Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
WE START 2023 WITH OUR SPEAKERS,
DR. PAUL HWANG, A SENIOR
INVESTIGATOR FOR THE LABORATORY
OF CARDIOVASCULAR AND CANCER
GENETICS AT THE NATIONAL HEART,
BLOOD AND LUNG INSTITUTE AND DRE
DIVISION OF CANCER EPIDEMIOLOGY
AND GENETICS AT THE NATIONAL
CANCER INSTITUTE.
OUR FIRST SPEAKER, DR. HWANG,
COMPLETED HIS BACHELOR'S IN
BIOCHEMISTRY AND CHEMISTRY AT
THE UNIVERSITY OF KANSAS IN
1985.
AS A FULBRIGHT SCHOLAR, GENETICS
RESEARCH AT THE INSTITUTE OF
TECHNOLOGY UNIVERSITY OF ZURICH
FOR A YEAR AFTER WHICH HE CAME
TO THE JOHNS HOPKINS UNIVERSITY
SCHOOL OF MEDICINE EARNING BOTH
HIS M.D. AND PH.D. IN 1993.
DR. HWANG COMPLETED HIS
INTERNSHIP AND RESIDENCY IN
INTERNAL MEDICINE AT THE
UNIVERSITY OF CALIFORNIA
SAN FRANCISCO FOLLOWED BY A
CLINICAL FELLOWSHIP IN
CARDIOLOGY AND POSTDOCTORAL
RESEARCH IN ONCOLOGY AT JOHNS
HOPKINS.
IN 2001, DR. HWANG JOINED NHLBI
AS A TENURED TRACK INVESTIGATOR
IN THE CARDIOVASCULAR BRANCH
BECOMING A SENIOR INVESTIGATOR
IN 2011 IN NHLBI'S CENTER.
DR. HWANG'S WORK ON A TUMOR
SUPPRESSOR PROTEIN P53
DEMONSTRATED -- AGAINST
OXIDATIVE AND OTHER EXPRESSES.
HIS WORK AS FOCUSED ON THIS LINK
BETWEEN CANCER AND MITOCHONDRIAL
METABOLISM WHICH ALSO IMPACTS
THE CARDIOVASCULAR SYSTEM.
BY USING MOUSE MODELS AS WELL AS
PERFORMING TRAN LAITIONAL
STUDIES IN PATIENTS WITH
LI-FRAUMENI SYNDROME, A CANCER
PREDISPOSITION DISORDER CAUSED
BY DIVERSE GERMLINE MUTATIONS IN
THE TP53 GENE WITH ACCOMPANYING
MUTATION SUBTYPE.
DR. HWANG'S GROUP CONTINUES TO
STUDY REGULATION OF MITOCHONDRIA
IN MODEL SYSTEMS, DETERMINING
RELEVANCE TO HUMAN DISEASES, AND
HE HAS AUTHORED MANY
PUBLICATIONS AND SERVED ON
VARIOUS EDITORIAL BOARDS.
HE'S AN ELECTED MEMBER AT THE
AMERICAN SOCIETY FOR CLINICAL
INVESTIGATION AS A AS A FELLO N
CARDIOLOGY.
OUR SECOND SPEAKER WILL BE
DR. PAYAL KHINCHA.
SHE COMPLETED PEDIATRIC
RESIDENCIES IN MAIMONIDES
MEDICAL CENTER IN NEW YORK, AND
THEN A FELLOWSHIP IN PEDIATRIC
HEMATOLOGY-ONCOLOGY IN
WASHINGTON, D.C., WHILE ALSO
EARNING A MASTER'S IN HEALTH
SCIENCES IN CLINICAL AND
TRANSLATIONAL RESEARCH AT GEORGE
WASHINGTON UNIVERSITY.
IN 2012, DR. KIN SHE JOINED ASA
CLINICAL FELLOW IN 2014 AND ROSE
TO STAFF CLINICIAN IN 2017 AND
SINCE 2018 HAS BEEN LEADING
NCI'S STUDY OF LI-FRAUMENI
SYNDROME AS A PRINCIPAL
INVESTIGATOR.
SHE SUCCESSFULLY APPLIED TO
CLINICAL INVESTIGATOR
DEVELOPMENT PROGRAM AND HAS BEEN
AN ASSIST TANT CLINICAL
INVESTIGATOR SINCE 2020.
HER RESEARCH FOCUSES ON
HEREDITARY CANCER PREDISPOSITION
SYNDROMES, SPECIFICALLY THOSE
AFFECTING CHILDREN.
ETIOLOGY, SCREENING, EARLY
DETECTION, RISK MODIFIERS AND
PREVENTION OF HEREDITARY CANCER.
HER RESEARCH AIMS INCLUDE
CHARACTERIZING CANCER RISK,
PATTERNS AND GENOTYPE-PHENOTYPE
CORRELATIONS OF CANCER WITH
SPECIFIC MUTATION TYPES OR TP53
AND LI-FRAUMENI SYNDROME.
