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