO SOME OF HER
CURRENT AND PAST MENTEES FOR
COMMENT, I WANT TO SHARE A FEW
WORDS PROVIDED.
BRIGITTE IS TRULY THE EPITOME OF
WHAT A MENTOR SHOULD BE, IT IS A
JOB SHE TAKES VERY SERIOUSLY.
SHE IS AN EXCEPTIONAL AND
ACCOMPLISHED CLINICIAN
RESEARCHER, WHAT MAKES HER
UNIQUE IS HER ABILITY TO LEAD BY
EXAMPLE.
SHE IS THE PERFECT COMBINATION
OF DIRECTION, HONESTY,
COMPASSION, THAT ALLOWS HER
TRAINEES TO WANT TO BECOME THE
BEST VERSION OF THEMSELVES.
SHE DOES NOT IMPART RULES BUT
PROVIDES GUIDANCE AND SUPPORT.
DESPITE HER SUCCESSES, SHE IS
EXTREMELY HUMBLE IN HER
INTERACTIONS WITH HER TRAINEES.
AND SHE'S A STRONG ADVOCATE AND
SUPPORTER OF FEMALE TRAINEES.
SHE SEEKS DIVERSITY IN TRAINEES
BY BACKGROUND AND OPINION, AND
IS ABLE TO CREATE SAFE
ENVIRONMENT WHERE TRAINEES ARE
ABLE TO SPEAK UP WITH THEIR
IDEAS AND CONCERNS.
SHE CONNECTS ON A PERSONAL
LEVEL, INDIVIDUALIZES MENTORSHIP
BASED ON NEEDS AND GOALS OF
EACH, ADAPTS STYLE ACCORDINGLY,
PROVIDING CLEAR SHORT- AND
LONG-TERM REALISTIC GOALS FOR
THEM, ENCOURAGES COLLABORATION,
ALWAYS MAKES SURE TO GIVE HER
TRAINEES CREDIT FOR THEIR WORK.
SHE PROVIDES THEM THE PLATFORM
TO PROGRESS TO THEIR OWN CAREERS
AND PROVIDES CAREER ADVICE WITH
HUMILITY DESPITE HER SUCCESSES.
AND FINALLY, WORKING WITH DR.
WIDEMANN HAS BEEN ONE OF THE
MOST MEANINGFUL EXPERIENCES OF
MY CAREER TO DATE, THROUGH HER
EXAMPLE I LEARN NOT ONLY HOW
CLINICAL RESEARCH TRULY SHOULD
WORK, BUT ALSO WHAT A DIFFERENCE
A STRONG AND SUPPORTIVE MENTOR
CAN MAKE IN ONE'S LIFE AND
CAREER.
THESE EXAMPLES HELP HIGHLIGHT
HOW DR. WIDEMANN EXEMPLIFIES
MANY OF THE SAME QUALITIES THAT
MADE DR. ANITA ROBERTS SUCH A
BELOVED SCIENTIST AND MENTOR.
IT IS A PLEASURE TO HONOR AND
WELCOME DR. BRIGITTE WIDEMANN
TODAY TO PRESENT THE 2022 ANITA
B. ROBERTS LECTURE ADVANCING THE
DEVELOPMENT OF EFFECTIVE
THERAPIES FOR CHILDREN AND
ADULTS WITH RARE TUMORS.
>>THANK YOU SO MUCH FOR THIS
TREMENDOUS HONOR.
I'M SPEECHLESS AND I LOOK VERY
MUCH FORWARD TO GIVING YOU A
LECTURE TODAY, HOPEFULLY WILL DO
DR. ANITA ROBERTS SOME JUSTICE.
I HOPE YOU CAN HEAR ME AND YOU
CAN SEE THE SCREEN.
THANK YOU, WSA.
IT'S REALLY AN EXTRAORDINARY
EXPERIENCE FOR ME.
I HAVE NO DISCLOSURES BUT WILL
DESCRIBE CLINICAL TRIALS WITH
INVESTIGATIONAL AGENTS.
AND I HOPE THROUGHOUT THE TALK
THAT YOU SEE THAT THE WORK OF
MANY IN THE PEDIATRIC ONCOLOGY
BRANCH THAT I'LL BE PRESENTING
TODAY REALLY ADDRESSES THE CCR
MISSION OF SOLVING IMPORTANT
CHALLENGING AND NEGLECTED
PROBLEMS IN CLINICAL RESEARCH.
READING ABOUT DR. ANITA ROBERTS,
WHO UNFORTUNATELY I NEVER MET,
ONE THING THAT'S STRUCK WITH ME
PARTICULARLY LAST NIGHT SHE SAID
RESEARCH TAKES A LONG, LONG
TIME.
I KNOW THE PUBLIC IS ALWAYS
LOOKING FOR A MAGIC BULLET, THEY
WANT TO SAY THIS DOES THAT, BUT
OUR OWN BIOLOGY IS INCREDIBLY
COMPLEX, SO THIS DOESN'T ALWAYS
DO THAT.
AS BASIC SCIENTISTS WE'RE ALL
DRIVEN BY OUR EXCITEMENT IN
FINDING ANSWERS, WE HOPE IT ENDS
UP AS SOMETHING THAT BECOMES
THERAPY.
BUT THAT DOESN'T HAPPEN UNLESS
YOU HAVE A BASIC UNDERSTANDING
OF THE PROCESS.
AND THAT'S WHAT MY WORK IS ALL
ABOUT.
AND THIS RESONATES WITH ME SO
MUCH, AS A CLINICAL RESEARCHER,
WE ALSO WANT TO GET TO THERAPIES
AND EFFECTIVE TREATMENTS BUT
I'VE LEARNED THERE'S NO WAY OF
CUTTING CORNERS.
AND THIS ALSO TAKES SUBSTANTIAL
TIME.
I WILL GIVE AN OVERVIEW TODAY
ABOUT PEDIATRIC CANCERS AND
WHERE WE STAND.
AND THEN AS REBECCA ALLUDE TO,
I TALK ABOUT THIS SERVING AS A
MODEL TO STUDY RARE DISEASES BY
TALKING ABOUT OUR RAS-OPATHY
THERAPIES, AND MYPART NETWORK,
AND THE VISIONARY LOOK AT THE
FUTURE WHERE WE HOPEFULLY BUILD
A NATIONAL STRATEGY TO ADVANCE
RARE TUMOR RESEARCH AND
UNDERSTAND THESE TUMORS AND
DEVELOP BETTER THERAPIES.
ONE THING I WILL HIGHLIGHT
THROUGH THE TALK, KEY
REQUIREMENTS FOR SUCCESSFUL RARE
TUMOR RESEARCH, PRESENCE OF A
BASIC RESEARCHER, INVESTED IN
HELPING US UNDERSTAND THE RARE
TUMOR, PRESENCE OF THE CLINICAL
CHAMPION, AND ALSO OF AN
ADVOCACY CHAMPION.
AND THEN IF YOU'RE LUCKY TO HAVE
A PEDIATRIC PARTNERSHIP SO YOU
CAN TREAT AND EVALUATE PATIENTS
ACROSS THE AGES, THAT REALLY
MAKES IT PERFECT.
SO, PEDIATRIC CANCERS ARE MUCH
LESS FREQUENT FOR AGES 0 TO 19,
THEY HAVE ABOUT 17,000 NEW
CANCER DIAGNOSES PER YEAR,
APPROXIMATELY 2 MILLION NEW
CANCER CASES IN THE UNITED
STATES.
ALL PEDIATRIC CANCERS ARE RARE
BUT I WILL FOCUS ON THE VERY
RARE CANCERS, DEFINED LATER.
DESPITE RARITY OF PEDIATRIC
CANCERS WE'VE MADE TREMENDOUS
PROGRESS OVER THE YEARS.
LOOKING BACK IN THE '50s AND
'70s TO CURRENT DAY, MORTALITY
RATE OF PEDIATRIC CANCERS HAS
SUBSTANTIALLY DECREASED, AND
WE'RE ACHIEVING CURES IN THE
MAJORITY OF PEDIATRIC CANCER
PATIENTS.
HOWEVER, AS THE PLOT ON THE
RIGHT SHOWS YOU, WHILE WE MADE
TREMENDOUS STRIDES IN ACUTE
LYMPHOPLASTIC LEUKEMIA, THERE
ARE SOME TUMORS WHERE PROGRESS
HAS BEEN MUCH LESS, STRIKING
EXAMPLE IS BRAINSTEM GLIOMA,
WITH NOT MUCH IMPROVEMENT IN
SURVIVAL.
HOW HAVE WE MADE PROGRESS IN
PEDIATRIC CANCERS, THERE ARE
MANY REASONS BUT I BELIEVE THE
MOST IMPORTANT IS THAT WE
COLLABORATE NATIONALLY AND
INTERNATIONALLY TO CONDUCT
CLINICAL TRIALS, CLINICAL TRIALS
AVAILABLE MOST PATIENTS WILL
INROLE, EXAMPLE SHOWN HERE FOR
THE ACUTE LYMPHOPLASTIC
LEUKEMIA, ST. JUDE TOTAL THERAPY
STUDIES.
YOU CAN SEE TREMENDOUS PROGRESS
MADE BY CONSECUTIVE CLINICAL
TRIALS THAT HAVE BEEN CONDUCTED
SO FOR MANY, MANY, PEDIATRIC
PATIENTS WE'RE ACHIEVING CURES
TO DATE.