ASSESSING SURVEILLANCE ON
INDIVIDUALS AND FAMILIES WITH
LFS, AND DETERMINING IF CHANGE
IN MITOCHONDRIAL FUNCTION IS
ASSOCIATED WITH CANCER INCIDENCE
IN THE LFS POPULATION.
DR. KHINCHA'S WORK HAS LED TO
IMPORTANT INSIGHTS INTO LFS,
INCLUDING THE NEED FOR
COMPREHENSIVE CANCER SCREENING
IN THESE PATIENTS.
OF SIGNIFICANCE, HER GROUP WAS
FIRST TO DESCRIBE THE BENEFICIAL
EFFECTS OF BREASTFEEDING IN
WOMEN WITH LFS IN REDUCING
FUTURE BREAST CANCER RISK.
SHE HAS PUBLISHED OVER 40 PAPERS
AND BOOK CHAPTERS IN THE FIELDS
OF LFS, DYSKERATOSIS CONGENITA
AND TELOMERE BIOLOGY, AND FOR
2023, SHE HAS RECEIVED THE NCI
DIRECTOR'S INNOVATION CLINICAL
INVESTIGATOR AWARD FOR HER
PROPOSAL, NOVEL STRIKE THAT STRR
EARLY DETECTION IN INDIVIDUALS
WITH LI-FRAUMENI SYNDROME.
SHE IS BOARD CERTIFIED IN
PEDIATRICS AND PEDIATRIC
HEMATOLOGY-ONCOLOGY.
NOW PLEASE WELCOME OUR SPEAKERS,
DR. HWANG AND DR. KHINCHA, WHOSE
PRESENTATION IS ENTITLED
TARGETING METABOLISM AND CANCER
PREVENTION IN LI-FRAUMENI
SYNDROME.
I'D LIKE TO START OUT BY
THANKING DR. BURKLOW FOR THIS
OPPORTUNITY TO PRESENT AT THE
CLINICAL CENTER GRAND ROUNDS.
SO IT'S IMPORTANT FOR ME TO
THANK MEMBERS OF MY LABORATORY
WHO HAVE DONE ALL THE WORK.
SO THE LEARNING OBJECTIVE TODAY
IS FOR ME TO TRY TO GIVE YOU AN
APPRECIATION OF THE CHANGES IN
MITOCHONDRIAL METABOLISM THAT
OCCUR IN A EARLY ONSET
HEREDITARY CANCER DISORDER KNOWN
AS LI-FRAUMENI SYNDROME CAUSED
BY P53 MUTATIONS THAT COULD
POTENTIALLY BE TARGETED FOR
CANCER PREVENTION.
I HAVE NO DISCLOSURES.
SO I SHOULD MENTION THAT THIS
BASIC AND TRANSLATIONAL
PRESENTATION WILL BE FOLLOWED BY
DR. PAYAL KHINCHA, WHO WILL
ACTUALLY GO OVER MORE OF THE
CLINICAL ASPECTS OF LI-FRAUMENI
SYNDROME, AND A PLANNED CHEMO
PREVENTION STUDY THAT AGAIN
DR. KHINCHA WILL GO OVER BASED
ON SOME OF THESE BASIC
TRANSLATIONAL WORK.
SO AS OUTLINED HERE, I'LL TRY TO
GIVE YOU AN OVERVIEW OF HOW WILD
TYPE AND MUTANT P53 CAN PROMOTE
MITOCHONDRIAL METABOLISM AND
THEN SHARE WITH YOU SOME
PREVIOUSLY PUBLISHED WORK IN
WHICH WE HAVE SHOWN THAT BOTH
THE GENETIC OR PHARMACOLOGIC
INHIBITION OR DISRUPTION OF
MITOCHONDRIAL FUNCTION CAN HAVE
CANCER PREVENTIVE EFFECTS AT
LEAST IN AN LFS MOUSE MODEL AND
THAT IT IS ALSO POSSIBLE
PHARMACOLOGICALLY -- IN LFS
PATIENTS WITH SIGNALING CHANGES
THAT APPEAR TO BE CANCER
PROTECTIVE, AT LEAST IN THE
MOUSE MODELS.
AND THEN I'LL FINISH OFF WITH A
LITTLE BIT MORE RECENT WORK
WHICH HAS SHOWN THAT INHIBITING
SPECIFIC ACTIVITY OF THE
MITOCHONDRIA -- OXIDATION CAN
ALSO HAVE CANCER-PREVENTIVE
EFFECTS.
SO JUST AS A GENERAL
INTRODUCTION, P53 WHICH IS
ENCODED BY THE HUMAN TP53 GENE
IS THE MOST FREQUENTLY MUTATED
TUMOR SUPPRESSOR GENE IN HUMAN
CANCERS, INDICATING ITS CRITICAL
IMPORTANCE IN CANCER FORMATIONS
IN PATIENTS.