I WANT TO HIGHLIGHT ONE EXAMPLE
OF SOLID TUMOR CLINICAL TRIALS
WHERE WE'VE SEEN TREMENDOUS
IMPROVEMENT IN A VERY DIFFICULT
HUMAN, HIGH RISK NEUROBLASTOMA,
VERY AGGRESSIVELY TREATED, I'M
SHOWING YOU HERE THE
KAPLAN-MEIER SURVIVAL PLOT OF A
RANDOMIZED CLINICAL TRIAL,
IMMUNOTHERAPY WITH ANTIBODY AND
INTERLEUKIN-2 WAS WE NEARED MANY
YEARS AGO, AND I KNOW ANITA
ROBERTS ALSO WORKED IN THE FIELD
OF RETINOID METABOLISM, SHOWS
PROGRESS FOR PATIENTS WITH
OVERALL POOR PROGNOSIS, A RECENT
STUDY DEMONSTRATED THAT EVEN TO
THIS DAY THE SURVIVAL BENEFIT IS
STILL THERE, BUT YOU CAN SEE
THAT WE'RE FAR FROM ACHIEVING
CURES FOR PATIENTS, FOR PATIENTS
WITH HIGH RISK NEUROBLASTOMA.
MY BRANCH FOCUSES ON TREATING A
VARIETY OF TUMORS, AND LIKE MANY
CLINICAL BRANCHES IN THE CCR, WE
HAVE AN EFFORT ON SOLID TUMORS,
BRAIN TUMORS, LEUKEMIAS, AND
THEN VERY RARE TUMORS.
I'M THRILLED THAT WE HAVE
RESEARCHERS THAT REALLY RANGE
FROM BASIC TO CLINICAL
RESEARCHERS AND HAVE THE SUPPORT
OF PSYCHOSOCIAL AND BEHAVIORAL
RESEARCH PROGRAM WHICH IS
OUTSTANDING, ADDRESSING RESEARCH
THAT IS HIGH RISK AND REQUIRES
LONG-TERM COMMITMENT.
I WILL START BY TELLING THE NF1
STORY, AND GIVE EXAMPLES TO
HOPEFULLY MAKE IT MORE
INTERESTING FOR THOSE WHO HEARD
THIS BEFORE.
NF1 IS A FAIRLY FREQUENT, MOST
FREQUENT SINGLE GENE DISORDER OF
THE NERVOUS SYSTEM, 3500 PEOPLE,
NEUROFIBROMA IN THE NF1 GENE
PRODUCTS FUNCTIONING A REGULATOR
AT GTPase, PRE-SENTING RAS
PATHWAY ACTIVATION BUT WHEN
MUTATED THE PATHWAY IS
ACTIVATED, PROMOTES TUMOR GROWTH
IN THE PATIENTS AND DEVELOPMENT
OF TUMORS WITH NF1.
ALSO RESIDES IN DISEASE
MANIFESTATION UNRELATED TO
TUMORS.
AS CLINICAL RESEARCHER AND
WORKING IN DEVELOPMENT, WHEN
MANY DRUGS WERE DEVELOPED, A
GOOD DISEASE TO FOCUS ON BECAUSE
THERE WERE NO EFFECTIVE
TREATMENTS.
OUR FOCUS WAS ON PLEXIFORM
NEUROFIBROMA, THE SECOND COLUMN,
DEVELOPED IN VERY YOUNG PATIENTS
WHILE HISTOLOGICALLY BENIGN WE
KNEW THEY CAN TRANSFORM TO
HIGHLY AGGRESSIVE VERY DIFFICULT
TO TREAT CANCERS, MALIGNANT
PERIPHERAL NERVE SHEATH TUMORS,
WE LEARNED THERE'S ANOTHER TUMOR
THAT LIKELY IS A STEP IN BETWEEN
PLEXIFORM AND NPNST, ATYPICAL
FIBROMA.
CDK CHARACTERIZES APOPTOTIC
TUMORS.
I START WITH A PATIENT EXAMPLE,
24-YEAR-OLD MALE WITH FAMILIAL
NF1, FROM LOUISIANA, DIAGNOSED,
A DELAY OF FOUR MONTHS WITH
NPNST OF RIGHT THIGH AND PELVIS,
HIS TREATMENT BACK HOME AS YOU
CAN SEE ON THE CT SCAN, THE
CORONAL ON THE LEFT,
UNFORTUNATELY THIS PATIENT
DEVELOPED PULMONARY METASTASES,
YOU CAN SEE THE LARGE PULMONARY
METASTASIS ON THE AXIAL CT SCAN.
AT THAT TIME, THE PATIENT WAS
REFERRED TO US AT THE NCI TO
ENROLL ON OUR CHEMOTHERAPY TRIAL
SARCO06.
OUR THORACIC SURGEON RESECTED,
PATIENT HAD NO RESPONSE TO
CHEMOTHERAPY, SUBSTANTIAL
COMPLICATIONS FROM THE
TREATMENT.
AFTER REMOVAL OF THE PULMONARY
DEVELOPED RECURRENCE THAT
PROGRESSED AS YOU CAN SEE, THE
PATIENT DIED.
HE DID TALK ABOUT WHAT HAPPENED
TO MY NEPHEWS WHERE ALSO HAVE
NF1, AND LOOKING AT THE MRI
SCANS ON THE UPPER RIGHT, THIS
PATIENT HAD SUBSTANTIAL
PLEXIFORM NEUROFIBROMA BURDEN
WITH SPINAL CORD COMPRESSION ON
THE TOP, WITH ABDOMINAL DISEASE
AND PELVIC DISEASE, AND TODAY WE
WOULD KNOW THIS IS A PATIENT
DEFINITELY AT RISK FOR
DEVELOPING MPNST, AND I WILL
COME BACK TO WHAT HAPPENED TO
ONE OF HIS NEPHEWS LATER.
OUR INITIAL FOCUS WAS TO DEVELOP
TREATMENTS FOR THE BENIGN TUMOR
CALLED PLEXIFORM NEUROFIBROMA.
AS YOU CAN SEE ON THE
PHOTOGRAPHS AND CORONAL MRI
DEMONSTRATING LARGE TUMOR IN THE
LEFT NECK AND ARM AND YOU CAN
SEE IT ON THE MRI, EVERYTHING
THAT IS BRIGHT OR WHITE IS
PLEXIFORM NEUROFIBROMA IN THE
NECK AND CHEST.
THIS IS ONE EXAMPLE HOW QUICKLY
TUMORS CAN PROGRESS, WHEN WE
STARTED THE WORK THERE WAS
REALLY NO EFFECTIVE MEDICAL
THERAPY AND BARELY ANY CLINICAL
TRIALS WERE CONDUCTED.
SO, I DEVELOPED A NATURAL
HISTORY STUDY OF NF1 TO
UNDERSTAND HOW THESE TUMORS GROW
AND CLINICAL TRIAL DESIGN, AND
FOR THIS NATURAL HISTORY STUDY
WE USED A THOUGHT CALLED
BIOMETRIC MRI ANALYSIS AS I SHOW
IN ONE PICTURE HERE, TO MEASURE
THE TUMORS.
A DEAR COLLEAGUE OF MINE TOLD ME
RECENTLY, WHEN YOU STARTED THIS
STUDY, I THOUGHT, WOW, THIS IS
REALLY BORING, AND I HAVE TO SAY
WHEN I STARTED THIS STUDY I
THOUGHT, HMM, I WOULD LIKE TO
CURE CANCER, AT LEAST TREAT
CANCER, AND FIND EFFECTIVE
TREATMENTS.
I'M GLAD I LISTEN TO MY MENTOR,
FRANK BALIS.
ONE KEY FINDING IS SHOWN HERE ON
THE GRAPH ON THE RIGHT SIDE
WHERE YOU SEE THE AGE OF THE
PATIENT AT THE INITIAL MRI, ON
THE Y-AXIS YOU SEE PERCENT
CHANGE IN TUMOR GROWTH PER YEAR,
YOU CAN CLEARLY SEE THE YOUNGER
KIDS HAVE THE MOST RAPIDLY
GROWING TUMORS WHICH MADE US
DETERMINED TO START DRUG
DEVELOPMENT IN THE YOUNG
PATIENTS WHO HOPEFULLY COULD
BENEFIT THE MOST.
WORK DONE BY THE TEAM ALSO
SHOWED THAT PLEXIFORM
NEUROFIBROMA WHEN THEY DEVELOP
MORBIDITY IS NOT REVERSIBLE AND
TUMORS TYPICALLY DON'T SHRINK
SUBSTANTIALLY OVER TIME
SPONTANEOUSLY.
AFTER CONDUCT OF A SERIES OF
NEGATIVE TRIALS, BY THIS I MEAN
TRIALS THAT NEITHER SHRINK
TUMORS NOR SLOW DOWN THE TUMOR
GROWTH, WE CONDUCTED A STUDY
WITH A MEK INHIBITOR RIGHT IN
THE RAS RAF PATHWAY, SPECIFIC
MEK INHIBITOR FOR CHILDREN WITH
INOPERABLE SYMPTOMATIC PLEXIFORM
NEUROFIBROMAS.
TO OUR GREAT SURPRISE, BECAUSE
THERE WERE NO PRE-CLINICAL DATA
AT THAT TIME, WE SAW A TUMOR
SHRINKAGE IN ALMOST ALL
PATIENTS.
BACK BARS ON THIS WATER FALL
PLOT GO DOWN, MAXIMUM WAS 50%,
THIS IS MODEST BUT SOMETHING WE
HAD SIMPLY NEVER SEEN BEFORE.
WE ALSO SAW CLINICAL IMPROVEMENT
AS YOU CAN READILY SEE IN THIS
PATIENT HERE, 10-YEAR-OLD, WITH
A VERY LARGE PELVIC PLEXIFORM
NEUROFIBROMA.
WE STOPPED GROWTH AND SHE HAD
LESS PAIN, IMPROVEMENT IN
APPEARANCE.
UNFORTUNATELY ON THIS EARLY
PHASE STUDY IT WAS A DOSE
FINDING STUDY, WE DID NOT
INCORPORATE PATIENT-REPORTED
OUTCOMES OR OTHER MEASURES OF
CLINICAL BENEFIT WHICH IS
REQUIRED FOR DRUG APPROVAL.
SO WE WENT ON TO DESIGN A
MULTI-SITE NCIC CLINICAL TRIAL,
SELUMETINIB, WITH GOAL TO
ACHIEVE REGISTRATION,
POTENTIALLY, EXTREMELY
CHALLENGING BECAUSE SHOWING
CLINICAL BENEFIT IN TUMORS THAT
OCCURRED ANYWHERE IN THE BODY IS
DIFFICULT.
HOWEVER, WE DID SUCCEED.
FIRST AS YOU CAN SEE ON THE
WATER FALL PLOT ON THE LEFT
LOWER PART OF THE SLIDE,
DEMONSTRATES AGAIN ALMOST ALL OF
THE TUMORS HAD SOME DECREASE IN
SIZE BY VOLUME MEASUREMENT, WE
COULD ALSO SHOW BY FUNCTIONAL
AND PATIENT-REPORTED OUTCOMES
THAT PATIENTS HAD IMPROVEMENT IN
PAIN, IMPROVEMENT IN
DISFIGUREMENT AS YOU CAN SEE ON
THE RIGHT, AND THEN BY
PATIENT-REPORTED OUTCOMES THERE
WAS SUBSTANTIAL IMPROVEMENT BOTH
PARENT REPORTED AND CHILD
REPORTED, AS RELATES TO SYMPTOMS
COMING FROM THE PLEXIFORM
NEUROFIBROMA.
A STUDY LOOKED AT HOW DOES THE
DRUG CHANGE THE NATURAL HISTORY
OF DECEIT.
AND THIS MADE ME HAPPY WE
CONDUCTED NATURAL HISTORY STUDY
WHERE YOU SEE IN RED PATIENTS
THAT WERE TREATED WITH
SELUMETINIB, THEY HAD A
DECREASE, MODEST, PLEXIFORM
NEUROFIBROMA, ON THE NATURAL
HISTORY STUDY NOT RECEIVING
SELUMETINIB.
HERE ON THE RIGHT YOU SEE
KAPLAN-MEIER PROGRESSION FREE
SURVIVAL, HOW THE CURVES
SEPARATE.
THIS DATA WAS TAKEN TO THE FDA
ALONG WITH CLINICAL TRIAL DATA,
AND THEN AFTER 30 YEARS AFTER
IDENTIFYING THE GENE AND 20
YEARS, I WOULD SAY, AFTER
INITIATING THE FIRST MEANINGFUL
CLINICAL TRIALS FOR NF1 RESULTED
IN FDA APPROVAL ARE SELUMETINIB
FOR CHILDREN WITH NF1, VERY LONG
TIME.
I'M GLAD TO SAY THAT SUBSEQUENT
DRUG APPROVALS AT LEAST FOR
SELUMETINIB WENT MUCH QUICKER
AND I'M PROUD OF THE TEAM.
YOU SEE SOME TEAM MEMBERS HERE
WHO WORKED REALLY HARD.
THE DATA FROM THIS ONE STUDY LED
TO APPROVAL IN MANY, MANY
COUNTRIES, AND THIS WITHIN A
VERY RAPID TIME STARTING IN
2020.
SO I THINK IT WAS VERY MUCH
WORTH THE EFFORT.
WE ALSO INITIATED A CLINICAL
TRIAL FOR ADULTS WITH PLEXIFORM
NEUROFIBROMAS, ONLY POSSIBLE
THROUGH COLLABORATION WITH THE
ADULT CLINIC, LET'S DO IT
TOGETHER, SO THEY SEE THE OLDER
PATIENTS AND WE SEE THE YOUNGER
PATIENTS.
THIS STUDY RECENTLY COMPLETED
ENROLLMENT, 33 PATIENTS, THIS IS
PRELIMINARY DATA BUT WE ALSO SAW
RESPONSES WITH 63% RESPONSE RATE
IN PATIENTS, AND VERY
IMPORTANTLY ON THIS STUDY WHICH
IS SOMETHING WE CANNOT DO IN
CHILDREN EASILY, WE WERE ABLE TO
OBTAIN SERIAL BIOPSIES
PRE-TREATMENT, ABLE TO SHOW THAT
INDEED BLOCKING THE TARGETS AND
BY DECREASING PHOSPHO-ERK, MANY
ADDITIONAL COMING FORWARD,
WONDERFUL FOR US IN THE CCR TO
HAVE THIS ABILITY TO COLLABORATE
WITH OUR ADULT PARTNERS.
I WANT TO HIGHLIGHT WHAT WE'VE
NOT ACCOMPLISHED.
TWO KEY ASPECTS THAT I WANT TO
HIGHLIGHT ON THIS SLIDE, THIS
WAS A PATIENT I MET FIRST WHEN
HE WAS 5 YEARS OLD.
TUMOR VOLUME WAS ABOUT 800 CC AT
THAT TIME.
HE PARTICIPATED IN MULTIPLE OF
MY TRIALS WITH NO IMPACT,
TREATED WITH SELUMETINIB,
DEVELOPED A TOXICITY, EJECTION
REFRACTION.
WE RESTARTED, TUMOR BEGAN TO
SHRINK.
THE PATIENT IS STILL ON TRIAL
AFTER MANY YEARS.
BUT YOU SEE WE NEED TO GIVE
SELUMETINIB CONTINUOUSLY FOR
VERY LONG TIME, IF WE WANT TO
HAVE SUSTAINED EFFECT.
AND ALSO THIS PATIENT WHILE WE
STOPPED THE TUMOR GROWTH DID NOT
ACTUALLY EXPERIENCE CLINICAL
BENEFIT.
SO WHAT CAN WE DO TO CHANGE THIS
AND TO POTENTIALLY MAXIMIZE THE
BENEFIT THAT ONE CAN GET FROM A
DRUG LIKE SELUMETINIB?
OUR TEAM HAS DEVELOPED VERY
INTERESTING AND INNOVATIVE STUDY
WHERE WE AIM TO GIVE CHILDREN
WHO ARE ASYMPTOMATIC, LOOK AT
THE BABY WHERE FACIAL TUMOR IS
BARELY VISIBLE, COMPARISON TO
WHEN SHE'S 3 YEARS OLD.
AND WE WILL START TREATING AND
THIS WILL BE A RANDOMIZED STUDY,
CHILDREN WITH ASYMPTOMATIC
PLEXIFORM NEUROFIBROMAS IN
CRITICAL LOCATIONS, EITHER WITH
SELUMETINIB OR OBSERVATION TO
SEE IF WE CAN PREVENT
DEVELOPMENT OF DISFIGURING
PAINFUL TUMORS AND SUSTAIN
RESPONSES, PART OF A NEW EFFORT
IN THE NCI, WHERE WE NOW HAVE
NCI PREVENTION CLINIC AND OTHER
CLINICAL TRIALS ACROSS THE CCR
CONTRIBUTING TO THIS EFFORT.
BASIC RESEARCHERS, I WANT TO
HIGHLIGHT WE NOW ALSO HAVE
GENETIC MOUSE MODELS OF NF
NEUROFIBROMAS THAT PREDICTED FOR
THE BENEFIT OF SELUMETINIB, DR.
NANCY RATNER IN CINCINNATI AND
DR. WAYNE CLAPPEN IN INDIANA
HAVE MODELS THAT HAVE
DEMONSTRATED BENEFIT OF MEK
INHIBITORS COMPARED TO OTHER
AGENTS, WE NOW HAVE VALIDATED
MOUSE MODELS SO FUTURE CLINICAL
TRIALS CAN BE MUCH MORE INFORMED
THAN OUR EARLY CLINICAL TRIALS
WERE.
COMING BACK TO THE PATIENT WITH
MPNST WHO UNFORTUNATELY DIED
FROM HIS DISEASE, WHERE WOULD WE
BE TODAY?
AND UNFORTUNATELY COMPARED TO 20
YEARS AGO DOES NOT HAVE BETTER
TREATMENT OPTIONS.
THE ONLY EFFECTIVE TREATMENT IS
COMPLETE SURGICAL RESECTION
WHICH FREQUENTLY IS NOT FEASIBLE
AND THE CLINICAL TRIALS WITH
TARGETED THERAPIES ALL
UNSUCCESSFUL, THE
PROGRESSION-FREE SURVIVAL WAS
VERY SHORT AND RESPONSES WERE
NOT DEMONSTRATED.
WE HAVE TRIAL REPORTED AT THE
CONNECTIVE TISSUE AND ONCOLOGY
SOCIETY IN A FEW WEEKS WITH A
HINT OF ACTIVITY CONNECTING
WITH mTOR INHIBITOR,
DEFINITELY NOT A HOME RUN.