AND THIS COULD BE BEST DESCRIBED
AS A TRANSCRIPTION FACTOR THAT
REGULATES MANY DIFFERENT
DOWNSTREAM GENES IN CELL CYCLE
REGULATION, DNA REPAIR OR
MAINTAINING GENOMIC INTEGRITY.
SO A NUMBER OF YEARS AGO, WE
SHOWED THAT BOTH WILD TYPE AND
MUTANT P53 CAN PROMOTE
MITOCHONDRIAL FUNCTION AND IT
DOES SO BY TRANS ACTIVATING A
NUMBER OF IMPORTANT GENES SUCH
AS SCO2, AND MITOCHONDRIAL
TRANSCRIPTION FACTOR -- AS WELL
AS MUCH MORE THAN WHAT'S
ACTUALLY LISTED ON THIS SLIDE IN
THE NUCLEUS, MANY MORE GENES
HAVE BEEN SHOWN TO BE REGULATED
BY P53.
IT ALSO HAS ACTIVITIES DIRECTLY
IN THE MITOCHONDRIA, ALSO
IMPORTANT FOR REGULATING THE
MITOCHONDRIAL GENOME, WHICH IS
SEPARATE FROM THE NUCLEIC
GENOME.
ALL WHICH IMPACT THINGS SUCH AS
EXERCISE CAPACITY, WHEREBY A
MUTANT P53 -- MUTANT ALLELE DOSE
DEPENDENT MANNER INCREASE
EXERCISE CAPACITY OF MICE IN
SINGLE POINT MUTATION SO THAT IN
THE HOMOZYGOUS MUTANT STATE,
MICE CAN -- MUTANT MICE CAN
EXERCISE TWICE AS MUCH, RUN
TWICE AS MUCH AS WILD TYPE
SIBILITIES.
SIBLINGS.
AT THAT TIME, THE IMPACT OF THIS
MITOCHONDRIAL FUNCTION WAS LESS
CLEAR ON TUMORIGENESIS, WHICH I
WILL BE GOING INTO SUBSEQUENTLY.
SO BESIDES JUST MOUSE MODELS AND
CELL LINES, WE ALSO WANTED TO
DETERMINE THE RELEVANCE OF THIS
ACTIVITY OF P53 IN THE
MITOCHONDRIA IN HUMANS UNDER
NORMAL PHYSIOLOGIC CONDITIONS.
SO AT THAT TIME EARLY ON, WE
TURNED TO THE LI-FRAUMENI
SYNDROME, AGAIN WHO HAVE
MUTATIONS OF P53 AND BECAUSE
WILD TYPE P53, WE INITIALLY
OBSERVED THAT WILD TYPE P53
PROMOTES MITOCHONDRIAL FUNCTION,
WE SPECULATED THAT MUTATIONS OF
P53, INDIVIDUALS WITH
MUTATIONINGS OF P53 MAY ACTUALLY
HAVE A DEFICIT IN MITOCHONDRIAL
FUNCTION AND MUCH TO OUR
SURPRISE AT THAT TIME, WE
ACTUALLY OBSERVED THAT USING
THIS VERY NONINVASIVE P51MRS
SPECTROSCOPY TECHNIQUE, WE WERE
ABLE TO SHOW AS A MARKER OF
MITOCHONDRIAL FUNCTION, WE WERE
ABLE TO SHOW THAT PATIENTS WITH
P53 MUTATIONS CARRIERS HAVE
FASTER RECOVERY TIME, SUGGEST
THAT IT HAS GREATER OX TAITION
PHOSPHORYLATION CAPACITY
COMPARED TO INDIVIDUALS WHO HAD
WILD TYPE P53.
THIS WAS FURTHER SUBSTANTIATED
IN MOUSE MODELS, NFS MOUSE
MODELS, AS I ALLUDED TO EARLIER,
AND MECHANISTICALLY, WE THINK
THAT THIS INCREASED
MITOCHONDRIAL ACTIVITY OCCURS
THROUGH, FOR EXAMPLE, THE MUTANT
P53 BEING ABLE TO INTERACT
WITH THE TRANSCRIPTION FACTOR
EPS2 TO -- TFAM.
YOU CAN SEE VERY NICELY IN A
MUTANT ALLELE DOSE-DEPENDENT
MANNER, H/H IS THE MUTANT
ALLELE, YOU CAN SEE THIS
INCREASED TFAM MRNA
TRANSCRIPTION, LOSS OF THE
PROTOTYPICAL WILD TYPE P53
TARGET CHAIN P21 THAT'S CRITICAL
FOR CELL CYCLE REGULATION.