I WANTED TO BRIEFLY HIGHLIGHT A
CLINICAL TRIAL THAT WILL START
COMBINING MEK INHIBITOR AND
PD-L1 INHIBITOR BASED ON
EXCITING DATA WITH SIGNIFICANT
SHRINKAGE ONLY WHEN ALL THREE
AGENTS ARE COMBINED, TAKEN TO
THE CLINIC SOON, AND I HOPE WE
WILL MAKE PROGRESS FOR
ESTABLISHED MPNST SOMETIME IN
THE NEAR FUTURE.
WHAT DO WE HAVE UNTIL THEN?
I WOULD SAY WE'VE MADE
SUBSTANTIAL PROGRESS,
POTENTIALLY DEVELOPING STRATEGY
TO PREVENT THE DEVELOPMENT
OFMPNST, IN PATIENTS, TEAM
IDENTIFIED MODULAR LESIONS WITH
THE RED ARROWS DEVELOPED OVER
TIME, BACKGROUND PLEXIFORM
NEUROFIBROMA THAT MAY NOT
ACTUALLY CHANGE.
WE CALL THESE LESIONS DISTINCT
MODULAR LESIONS, THEY HAVE A
DIFFERENT GROWTH PATTERN
COMPARED TO THE PLEXIFORM
NEUROFIBROMAS, THEIR GROWTH IS
INDEPENDENT OF AGE, AND
SOMETIMES EXCEEDS THE GROWTH OF
PLEXIFORM NEUROFIBROMAS IN TECH
IN ADULTS, IN A WONDERFUL
CONFERENCE, RESPOND --
SPONSORED BY THE TUMOR
FOUNDATION, INCLUDING OUR
PATHOLOGISTS HERE, IDENTIFIED
ATYPICAL NEUROFIBROMA,
BORDERLINE TUMORS THAT ARE NOT
MALIGNANT BUT ARE AT RISK OF
TRANSFORMING TO MALIGNANT
TUMORS.
SO, WITH THIS WE ESTABLISHED A
HYPOTHESIS THAT MOST MPNST MAY
ARISE FROM THE ATYPICAL
NEUROFIBROMA PRECURSOR, NOT FROM
PLEXIFORM NEUROFIBROMAS,
OFFERING THE OPPORTUNITY FOR
MARGINAL RESECTIONS OF ATYPICAL
NEUROFIBROMAS, MEANING RESECTION
THAT DOES NOT HAVE TO BE WITH
BROAD NEGATIVE MARGINS AND MUCH
LESS MORBID, AND A NEUROSURGEON
FROM NINDS PERFORMED SURGERIES
ON MORE THAN 40 PATIENTS, VERY
SUCCESSFULLY.
WE OF YOU SEE HIS THEORY HERE
THAT THESE NODULES THAT EXPAND
ATYPICAL NEUROFIBROMAS CAN BE
EXCISED WITHOUT ACTUALLY
SEVERING THE NERVE AND PATIENTS
FOR THE MOST PART REMAIN TO HAVE
COMPLETELY NORMAL FUNCTION.
ALSO VERY EXCITED, I'LL TALK
ABOUT THIS IN A MOMENT, WORK
FROM TAYLOR SUNDBY AND JACK
SHERN, WHO DEVELOPED SERIAL
DETECTION OF CELL-FREE DNA AS
MARKER FOR MALIGNANT
TRANSFORMATION, COLLABORATING
WITH THE SAME TEAM, ZHANG, TO
STUDY THIS BETTER IN AND ANDRE A
GROSS DEVELOPED INHIBITOR FOR
ATYPICAL NEUROFIBROMAS, WE CAN
TREAT THESE TUMORS.
AGAIN, WE HAVE BASIC SCIENCE
COLLABORATORS NOW HAVE
ESTABLISHED MODELS THAT ACTUALLY
SHOW MALIGNANT TRANSFORMATION
FROM PLEXI FORMS.
THIS IS A FIGURE FROM TAYLOR'S
PAPER THAT IN COLLABORATION WITH
WASHINGTON UNIVERSITY, BLOOD
SAMPLES FROM HEALTHY VOLUNTEERS,
PLEXYFORM NEUROFIBROMAS AND
MPNST, COPY-NUMBER VARIATION TO
SEPARATE AND DISTINGUISH FROM
PLEXYFORM NEUROFIBROMA, BASED ON
ANECDOTAL, WE CAN MONITOR
RESISTANCE AND RESPONSE
POTENTIALLY ON CLINICAL TRIALS.
COMING BACK TO MY PATIENT, THIS
IS CELL BODY MRI SERIES OF HIS
NEPHEW, FOLLOWED FOR A NUMBER OF
YEARS.
CORONAL MRIs, AND THE
STRUCTURE OF THE SCIATIC NERVES,
THIS IS WHAT YOU SEE THROUGHOUT
HIS BODY, TUMOR BURDEN.
IF YOU FOCUS NEXT TO HIS LEFT
KIDNEY, THERE'S A PERIPHERAL
TUMOR AT AGE 15 AND 18, AND AGE
21 ENLARGING.
YOU SEE THE SAME ON AXIAL SCANS
ON LOWER PANEL.
WHEN WE DO SOMETHING WE CALLED
DIFFUSION WEIGHTED IMAGING ON
MRI, WE GET A COEFFICIENT, IF
IT'S LESS THAN 1 IT MEANS
DIFFUSION RESTRICTION AND THIS
IS CONCERNING, POTENTIAL
DEVELOPMENT OF MPNST.
ON FDG-PET SCANNING WE SAW THERE
WAS SUBSTANTIAL UPTAKE IN THIS
TUMOR.
AFTER OBTAINING A BIOPSY THIS
LESION WAS REMOVED AND IT WAS
INDEED AN ATYPICAL NEUROFIBROMA
NEOPLASM OF UNCERTAIN POTENTIAL,
REMOVED TWO LESIONS IN THE
PATIENT OVER THE YEAR, AND I
HOPE THAT MY CONCLUSION THAT WE
MAY HAVE PREVENTED AN MPNST IN
THIS PATIENT IS CORRECT.
I WOULD LIKE TO SHOW THIS IS
TRICKY THOUGH.
THIS IS A 33-YEAR-OLD FEMALE,
ALSO WITH FAMILIAL NF1, WHO WE
FOLLOWED FOR MANY YEARS, AT THE
NIH, WHO ALSO HAS A HISTORY OF
PRIOR MPNST, YOU CAN SEE CLEARLY
INCREASING PERIPHERAL TUMOR NEXT
TO THE LEFT SCAPULAR.
LOWER PANEL YOU CAN SEE INCREASE
IN SUV MAX TO 15.9, PRESENT AT
THE MOST RECENT EVALUATION, THAT
IS DEFINITELY CONCERNING FOR AN
MPNST, WAS THE COEFFICIENT LESS
THAN 1.
WE OBTAINED A BIOPSY OF THE
LESION, ATYPICAL, PROCEEDED WITH
SURGERY WITH MARGINAL RESECTION.
HOWEVER, THIS TUMOR ACTUALLY WAS
HIGH GRADE MPNST.
WE'RE FORTUNATE WE CAN
COLLABORATE WITH JACK'S LAB AND
WITH JOANNE WITH HIGHLY TALENTED
POSTDOC IN HIS GROUP, SO THEY
PERFORMED SINGLE CELL SEQUENCING
ON OUR NF1 TUMORS, AND SHOWN
HERE IS THE DIAGNOSTIC BIOPSY
WHICH FOR US WAS AN ANNUBP, AND
A FEW WEEKS AGO MPNTS.
USING SINGLE CELL ANALYSIS YOU
CAN SEE HERE ALL THE CELL TYPES
THEY SAW IN BOTH OF THESE
TUMORS, MALIGNANT TUMORS, CELLS,
VARIETY OF OTHER CELLS.
BY USING SOMETHING THAT'S CALLED
INFERCNV LOOKED AT THE CELLS
LIKELY MALIGNANT CELLS TO
IDENTIFY WHAT EXACTLY THE
MALIGNANT CELLS ARE, AND
IDENTIFIED EVERY ROLE OF CELL,
CHROMOSOMES ON TOP.
CHANGE IN 17, PRESENT IN THE
MALIGNANT CELLS IN PARTICULAR
PATIENT, THERE WERE MANY, MANY
MALIGNANT CELLS.
WHAT WAS REALLY INTERESTING WAS
WHEN THEY SEPARATED AND LOOKED
AT THE INITIAL SAMPLE UNDER THE
MICROSCOPE THAT LOOKED LIKE AN
ANODE, AND THE RESECTION WERE
VERY SIMILAR.
AND I BELIEVE THIS IS
POTENTIALLY SOMETHING THAT CAN
TEACH US FOR FUTURE PATIENTS
BECAUSE CLEARLY KNOWING THAT
THIS WAS AN MPNST PRIOR TO
RESECTION WOULD HAVE IMPACTED ON
THE SURGICAL MANAGEMENT OF THIS
PATIENT.
JOANNE AND JACK AND TEAM ARE
ESTABLISHING A SINGLE CELL
ATLAS, 55 SPECIMENS, 25
PLEXIFORMS, I THINK THIS WILL BE
VERY IMPORTANT FOR US TO
UNDERSTAND MORE ABOUT THE CLONAL
EVOLUTION OF TUMORS, AND
HOPEFULLY ALSO IDENTIFY
POTENTIAL OPPORTUNITIES FOR
TREATMENT.
THIS SHOWS THE DISCOVERY THEN
SUBSEQUENTLY BY LOOKING AT THE
DIFFERENT TUMORS, WHAT CELL
TYPES THEY ARE, 34 CLUSTERS, 7
MAJOR CELL TYPES, HAVE BEEN ABLE
TO SEPARATE THESE DIFFERENT
CLUSTERS SO THAT WE CAN SEPARATE
OUT THE PLEXIFORMS, ATYPICALS,
CHANGES WITH EXPANSION OF THE
MALIGNANT CELLS AND MPNST,
CHANGES IN IMMUNE COMPARTMENT
MAY HELP US IN THE DEVELOPMENT
OF MORE TARGETED TREATMENT
APPROACHES.
WE HAVE DEVELOPED A IN A NATURAL
HISTORY STUDY, TARGETING HIGH
RISK MALIGNANT TRANSFORMATION,
THEY WILLING UNDERGO
STANDARDIZEDs MEDICAL AND
CLINICAL EVALUATION, IMAGING,
SERIAL BLOOD SAMPLES, MANAGEMENT
USING AN ALGORITHM,
PROSPECTIVELY AND IN A
STANDARDIZED FASHION.
DEPENDING ON WHETHER THERE'S
CONCERN FOR MPNST FOR AN
ATYPICAL NEUROFIBROMA, NO
CERTAIN MANAGEMENT WILL DIFFER,
I HOPE THIS STUDY WILL GET US TO
SOLVE THE BETTER DIAGNOSIS AND
TREATMENT FOR PATIENTS WITH
THESE TUMORS.
GOING BACK TO THE BORING NATURAL
HISTORY STUDY I ALSO LOOKED WHAT
HAVE WE ACCOMPLISHED OVER THE
YEARS, AND SHOWN HERE ARE
MANUSCRIPTS THAT MADE
SUBSTANTIAL ADVANCES IN BASIC
SCIENCE.
WE NOW DO HAVE AN ASSAY FOR CELL
FREE DNA WHICH WILL HELP US WITH
PATIENTS ON THIS STUDY.
WE'VE CHARACTERIZED GROWTH OF
TUMORS.
RESECTION IS A STRATEGY TO
PREVENT MPNST, WE'VE LEARNED
ABOUT SOCIAL AND EMOTIONAL
FUNCTION, PAIN AND PAIN
INTERFERENCE, AND WE'VE RECEIVED
REGULATORY APPROVAL AT THE SAME
TIME AS WE PUBLISHED THE PAPER
ABOUT THIS STUDY.
IN ADDITION, THE NATURAL HISTORY
STUDY SERVES AS THE MOM FOR
SOMETHING ALONG THOSE LINES FOR
THE NEW EFFORT DIRECTED BY DCEG,
NCCR INVESTIGATORS WITH
ENGAGEMENT OF THE RAS INITIATIVE
AND ADVOCACY GROUPS, ADVANCING
RASOPATHY THERAPIES, A WONDERFUL
EFFORT FROM THE GET-GO INCLUDES
PRE-CLINICAL WORK, DEVELOPMENT
OF RASOPATHY CLINIC, AND A
PUBLIC HEALTH GENOMICS APPROACH
DIRECTED BY DOUG STEWART.
THERE WILL BE MORE COMING.
THE IN THE HISTORY STUDIES
INFORM THE RARE RESEARCH TUMORS
I TALK ABOUT NOW.
WE MENTIONED THAT EVERY
PEDIATRIC CANCER IS RARE.
THE FOCUS OF THE REMAINDER OF
THE TALK ABOUT BE ON VERY RARE
PEDIATRIC CANCERS, LESS THAN 2
MILLION CASES PER YEAR,
APPROXIMATELY 11% OF ALL
PEDIATRIC CANCERS.
TREMENDOUS CHALLENGES COME FROM
THIS INCLUDING ESTABLISHING
DIAGNOSIS, INCOMPLETE
UNDERSTANDING OF THE NATURAL
HISTORY STUDY, NO STANDARD CARE,
NO CLINICAL TRIALS FOR MANY OF
THESE TUMORS, LACK OF
PRE-CLINICAL MODELS, AND
DIFFICULTY CONDUCTING
PRE-CLINICAL STUDIES.
CHRISTINA VIVELO FROM MYPART
TEAM LOOKED AT RARE TUMOR
RESEARCH PUBLICATIONS, IT'S
CLEAR A HUGE INTEREST HAS
INCREASED OVER THE LAST YEARS,
THAT ALSO MANY PROGRAMS, PUBLIC
AND PRIVATE, AND ADVOCACY THAT
STUDY RARE TUMORS WHICH LEADS ME
TO BELIEVE THERE ALREADY
TREMENDOUS PROGRESS.
HOWEVER, THE PROGRAMS DON'T
REALLY TALK TO EACH OTHER THAT
MUCH.
BEFORE I TALK ABOUT MY PART, I
WANT TO BRIEFLY MENTION THE FDA
REALLY IS A PARTNER FOR RARE
TUMOR RESEARCH, THEY UNDERSTAND
HOW DIFFICULT IT IS TO DO THIS.
AND HAVE IMPLEMENTED A FEW
STRATEGIES TO HELP US.
ONE IS FDA RECOMMENDS INCLUSION
OF CHILDREN IN ADULT EARLY
CLINICAL TRIALS, IF IT IS TARGET
APPROPRIATE.
THE FDA ALSO HAS THE RACE ACT
WHICH REQUIRES TO CONDUCT
CLINICAL TRIALS IN MOLECULAR
AGENTS ARE RELEVANT TO PEDIATRIC
CANCERS AND FINALLY THE FDA HAS
DEVELOPED DRAFT GUIDANCE FOR THE
DEVELOPMENT OF NATURAL HISTORY
STUDIES, NATURAL HISTORY STUDIES
CAN SERVE AS CONTROL GROUP FOR
THE POTENTIAL DRUG APPROVAL
WITHOUT HAVING TO CONDUCT
RANDOMIZED CLINICAL TRIAL.
AND BASED ON THIS, THERE HAVE
BEEN A NUMBER OF FDA APPROVALS
FOR VERY RARE TUMORS, AND THIS
IS REALLY WONDERFUL FOR ME TO
SEE THE BEST EXAMPLE IS AN
INHIBITOR APPROVED FOR VERY
YOUNG PEDIATRIC AND ADULT
PATIENTS PROVIDING THERE ARE
Trk FUSIONS.
I'M FOCUS ON THE CANCER MOONSHOT
SUPPORTED PROGRAM, ESTABLISHED
AND CO-DEVELOPED INITIALLY BY
COLLEEN RILEY AS BASIC SCIENTIST
AND MYSELF, BUT IT IS A HUGE
TEAM WORKING ON THIS, FOCUSING
ON CHILDREN AND ADOLESCENTS AND
YOUNG ADULTS.
NCI DEFINITION IS LESS OR EQUAL
30 YEARS OLD WITH TUMORS THAT
ARE DIFFICULT TO TREAT AND VERY
RARE.
AND WE -- I GIVE YOU THE -- WE
ARE DOING STUDY, PART OF MY PART
IS TO DEVELOP NATURAL HISTORY
STUDY CO-LED BY MARY FRANCES AND
HEIDI, ADULT ONCOLOGIST, MARY
FRANCES IS PEDIATRIC ONCOLOGIST.
THIS INCLUDES STANDARDIZED
LONGITUDINAL RETROSPECTIVE AND
PROSPECTIVE EVALUATIONS
INCLUDING MEDICAL AND FAMILY
HISTORY, PATIENT-REPORTED
OUTCOMES, CLINICAL EVALUATION,
EXTENSIVE DATA EXTRACTION,
PATIENTS WITH RARE SOLID TUMORS
OR BIOLOGICAL RELATIVES ARE
ELIGIBLE.
WE PROVIDE TREATMENT
RECOMMENDATIONS IN COLLABORATION
WITH PATHOLOGY AT NCI, CONDUCT
PROFILING, HAVE GENETIC
COUNSELING, AND WE ARE
DEVELOPING ANNOTATED BIOSPECIMEN
REPOSITORY.
SHOWN HERE IS WHAT HAPPENINGS
WITH THE SAMPLES WE GET, FOR THE
MOST PART ARE PARAFFIN EMBEDDED
SLIDES, IN COLLABORATION WITH
LAB OF PATHOLOGY WE PERFORM TSO
500 PANEL SEQUENCING, CLINICALLY
APPROVED FOR EXOME SEQUENCING
AND RNA SEQUENCING, AND THEN WE
DO A NUMBER OF ANALYSES FOR
RESEARCH SUCH AS METHYLATION
ARRAYS, AND WHOLE GENOME
SEQUENCING.
IN ADDITION WE DO BLOOD
BIOMARKERS, POTENTIAL BIOMARKERS
IN THESE PATIENTS.
IN COLLABORATION WITH MULTIPLE
INVESTIGATORS IN THE CCR WE'RE
CONDUCTING IMMUNE CELLS AND HAVE
ESTABLISHED A LYMPHOCYTE PANEL
AND MYELOID PANEL AND SAMPLES
NOW, A NUMBER OF PATIENTS, WAY
MORE THAN 100 PATIENTS, WOULD
SUPPORT BY THE NCI CANCER DATA
KNISH INITIATIVE, EXPANDING THE
EFFORT TO INCLUDE MANY OTHER
TUMORS TO ESTABLISH IN
COLLABORATION WITH MULTIPLE
BRANCHES IN THE CCR, AND
PEDIATRIC SINGLE CELL TUMOR
ATLAS.