SO WITH LOSS OF WILD TYPE
ACTIVITY YOU ACTUALLY SEE A GAIN
OF MITOCHONDRIAL BIOGENESIS AND
WE THINK THROUGH THIS GAIN OF
FUNCTION OF MUTANT P53
TRANSCRIPTION FACTORS.
AND SO WITH THE GROWING EVIDENCE
THAT MITOCHONDRIAL METABOLISM IS
IMPORTANT IN CANCER FORMATION,
WE WONDERED WHAT MIGHT BE THE
EFFECT OF DISRUPTING
MITOCHONDRIAL FUNCTION IN THE
LFS MOUSE MODEL, AND THIS IS
USING THE HUMAN HOT SPOT MUTANT
P53 MODEL, THE 175 MOUSE IN THE
172 POSITION.
AND WE TURNED TO THE THYMUS
TISSUE BECAUSE THAT'S WHERE MOST
OF THE TUMORS THAT T-CELL
INFORMERS DEVELOP IN LFS MOUSE
MODELS.
SO WE WERE ABLE TO SHOW THAT IF
WE CROSS THESE MICE WITH MUTANT
MICE, WE ACTUALLY INTRODUCE --
INTO THE GENOME AND DISRUPT
MITOCHONDRIAL FUNCTION THAT WE
WERE ABLE TO DECREASE
MITOCHONDRIAL -- CONSUMPTION IN
THE THYMUS TISSUE, AGAIN THE
TISSUE WHERE TUMORS DEVELOP IN
THE LFS MOUSE MODELS.
INCREASINGLY THERE'S AN INCREASE
IN BLOOD -- LEVEL -- THERE'S A
TREND THERE.
SUGGESTING THAT THERE MAY BE
COMPENSATORY INCREASE IN
GLYCOLYSIS AND WE'RE ABLE TO
SHOW THAT AT THE BIOGENESIS
LEVEL AS WELL IN THE
MITOCHONDRIAL PROTEINS AS WELL
AS THE GLYCOLYSIS -- IN SKELETAL
MUSCLE.
THE IMPORTANT QUESTION IS,, DOES
MODERATING MITOCHONDRIAL
FUNCTION IN THE THYMUS TISSUE
AFFECT CANCER DEVELOPMENT.
AND THE ANSWER IS YES, WE WERE
ABLE TO ACTUALLY SHOW THAT
COMPARED TO THE LFS GENETIC
BACKGROUND WHICH DEVELOP TUMORS
AND CANCER-FREE SURVIVAL, YOU
CAN SEE THERE WAS A 40% INCREASE
IN CANCER-FREE SURVIVAL IN THE
HETEROZYGOUS MUTANT MICE AND IN
HOMOZYGOUS THERE WAS A -- IN
CANCER SURVIVAL BY INCLUDING
THIS MUTATION.
SOME OF YOU MAY ALREADY KNOW THE
HOMOZYGOUS MUTANT MICE ACTUALLY
HAVE A VERY SEVERE -- THE
HETEROZYGOUS STATE HAS ONLY A
MILD MITOCHONDRIAL EFFECT AND
ACTUALLY HAVE BEEN SHOWN TO HAVE
NO OVERT PHENOTYPE, ACTUALLY
HAVE NORMAL LIFESPAN.
SO INTRODUCING A MILD
MITOCHONDRIAL GENETIC -- MILD
DEFICIENCY MITOCHONDRIA, YOU CAN
SEE THERE WAS A VERY NICE
IMPROVEMENT.
WE ALSO WONDERED ABOUT WHAT
SIGNALING PATHWAYS MIGHT
CONTRIBUTE TO SUCH A PHENOMENON,
SO WE LOOKED AT THYMUS TISSUE
AGAIN AND IT'S KNOWN THAT THE
MUTANT P53 DOWNREGULATES
AUTOPHAGY AND YOU WOULD EXPECT
THAT WITH POLYMER US GAMMA
MUTANT WHERE WE ACTUALLY
INCREASE MITOPHAGY AND AUTOPHAGY
AND INDEED, WE WERE ABLE TO SHOW
THAT IF YOU CROSS AGAIN THE HET
ZYGHETEROZYGOUS STATE INTO THE
BACKGROUND -- IMPORTANTLY, THE
DOWNSTREAM SIGNALING TARGETS
SUCH AS CYCLIN D1, WAS ACTUALLY
DOWN REGULATED IN THYMUS TISSUE.
SO ALTHOUGH WE DO NOT HAVE
EVIDENCE THAT THIS IS THE ONLY
PATHWAY INVOLVED, THIS SORT OF
SIGNALING, ANTIPROLIFERATIVE
SIGNALING PROBABLY CONTRIBUTE TO
THIS CANCER PREVENTIVE EFFECT BY
MILDLY DISRUPTING MITOCHONDRIAL
FUNCTION.