AND I'M SHOWING YOU NOW WHERE WE
ARE WITH ENROLLMENT ON THE
BIPART STUDY, STARTING IN 2019
WE HAVE ENROLLED 451
PARTICIPANTS, WE HAVE A
WONDERFUL SUPPORTIVE TEAM.
YOU SEE SOME OF THE FACES ON THE
RIGHT UPPER CORNER.
BOTH PEDIATRIC AND ADULT
PATIENTS, FROM SIX CONTINENTS,
AND 46 STATES IN THE UNITED
STATES.
HERE YOU SEE THE TYPES OF TUMORS
THAT WE HAVE ENROLLED.
YOU CAN CLEARLY SEE
NEUROENDOCRINE TUMORS,
INTESTINAL STROMAL TUMORS,
ADRENOCORTICOID CARCINOMA, AND
NUMBERS WHERE WE CAN REALLY
LEARN FROM.
WE HAVE MANY ADDITIONAL TUMORS
WHERE WE HAVE SMALLER NUMBERS,
AND THAT'S SOMETHING I WILL
ADDRESS LATER, WHERE WE NEED
MORE NUMBERS TO IMPROVE OUR
LEARNING FOR THESE SPECIFIC
TUMORS.
COLLEEN RILEY IS CURRENTLY
ANALYZING THE SAMPLES WE HAVE
RECEIVED FROM THE TUMORS.
AND AS I SAID, THIS IS FOR THE
MOST PART PARAFFIN-EMBEDDED
TISSUE, OUT OF I THINK 160-SOME
PATIENTS WHERE WE GOT TISSUE
FROM THE FIRST 200 PATIENTS
ONLY, WE SUCCEEDED WITH TSO OR
LAB OF PATHOLOGY SUCCEEDED WITH
TSO IN 125 OF THEM.
WE CAN SEE HERE IT'S NOT ONLY
AGE OF THE SAMPLE BUT OTHER
FACTORS THAT IMPACT ON WHETHER
WE ARE SUCCESSFUL TO GET PANEL
SEQUENCING DONE.
HERE WE SEE IN WORK DONE,
RESULTS OF PANEL SEQUENCING FOR
PATIENTS WITH ACC, 26 PATIENTS,
WE HAVE THE SAME VARIANT IN MORE
THAN THREE PATIENTS.
FOR EXAMPLE YOU CAN SEE FOR ACC,
TP A 53 WAS MOST FREQUENTLY
SEEN.
WHERE WE HAD 23 PATIENTS WITH
MORE THAN THERE, GIVEN WE SEE
SDH DEFICIENCY, AND FOR PATIENTS
WITH MEDULLARY THYROID CARCINOMA
FOR THE PATIENTS THAT WE SEE IT
IS RET WE MOST FREQUENTLY SEE
AND FOR CORDOMA, THE LEAST,
PATIENTS WITH POORLY
DIFFERENTIAL THE CORDOMA, YOU
CAN ALSO SEE ACTIONABILITY AND
WHETHER THESE ARE PATHOGENIC OR
LIKELY PATHOGENIC VARIANTS WE
SEE, FOR EXAMPLE IF YOU LOOK AT
THE PLOT ON THE RIGHT, LOWER
HAND, TO BE EXPECTED MEDULLARY
THYROID CARCINOMA, AT THE MOST
ACTIONABLE MUTATIONS WITH RET
WHERE WE HAVE EFFECTIVE MEDICAL
THERAPY, EXPANDING THIS TO
ANALYZE ALL OF THE DATA,
HOPEFULLY WILL RESULT IN A
PUBLICATION SOON.
WE'RE COLLECTING MANY, MANY
DATA, CLINICAL DATA, IMAGING
DATA, PATHOLOGY DATA, AND I'VE
BEEN VERY FORTUNATE TO WORK WITH
NIDA, NIH INTEGRATED DATA
ANALYSIS PLATFORM, TO REALLY
MAKE SENSE OF THE DATA, THIS HAS
BEEN WONDERFUL OPPORTUNITY FOR
US TO BRING DATA FROM MULTIPLE
SOURCES TOGETHER.
HOW DO WE GET THE RESULTS TO OUR
PATIENTS THAT ARE THE MOST
IMPORTANT PATIENTS GET RESULTS
INCLUDING THE TSO 500 PANEL
SEQUENCING, FROM THE NIH
CLINICAL CENTER PORTAL,
COMMUNICATE TREATMENT WITH
RECOMMENDATIONS WITH THE
PATIENTS DIRECTLY, AND HAVE
WEEKLY DISCUSSIONS WITH OUR
GENETIC COUNSELOR, LAB OF
PATHOLOGY, CLINICIANS, REVIEW
PATHOLOGY OF THE PATIENTS AND
THEN MAKE OUR RECOMMENDATIONS.
WE HAVE NEWSLETTER, SOCIAL
MEDIA, AND PUBLICATIONS TO SHARE
DATA AND SUMMARIES OF
PUBLICATIONS.
COMMUNICATION IS A HUGE EFFORT,
DIRECTED BY CHRISTINA, AS YOU
CAN SEE HERE WE HAVE MADE
SUBSTANTIAL EFFORT OF SPREADING
THE NEWS ABOUT MY PART, MANY
SUBSCRIBERS VISIT FOR
INFORMATION MOSTLY ABOUT RARE
TUMORS.
ADVOCACY IS CRITICAL TO WORKING
IN RARE TUMORS, AND ABBY
SANDLER DIRECTS THIS EFFORT,
FOUNDATIONS STUDY RARE TUMORS,
AND I WOULD LIKE TO HIGHLIGHT
EFFORT IN PEDIATRIC CORDOMA,
SPEARHEADED BY MARY FRANCES.
CHORDOMA IS A RARE SARCOMA,
ORIGINATES IN THREE LOCATIONS,
APPROXIMATELY 325 CASES NEW IN
THE UNITED STATES PER YEAR BUT
APPROXIMATELY ONLY 30 OR SO
PEDIATRIC CHORDOMAS.
THESE TUMORS ARE TYPICALLY
POSITIVE FOR BRAKEORI, TYPICALLY
SMARCB1 DEFICIENT.
ON THE RIGHT LOWER PANEL, A PET
SCAN WITH SUBSTANTIAL UPTICK AT
BASELINE, SUBSTANTIAL
IMPROVEMENT AFTER FOUR CYCLES.
CHORDOMA GAVE US THE BACKGROUND
WE HAVE, BASIC SCIENCE
CHAMPIONS, AND WE ESTABLISHED A
PARTNERSHIP WITH CHORDOMA
FOUNDATION, DEVELOPED OUR
NATURAL HISTORY STUDY, HAD THE
FIRST PEDIATRIC CHORDOMA CLINIC,
WHERE WE BRING EXPERTS FROM THE
OUTSIDE TO THE NIH CLINICAL
CENTER WITH PATIENTS, AND THE
PATIENTS ARE SEEN AND GET
INDIVIDUALIZED RECOMMENDATIONS,
REALLY TREMENDOUS EXPERIENCE FOR
THE PATIENTS, SUBSEQUENTLY WE
HAVE ENGAGED IN PARTICIPATING IN
THE BOSTON TUMOR BOARD FOR THESE
PATIENTS, IT'S HAPPENING ON AN
EVERY-OTHER-WEEK BASIS.
AND WE ARE PROUD TO SAY THAT WE
ALSO HAVE ENROLLED MANY, MANY
PEDIATRIC PATIENTS SUBSEQUENTLY
ON OUR PEDIATRIC ARM OF THE
MYPART STUDY, MARY FRANCES AND
LINY JOHN ARE LEADING, MEDIAN
AGE IS 34 YEARS, THIS IS YOUNGER
THAN THE MEDIAN AGE OF CHORDOMA
ALL OVER, AND IN THE UNITED
STATES, AND WE HAVE ENROLLED
SOME PATIENTS WITH POORLY
DIFFERENTIATED SMARCB1, SOME ARE
INTERNATIONAL PATIENTS AND THEY
CAN PARTICIPATE REMOTELY IN
CLINICS, WE JUST HAD OUR VIRTUAL
CHORDOMA CLINIC FOR FIVE
PATIENTS, FOR ANOTHER FIVE THAT
ATTENDED IN PERSON, 12 EXTERNAL
CLINICIANS THAT ALL
PARTICIPATED, VIRTUALLY, BUT
IT'S BEEN A TREMENDOUS
EXPERIENCE TO SEE HOW PATIENTS
CAN GET THEIR KEY QUESTIONS
ADDRESSED BY EXPERTS THAT DON'T
EXIST IN JUST ONE CENTER.
THEY REALLY COME FROM ACROSS THE
COUNTRY.
IF YOU CAN BRING THOSE TOGETHER
PATIENTS REALLY CAN BENEFIT
SUBSTANTIALLY FROM THIS.
IN COLLABORATION, WE ARE ALSO
ESTABLISHING MODELS OF MANY
TUMORS AS LONG AS PATIENTS HAVE
SURGERY AND ONE EXAMPLE IS SHOWN
HERE OF CHORDOMA PDX, THE LAB IS
WORKING WITH US IN THE LAB TO
SEE HOW WE CAN UNDERSTAND
CHORDOMA BETTER AND POTENTIALLY
DEVELOP TREATMENTS.
I MENTIONED THAT CHORDOMA,
PEDIATRIC CHORDOMA, CAN BE
RESPONSIVE TO IMMUNOTHERAPY, AND
MARY FRANCES AND OTHERS ARE
CONDUCTING PHASE 2 TRIAL OF PD-1
INHIBITOR FOR SMARCB1 TUMORS,
MULTI-SITE NIH OF
NCI-COORDINATED CLINICAL TRIALS
FOR SMARCB1 TUMORS.
RARE COHORTS FROM FULLY
DIFFERENTIATED CHORDOMA,
MEDULLARY CARCINOMA, MALIGNANT
TUMOR, ATYPICALLY TERATOID
TUMORS AND OTHERS TO SEE IF OUR
OUTREACH TO THE CHORDOMA
FOUNDATION AND PARTNERSHIPS WILL
HELP GET ENROLLMENT ON THE TRIAL
IN EFFICIENT MANNER.
I WOULD ALSO HIGHLIGHT WORK THAT
IS ENTIRELY NOT MY WORK BUT OF
OUR COLLABORATORS, AND
SUBSTANTIAL EFFORT IN CHORDOMA
WITH DEVELOPMENT OF VACCINES,
BRACHYURY VACCINES, ONE PATIENT
ON THE RIGHT, THE PHOTOGRAPHY
AND IMAGERY AND VOLUMETRIC
ANALYSIS, SHOWED DRAMATIC
RESPONSE TO BRACHYURY VACCINE,
DEVELOPED CYTOKINE RELEASE
SYNDROME, WE'RE GRATEFUL FOR
COLLABORATION WITH THOSE WHO
HELPED US UNDERSTAND THESE
TUMORS AND WOULD LIKE TO GIVE A
SHOUT OUT TO A NEW PROGRAM IN
THE CENTER FOR IMMUNO-ONCOLOGY,
THIS REALLY WILL PROVIDE A BASIS
FOR VERY COMPREHENSIVE PROGRAM
IN PEDIATRIC AND ADULT PATIENTS
WITH CHORDOMA.
THE LAST TWO SLIDES I THINK,
THREE SLIDES, I HAVE HIGHLIGHTED
THIS EFFORT, AGAIN GOING BACK TO
THE NEED TO DEVELOP TRIALS FOR
PEDIATRIC AND ADULT PATIENTS,
WHEN THERE IS THE SCIENTIFIC
RATIONALE, VERY GRATEFUL FOR THE
DEVELOPMENT OF THERAPEUTICS
CLINIC WITH ALICE CHEN,
GERALDINE AND JIM DOROSHOW, WE
WILL TREAT YOUNGER PATIENTS ON
ADULT CLINICAL TRIALS AND ADULT
TEAM WILL TREAT OLDER PATIENTS
ON STUDIES THAT ORIGINATE FROM
THE PEDIATRIC ONCOLOGY BRANCH.
I WANT TO GIVE ONE EXAMPLE.
THIS IS THE LAST EXAMPLE I'LL
GIVE FOR TODAY, A PD-L1
INHIBITOR, ADULT CLINICAL TRIAL
RUN BY ALICE CHEN AND GERALDINE
O'SULLIVAN, IT'S A RARE SARCOMA
CHARACTERIZED BY A GENE, A TUMOR
GROWS SLOWLY, UNRELENTLESSLY,
UNRESPONSIVE TO CHEMOTHERAPY.
IN THE CLINICAL TRIAL THAT WAS
CONDUCTED, AN OBJECTIVE RESPONSE
RATE OF 37%, IN PATIENTS WITH
ALVEOLAR SOFT PART SARCOMA,
PEDIATRIC BRANCH IS THE ONLY
SITE WHERE WE CAN ENROLL
PATIENTS TWO YEARS TO TWELVE
YEARS OF AGE, OTHER SITES CAN
ENROLL ADOLESCENTS AND YOUNG
ADULTS.
BASED ON THE RESPONSE THE FDA
GRANTED BREAKTHROUGH THERAPY
DESIGNATION, I'M SHOWING EXAMPLE
OF ONE OF THE PEDIATRIC PATIENTS
ENROLLED, VERY SUBSTANTIAL
PULMONARY METASTASIS AT
ENROLLMENT, PATIENTS ON CYCLE
NUMBER 60, NEAR RESOLUTION OF
THE DISEASE AND COLLABORATOR ON
THIS STUDY IS JOHN GLOD, OUR
CLINICAL DIRECTOR IN THE POB.
I HOPE I HAVE SHOWN YOU WHAT
WE'VE LEARNED FROM THE MYPART
EXPERIENCE, THAT ADVOCACY IS
CRITICAL AS WELL AS BASIC AND
CLINICAL TUMOR EXPERTISE.
WE NEED CHAMPIONS FOR THESE
DISEASES.
RARE TUMOR CLINICS PROVIDE
UNIQUE INSIGHT WE COULD NOT GET
FROM SEEING INDIVIDUAL PATIENTS
AT MULTIPLE DIFFERENT SITES.
BUILDING COHORTS IS RESOURCE AND
TIME INTENSIVE, AS DR. ROBERTS
SAID, IT TAKES A LONG TIME.
I THINK WE HAVE TO FOCUS ON
SELECT TUMOR TYPES TO MAKE THE
MOST PROGRESS.
IN ORDER TO MAKE PROGRESS IN
MULTIPLE RARE TUMORS AT THE SAME
TIME I BELIEVE WE NEED TO HAVE
EFFECTIVE PARTNERSHIPS WITH
MULTIPLE OTHER PARTICIPATING
SITES AND THE NCI CANCER DATA
INITIATIVE, ESTABLISHED IN 2019,
SUBSTANTIAL FUNDING FOR TEN
YEARS TO DEVELOP DATA ECOSYSTEM
AND TO LEARN OPT MIAMI FROM
EVERY CHILD WITH CANCER AND
BRINGING DATE -- DATA FROM
MULTIPLES SOURCES PROVIDE THE
OPPORTUNITY TO COME TRUE.
THIS BUILDS UPON ONE EFFORT IN
THE CCDI, MOLECULAR
CHARACTERIZATION INITIATIVE,
WHICH IS CO-CHAIRED BY JACK AND
KATIE AND MALCOLM.
CHILDREN IN PROJECT EVERY CHILD
ARE ABLE TO RECEIVE
STATE-OF-THE-ART MOLECULAR
DIAGNOSIS AT THE TIME OF
DIAGNOSIS.
RESULTS OF THE SEQUENCING ARE
RETURNED WITHIN 21 DAYS.
THIS IS CURRENTLY OPEN FOR NEWLY
DIAGNOSED CNS AND RARE TUMORS, A
NEED FOR RELAPSE TUMORS
UNDERSTANDING TO GET ENHANCED
CLINICAL ANNOTATION BUT IF WE
CAN BUILD ON THIS AND EXTEND TO
TRUE NATIONAL EFFORT FOR RARE
TUMORS I THINK WE CAN MAKE
PROGRESS MUCH MORE QUICKLY, I DO
WANT TO HIGHLIGHT THERE WILL BE
VIRTUAL WORKSHOP ON THIS TOPIC
ON NOVEMBER 18, BY THE CCDI, AND
I HOPE YOU CAN PARTICIPATE.
WE LOOK FORWARD TO COLLABORATING
WITH AS MANY BASIC AND CLINICAL
RESEARCHERS AS POSSIBLE.
I WOULD LIKE TO THANK THE WSA
AGAIN FOR THIS TREMENDOUS HONOR.
I THANK OUR PATIENTS FAMILIES,
ADVOCATES, CCR, DCEG, AND I
PRESENTED WORK OF MANY AND IF I
FAILED TO ACKNOWLEDGE PLEASE
FORGIVE ME.
FINALLY OBVIOUSLY MOST
IMPORTANT, I WANT TO THANK ALL
THE PATIENTS THAT CONTRIBUTED TO
THIS EFFORT.
THANK YOU SO MUCH.
>>THANK YOU, DR. WIDEMANN, FOR
THE COMPREHENSIVE TALK.
IT TAKES -- PEOPLE SAY IT TAKES
A VILLAGE TO RAISE A CHILD.
IT TAKES COMMUNITIES TOO, TO
SOLVE THIS CANCER ISSUE, RARE
TUMOR ISSUE.
SO THERE'S A COUPLE QUESTIONS IN
THE CHAT.
AND ONE OF THEM CAME FROM MARY,
WHO ASKED THAT MUTATIONS THAT
CAUSE RARE TUMORS TYPICALLY
INHERITED OR ARE THEY
STOCHASTIC?
>>YEAH, SO ALL IN ALL, FOR
PEDIATRIC CANCERS, WE HAVE NOW
DATA THAT INDICATES ABOUT 12%
HAVE GENETIC GERMLINE
PREDISPOSITION, SOMETHING WE DID
NOT KNOW PRIOR TO THE SEQUENCING
EFFORTS.
BUT IT'S ACTUALLY A SUBSTANTIAL
NUMBER, AND I BELIEVE THIS WOULD
BE AN EXCELLENT COHORT, FOR
EXAMPLE, IF WE CAN IDENTIFY THE
COHORT, THROUGH MOLECULAR
CHARACTERIZATION INITIATIVE TO
FOLLOW PROSPECTIVELY AS ONE OF
THE COHORTS BECAUSE THESE
PATIENTS ARE AT INCREASED RISK
TO DEVELOP TUMORS, SOME OF WHICH
ARE VERY RARE.
>>OKAY.