SO AT THIS POINT, THE QUESTION
WAS, IS IT POSSIBLE TO REPRODUCE
THIS GENETIC BENEFIT OF TUMOR
SUPPRESSION BY INHIBITING
MITOCHONDRIA PHARMACOLOGICALLY,
WITH THE IDEA THAT POTENTIALLY
THIS SORT OF STRATEGY COULD BE
USED FOR CHEMO PREVENTION IN
PATIENTS WITH LI-FRAUMENI
SYNDROME.
TO DO THIS, WE TURNED TO
METFORMIN.
METFORMIN, AS MANY OF YOU
ALREADY KNOW, IS A VERY
WELL-KNOWN ANTIDIABETIC DRUG,
VERY GOOD DRUG, HAS A MYRIAD OF
DIFFERENT METABOLIC EFFECTS AND
ONE OF THE EFFECTS IS THAT IT'S
KNOWN TO INHIBIT MITOCHONDRIA
EXPRESSION THROUGH COMPLEX 1.
IT IS A VERY SAFE AND WELL
TOLERATED MEDICATION, AND THE
BEST THING HERE OR ONE OF THE
BEST THINGS HERE IS THAT IT IS
NOT HYPOGLYCEMIC, SO IT CAN BE
TAKEN BY ANY INDIVIDUAL WITHOUT
DIABETES WITHOUT WORRYING ABOUT
HYPOGLYCEMIA.
SO WE DID A EXPERIMENT WITH
MICE.
WE HAD THEM DRINKING METFORMIN
IN DRINKING WATER LONG TERM, AND
THESE WERE DOSES THAT HAD BEEN
SHOWN TO RESULT IN PLASMA LEVELS
OF METFORMIN THAT ARE
THERAPEUTIC, AT LEAST AT THE
HUMAN THERAPEUTIC DOSES.
SO THIS IS NOT USING
SUPERPHYSIOLOGIC DOSES OF
METFORMIN IN MICE, AND WE WERE
ABLE TO SHOW DOSE-DEPENDENT
DECREASE IN OXYGEN CONSUMPTION
IN THE THYMUS TISSUE, INHIBITING
RESPIRATION AND THE CYCLIN D1 IS
ALSO DECREASED COMPARED TO
DRINKING PLAIN WATER.
IMPORTANTLY, WE WERE ABLE TO
SHOW A 25% INCREASE IN
MEDIAN-FREE -- CANCER-FREE
SURVIVAL USING THE
DOSE-DEPENDENT -- USING THE
HIGHER DOSE HERE.
AGAIN, THERAPEUTIC HUMAN
THERAPEUTIC DOSES.
SO ENCOURAGED BY THESE RESULTS,
WE COLLABORATED WITH NCI
INVESTIGATORS WHO WERE
INTERESTED IN LOOKING AT
METFORMIN AS -- LOOKING AT THE
SAFETY OF METFORMIN IN LFS
PATIENTS AND OUR END POINT WAS
TO MEASURE THE MITOCHONDRIAL
FUNCTIONS BEFORE, DURING AND
POST TREATMENT.
AND THIS WAS WORK DONE IN
COLLABORATION INITIALLY WITH DRN
SAVAGE AND DR. KHINCHA.
SO THIS IS A SCHEME OF THE
PILOT, THE LFS PATIENTS WAS
GIVEN METFORMIN AS YOU CAN SEE
HERE, DOSE ESCALATING
500 MILLIGRAMS PER DAY,
INCREASED UP TO A TOTAL OF
2,000 MILLIGRAMS DAILY OVER THE
COURSE OF EIGHT WEEKS AND THIS
IS FDA-APPROVED DOSE OF -- THE
WASHOUT PERIOD OF SIX WEEKS AT
THE END.
AND WE WERE ABLE TO SHOW IN EX
VIVO IS LATED THAT INDEED WE
COULD SHOW MITOCHONDRIAL OXYGEN
CONSUMPTION DECREASE IN THE
BLOOD MONOCYTES OF THIS PATIENT
TAKING THE PEAK DOSES OF
METFORMIN AT 8 WEEKS AND 14
WEEKS, AND WITH WASHOUT AFTER
6 WEEKS OF WASHOUT, THERE WAS
SOME RECOVERY AS SHOWN HERE.
AND IN TERMS OF BIOMARKERS IN
THE BLOOD, WE WERE ABLE TO SHOW
HERE, WE JUST LOOK AT CYCLIN D1,
THAT THERE WAS A DECREASE IN
PSYCYCLIN D1 LEVELS AND THIS IS
WHAT WE OBSERVED IN THE THYMUS
TISSUE IN LFS MICE AS YOU MAY
RECALL.
LASTLY, WE WERE ABLE TO OBTAIN
NONINVASIVE IN VIVO EVIDENCE OF
MITOCHONDRIAL INHIBITION IN
SKELETAL MUSCLE USING P31MR SPEC
TSPECTROSCOPY THAT I MENTIONED
EARLIER.