SO, ANOTHER QUESTION IS VERY
IMPRESSIVE WORK, HOW WAS
SELUMETINIB SELECTED FOR THE
STUDIES AND SIDE EFFECTS IN
CHILDREN.
>>YEAH, A GREAT QUESTION.
SELECTION WAS VERY PRAGMATICAL,
WHAT I COULD GET ACCESS TO.
AS THE AUDIENCE LIKELY KNOW,
THERE ARE MANY MEK INHIBITORS
THAT WERE ALL DEVELOPED AT THE
SAME TIME.
IT WAS IMPOSSIBLE WHEN I WAS
TRYING TO CONDUCT THE STUDY TO
GET ANY DRUG COMPANY TO SAY YES,
YOU CAN DO THIS STUDY.
EVERYBODY SAID I'M TOO
CONCERNED, THIS IS A YOUNG
PATIENT POPULATION, THEY DON'T
HAVE CANCER, SO THESE WERE THE
LIMITATIONS FROM THE COMPANIES.
I HAVE TO REALLY THANK NCIC
BECAUSE THEY SAID, WE'LL LET YOU
DO THIS STUDY, AND SO I GOT THE
DRUG FROM CTEP AFTER TRYING AND
CTEP HAD SELUMETINIB AS THE
AGENT.
IN HINDSIGHT I WAS HAPPY, IT HAS
A VERY SHORT HALF-LIFE SO WHEN A
PATIENT DEVELOPS A SIDE EFFECT
IT REVERSES MORE QUICKLY THAN
SOME OF THE OTHER MEK
INHIBITORS.
>>SEEMS LIKE IT'S REALLY
WORKING WELL, EVEN THOUGH NOT
COMPLETE.
>>THAT IS CORRECT.
>>YEAH, YEAH, AMAZING.
SO I HAVE A COUPLE OF GENERAL
QUESTIONS.
ONE IS, IT SEEMS LIKE -- IS
THERE ANY SPATIAL PREFERENCE FOR
THE TUMOR ARISING FOR THE
NEUROBLASTOMA, IS THERE
LOCATIONAL PREFERENCE?
>>YES.
>>IT SEEMED LIKE A LOT OF HEAD
AND NECK REGION.
>>SO, NEUROFIBROMAS OR
NEUROBLASTOMAS.
>>NF1.
>>YEAH, SO THAT'S A GREAT
QUESTION.
I WOULD SAY THEY ARISE ANYWHERE,
PERIPHERAL NERVE.
I THINK TRUNK IS ONE OF THE MOST
FREQUENT LOCATIONS THAT WE HAVE.
>>OKAY.
>>MANY OF THE PATIENTS HAVE
MULTIPLE BODY PARTS INVOLVED,
THIS IS SOMETHING WE'VE LEARNED
FROM WHOLE BODY MRI THAT WE USE.
AND THAT I NEED TO ACTUALLY LOOK
BACK AND GIVE YOU THE
PROPORTIONS.
WE HAVE SEEN THEM EVERYWHERE,
THERE'S DEFINITELY NOTHING THAT
IS STRIKING COMMON, CERVICAL
AREA AND PELVIC AREA IS MORE
FREQUENT THAN THORACIC, ONE
THING I CAN SAY.
>>IT SEEMED LIKE LOOKING AT THE
IMAGES.
>>YEAH.
>>SEEMED LIKE A LOT OF THEM
WERE HIGHER UP.
THIS OTHER QUESTION I HAVE IS
KIND OF -- SO FROM YOUR SINGLE
CELL DATA, IT SEEMED LIKE IF I'M
CORRECT THAT THERE'S A LOT OF
SIMILARITY IN THE PROFILE
BETWEEN STAGES.
>>I THINK MOST SIMILARITY IS --
JACK CAN SPEAK BEST TO THIS,
BETWEEN PLEXIFORMS AND ATYPICAL
NEUROFIBROMAS THEY ARE VERY
SIMILAR, THIS IS SOMETHING THEY
ARE TEASING APART.
THE PLEXYFORMS THAT ARE BENIGN,
ATYPICALS THAT ARE ATYPICAL
UNDER THE MICROSCOPE AND THEN
ATYPICAL TUMORS THAT WE'RE MOST
CONCERNED ABOUT MALIGNANT
TRANSFORMATION TRYING TO
UNDERSTAND DIFFERENCES BUT THE
MPNSTs ARE DISTINCT.
>>I SEE.
SO THE T IS LIKE TRYING TO FIND
THE MOLECULAR LINK THAT MAKES IT
JUMP TO BE THE MALIGNANT --
>>YES, AND THE ONE LINK WE HAVE
IS THIS CDKN TO A LOSS, NOT
PRESENT IN PLEXFORMS, ALSO
PRESENT IN MPNST.
>>A QUESTION FROM MARY AGAIN.
HOW COMBINATION THERAPIES HAVE
BEEN USED THAT TARGET DIFFERENT
GENE BROADS, IF SO DOES
COMBINATION THERAPY REDUCE OR DO
YOU NOT SEE --
>>THANK YOU FOR THE QUESTION.
WE'RE EXPLORING AND WILL SOON
OPEN WITH THE NF CLINICAL TRIALS
CONSORTIUM, FIRST TRIAL
COMBINING TWO THERAPIES FOR
BENIGN PLEXIFORM NEUROFIBROMAS,
WILL BE A COMBINATION OF KINASE
INHIBITOR, CABOZANTANIB AND
SELUMETINIB, FOR MPNST 100% I
THINK WE'LL NEED COMBINATORIAL
TREATMENT TO EVEN GET TO THE
POINT WHERE WE SEE WE CAN SHRINK
THE TUMORS AND BENEFIT PATIENTS
WHICH WE'VE NOT BEEN ABLE TO DO
DATE.
>>A QUESTION FROM THE AUDIENCE,
THANK YOU FOR COMPREHENSIVE
REPORT OF ALL THE TREMENDOUS
EFFORTS WITHIN THE POB FOR
PEDIATRIC RARE TUMORS.
HATS OFF TO YOU.
I'M SURE YOU GET ANY NUMBER OF
REQUESTS TO COLLABORATE WITH
INDUSTRY TO FILL UNMET NEEDS YOU
MENTIONED.
BUT IT WOULD HELP TO KNOW HOW WE
COULD GET INVOLVED BY CONNECTING
EFFECTIVELY WITH INTERESTING
RESEARCHERS EXTRAMURALLY.
>>YEAH, SO WE ACTUALLY
COLLABORATE EXTENSIVELY, REALLY
EXTENSIVELY, POB IS ONE OF THE
MOST COLLABORATIVE BRANCHES,
THAT DOESN'T ONLY APPLY TO MY
WORK OR MYPART WORK BUT LEUKEMIA
SECTION AND EVERYBODY ELSE.
WE DO THINK EXTRAMURAL
PARTNERSHIPS ARE CRITICAL, SOME
MECHANISMS HOW THEY ACTUALLY
SUPPORT THROUGH NIH UO1 GRANTS,
FOR EXAMPLE, WHERE WE CAN HAVE
AN EXTRAMURAL P.I. AND
INTRAMURAL P.I., BUT WE NEED
EXTRAMURAL COLLABORATORS, EVEN
THOUGH WE HAVE SUBSTANTIAL
EXPERTISE IN INTRAMURAL AND NCI
THERE'S SO MUCH EXTRAMURAL
INVESTIGATORS CONTRIBUTE AND
THERE ARE MECHANISMS AND I THINK
WE CAN COLLABORATE EVEN IF NO
FUNDS ARE EXCHANGED, IT'S
CRITICAL.
FOR THE RARE TUMOR WORK WE NEED
THE EXTRAMURAL CLINICIANS TOO
BECAUSE WE DON'T HAVE ALL OF THE
CLINICAL EXPERTISE FOR THAT RARE
TEAMS, THAT'S WHAT WE BRING WHEN
WE HAVE THE RARE TUMOR CLINICS.
>>SO, ANOTHER QUESTION IS, IS
THERE ANY IMMUNE CELL
INFILTRATION IN THE NF1 TUMORS.
>>REPEAT.
>>IS THERE ANY IMMUNE CELL
INFILTRATION?
>>YEAH, SO THERE'S
SUBSTANTIALLY, THESE TUMORS ARE
ACTUALLY KNOWN TO HAVE MAST
CELLS AND MYELOID CELLS, I
BELIEVE THIS IS SOMETHING TRIED
TO BE TARGETED WITH THERAPIES,
ROSY DID A STUDY, AND THE CLAPP
STUDY DID A STUDY,
MICROENVIRONMENT, AS A SINGLE
AGENT I THINK IT HAS NOT BEEN
SUCCESSFUL ON LIMITED SUCCESS I
WOULD SAY, COMBINATORIAL
STRATEGIES HAVE NOT BEEN
EXPLORED.
>>OKAY.
SO THAT'S ALL THE QUESTIONS I
SEE ON THE CHAT SO FAR.
AND ARE THERE ANY OTHER
QUESTIONS FROM THE PANEL?
WELL, IF NOT, I'D LIKE TO TAKE
THE OPPORTUNITY TO THANK YOU
AGAIN, DR. WIDEMANN, FOR THE
WONDERFUL LECTURE AND
CONGRATULATIONS ON THE AWARD.
>>THANK YOU SO MUCH.
I APPRECIATE THE QUESTIONS AND
THE AUDIENCE AND VERY MUCH THE
NOMINATION.
>>THANK YOU.
BYE.
>>BYE.
>>THAT CLOSES THE SESSION.