GENERATION OF THE EXERCISE
DEPLETION AND SO THE FASTER IT
IS, THE GREATER THE CAPACITY, SO
YOU CAN SEE COMPARED TO CONTROL
BASELINE WITHOUT -- BEFORE
METFORMIN TREATMENT THAT THERE'S
AN INCREASE IN RECOVERY TIME
CONSTANT, INDICATING THIS
DECREASE OF OXIDATIVE
PHOSPHORYLATION AT THE TIMES OF
THE -- TREATED TIMES OF 8 WEEKS
AND 14 WEEKS AND THEN AFTER
6 WEEKS OF WASHOUT, WE CAN SEE
THE CHANGE IN TIME CONSTANT
BECOMES NON-SIGNIFICANT.
AND SO THIS AT LEAST WAS VERY
GOOD EVIDENCE FOR US THAT WE
COULD IN VIVO SHOW EVIDENCE OF
DECREASED MITOCHONDRIAL FUNCTION
IN A TISSUE THAT GIVES RISE TO
ONE OF THE PROTOTYPICAL TUMORS
OF LI-FRAUMENI SYNDROME, WHICH
IS RHABDOMYOSARCOMA.
SO BASED ON THIS, DR. KHINCHA
WILL DISCUSS SOME OF THE PLANS
ABOUT POTENTIAL METFORMIN CUOMO
PREVENTION STUDY IN THE NEXT
PART OF THIS GRAND ROUNDS.
IN TERMS OF US BACK IN THE
LABORATORY, A QUESTION THAT
AROSE IS THAT CAN WE INHIBIT
SPECIFIC ACTIVITY OF THE
MITOCHONDRIA RATHER THAN
GLOBALLY INHIBITING
MITOCHONDRIAL RESPIRATION BY
COMPLEX 1 USING METFORMIN, IS
THERE SPECIFIC ACTIVITY THAT CAN
INHIBIT MITOCHONDRIA THAT CAN
ALSO BE PROTECTIVE AGAINST
TUMORIGENESIS.
AND TO DO THIS, WE TURNED TO
FATTY ACID OXIDATION OF THE
MITOCHONDRIA.
THERE'S OBVIOUSLY INCREASING
EVIDENCE IN THE LITERATURE
SHOWING THAT FATTY ACID
METABOLISM CONTRIBUTES TO
TUMORIGENESIS, AND IN FACT, IN A
RECENT MOUSE THAT WE MADE, THIS
IS ANOTHER LFS MUTANT MOUSE, THE
178.
IN HUMANS IT'S 181.
WE ACTUALLY OBSERVED INCREASE
LIPOLYSIS IN WHITE ADIPOSE
TISSUE.
MECHANISTICALLY THIS APPEARS TO
BE WITH THE MUTANT P53 BINDING
TO BINDING SITE OF THE
ADRENERGIC BETA RECEPTOR 3 THAT
SIGNALS DOWNSTREAM TO INCREASE
LIPOLYSIS AND GIVES IT THIS LOW
BODY FAT PHENOTYPE.
IN FACT, EARLY ON IN OUR
STUDIES, WE ACTUALLY OBSERVED
INCREASED FATTY ACID OXIDATION
IN THE HOT SPOT MUTANT MOUSE
THAT WE'RE USING FOR ALL OUR
STUDIES.
IN FACT, IF YOU DO WHOLE BODY
METABOLISM STUDIES, YOU CAN SEE
THAT THE HOMOZYGOUS MUTANT MICE
SHOWN HERE H/H ACTUALLY HAVE A
LOWER RESPIRATORY EXCHANGE
RATIO, CO2 PRODUCTION OF OXYGEN
CONSUMPTION.
THAT'S A MARKER THAT THESE MICE
PREFER TO USE IN FATTY ACIDS
VERSUS CARBOHYDRATES FOR THEIR
OXIDATIVE M METABOLISM.
SO WE WONDERED WHETHER WE COULD
PERHAPS INHIBIT THIS ACTIVITY,
AND WE TOOK ADVANTAGE OF A MOUSE
THAT'S ACTUALLY AVAILABLE TO US,
THE MYOGLOBIN KO MOUSE.
YOU CAN SEE THEY HAVE A
HIGHER -- KNOCKOUT MICE HAVE A
HIGHER RESPIRATORY EXCHANGE
RATIO.
SO IF WE CROSS THESE TWO MICE
THAT HAVE LOW LFS, HIGH RER,
KNOCKOUT, CAN WE NORMALIZE IT,
WITH IWHICH IS A SIMPLE IDEA.
WE WERE ABLE TO SHOW WHEN WE
MADE A DOUBLE MUTANT MOUSE, YOU
CAN SEE THAT THE THYMUS FATTY
ACID THYMUS TISSUE AGAIN WHERE
THE TUMOR DEVELOPS, THE FATTY
ACID OXIDATION WAS ACTUALLY
DECREASED ALMOST TO WILD TYPE
LEVELS.
AND WE WERE ABLE TO SHOW THIS
30% IMPROVEMENT IN CANCER-FREE
SURVIVAL, MEDIAN CANCER-FREE
SURVIVAL IN THE DOUBLE MUTANT
MICE SIMPLY BY DOWNREGULATING
FATTY ACID OXIDATION.
SO FINALLY, WE WANTED TO KNOW,
IS THERE -- RATHER THAN JUST --
SO ONE OF THE REASONS -- WE
BELIEVE THE REASON WHY THIS
INCREASED FATTY ACID OXIDATION
IN THE KNOCKOUT MICE --
DIMINISHED -- AND FATTY ACID
OXIDATION IS A VERY
OXYGEN-INTENSIVE PROCESS AND SO
CARBOHYDRATES ARE PREFERRED
PERHAPS BY THESE MICE.
BUT WE WANTED TO TEST THIS
WHETHER THIS IS A CELL
AUTONOMOUS PROCEDURE, I THINK I
JUMPED ONE SLIDE AHEAD, SORRY.
THIS IS JUST TO SHOW THAT THE
MYOGLOBIN KNOCKOUT CORRECTS THE
SIGNALING IN THE THYMUS TISSUE.
LOOKING HERE AT THE MTOR
SIGNALING TARGET, YOU CAN SEE
THE LFS MICE WITH WILD TYPE --
HAVE INCREASED CELL GROWTH, YOU
CAN SEE WHEN YOU REMOVE THE
MYOGLOBIN, THERE'S DECREASED
SIGNALING.
JUMPING BACK AGAIN, WE WANTED TO
TEST WHETHER THIS DECREASE IN
FATTY ACID OXIDATION BEING
CANCER PROTECTIVE COULD BE
DEMONSTRATED AT THE CELL
AUTONOMOUS LEVEL, SO WE TOOK
ADVANTAGE OF ANOTHER KNOCKOUT
MOUSE AVAILABLE TO US.
THIS IS THE CP T2 KNOCKOUT
MOUSE.
THE CPT2 IS IMPORTANT FOR FATTY
ACID TRANSPORT INTO THE
MITOCHONDRIA FOR ITS OXIDATION,
AND SO WE TOOK A HETEROZYGOUS
MICE WITH THIS AND CROSSED THEM
WITH CD4 CRE MICE, SO THESE MICE
WOULD ONLY HAVE KNOCKOUT OF
FATTY ACID OXIDATION OR
SUFFICIENCY -- IN THE T-CELLS
WHERE THE TUMORS DEVELOP.
AGAIN, JUST SHOWING THAT WE
COULD DECREASE FATTY ACID
OXIDATION MILDLY IN THESE MICE
WHEN CROSSED AGAIN WITH THE
CD4 CRE MICE AND MOST
IMPORTANTLY, WE WERE ABLE TO
SHOW THIS APPROXIMATELY 30%
IMPROVEMENT IN CANCER-FREE
SURVIVAL WITH A SLIGHT DECREASE
IN FATTY ACID OXIDATION.
SO NOT ONLY JUST GLOBALLY
INHIBITING MITOCHONDRIA, BUT
JUST SELECTIVITY INHIBITING ONE
ACTIVITY OF THE MITOCHONDRIA
APPEARS TO BE ABLE TO CONFER
THIS CANCER-PREVENTIVE EFFECT.
SO TO SUMMARIZE, I HOPE I'VE
BEEN ABLE TO SHOW YOU THAT BOTH
BY GENETIC -- INHIBITION OF
MITOCHONDRIAL FUNCTION THAT WE
CAN HAVE CANCER-PREVENTIVE
EFFECTS IN ASSOCIATION WITH THIS
ANTIPROLIFERATION SIGNALING THAT
WE WERE ABLE TO OBSERVE.
AND THAT IT IS ALSO POSSIBLE
USING A VERY BENIGN DRUG SUCH AS
METFORMIN, WELL TOLERATED DRUG,
SO INHIBIT MITOCHONDRIAL
RESPIRATION IN LFS PATIENTS,
WITH, AGAIN, ANTI -- SIGNALING
BIOMARKERS IN THE BLOOD THAT WAS
ASSOCIATED WITH CANCER
PREVENTION IN THE MOUSE MODEL.
AND THIS THEN GIVES WAY TO
CONSIDER METFORMIN
CHEMOPREVENTION STUDY THAT
DR. KHINCHA WILL GO INTO IN THE
NEXT PRESENTATION.
AND IT ALSO POSSIBLE TO DO THIS.
MOST SPECIFICALLY TARGETING
FATTY ACID OXIDATION AND THEY
ARE VERY SPECIFIC FDA-APPROVED
DRUGS OR FATTY ACID OXIDATION
INHIBITORS AVAILABLE THAT ALSO
WE TESTED.
SO I WILL STOP HERE AND END WITH
ACKNOWLEDGING WORK THAT -- THIS
IS WORK THAT REALLY COULDN'T
HAVE BEEN DONE WITHOUT THE
PARTICIPATION OF THE LFS STUDY
PARTICIPANTS, THEIR TIME AND
DEDICATION, MY LAB MEMBERS, BOTH
PAST AND PRESENT MEMBERS, AND
THE MANY COLLABORATORS LISTED
HERE THAT HAVE CONTRIBUTED TO
THE STUDY OVER THE YEARS AND
ESPECIALLY DR. KHINCHA AND
DR. SAVAGE AND ANNUNZIATA.
THANK YOU.
DR. HWANG, THANK YOU SO MUCH FOR
THAT PRESENTATION.
THAT WILL HOPEFULLY SEGUE WELL
INTO WHAT I'M TALKING ABOUT.
AND I WILL BE TALKING MORE ABOUT
THE CLINICAL ASPECTS, TAKING A
LITTLE BIT OF A SWITCH, TALKING
ABOUT THE CLINICAL ASPECTS OF
LI-FRAUMENI SYNDROME, A BIT
ABOUT THE PHENOTYPES, WHAT'S
AVAILABLE FOR PRIMARY AND
SECONDARY CANCER PREVENTION, AND
HOPEFULLY END WITH SHARING WITH
YOU WHY THE WORK OF DR. HWANG
AND SO MANY OF HIS LAB MEMBERS
AND COLLABORATORS IS SO
IMPORTANT IN THIS SIN CHROME.
-- SYNDROME.
I HAVE NO DISCLOSURES FOR
TODAY'S TALK.
SO IN THE CLINICAL GENETICS
BRANCH, WE STUDY RARE DISEASE
AND SPECIFICALLY WE STUDY RARE
DISEASE THAT LEAD TO AN
INCREASED RISK OF CANCER.
MOST OF THE WORK THAT WE DO
SPANS THE SPECTRUM FROM ETIOLOGY
IN PHENOTYPE THROUGH EARLY
DETECTION IN CANCER SCREENING,
IMPACT MANAGEMENT, PREVENTION
AND POPULATION IMPACT OF THESE
SYNDROMES.
AND I'LL BE TOUCHING UPON MOST
OF THESE TODAY AS I TRY TO GIVE
YOU A WHIRLWIND TOUR OF WHAT LFS
ENTAILS AND SOME OF THE WORK
WE'RE DOING IN LFS.
SO LI-FRAUMENI SYNDROME OR LFS
WAS FIRST DESCRIBED IN 1969 HERE
AT THE NIH IN THE NATIONAL
CANCER INSTITUTE BY DRS. LI AND
FRAUMENI, FIRST AS EARLY ONSET
IN BREAST CANCERS.
WHAT YOU SEE IS MULTIPLE
GENERATIONS, MULTIPLE FAMILY
MEMBERS AFFECTED WITH A NUMBER
OF DIFFERENT CANCER TYPES.
WHILE IT WAS DESCRIBED IN 1969,
IT WASN'T UNTIL 1990, WHEN
GERMLINE -- AND I UNDERLINED
GERMLINE BECAUSE AS DR. HWANG
MENTIONED, P53 IS THE MOST
COMMONLY MUTATED GENE IN HUMAN
CANCER, BUT LI-FRAUMENI SYNDROME
IS SPECIFICALLY ASSOCIATED WITH
GERMLINE P53 VARIATION THAT WAS
FIRST ASSOCIATED IN 1990.
AND TO DATE, P53 VARIANTS REMAIN
THE ONLY KNOWN GENETIC CAUSE OF
LFS AND ACCOUNT FOR BETWEEN 70
TO 80% OF THOSE CLASSIC
CANCER-RIDDLED PEDIGREES THAT I
SHOWED YOU EARLIER, AND IT IS
INHERITED IN AUTOSOMAL DOMINANT
FASHION.
NOW OVER THE YEARS AS WE'VE
LEARNED MORE AND MORE ABOUT LFS
AND AS GENE PANEL TESTING HAS
BECOME MORE AND MORE THE NORM IN
ONCOLOGY CLINICS, WE SEE THAT AS
MANY OF THE HERITABLE CANCER
SYNDROMES, LFS HAS A SPECTRUM
THAT SPANS FROM THE VERY SEVERE
CANCER RIDDLED PEDIGREES ALL THE
WAY DOWN TO INCIDENTAL CARRIERS
WHERE P53 IS FOUND ON A GENETIC
TESTING STUDY, BUT THEY DON'T
REALLY HAVE THE CLASSIC CANCER
OR FAMILY HISTORY AND WHAT THIS
SPECTRUM REALLY MEANS IS
SOMETHING WE'RE TRYING TO
UNDERSTAND MORE.
NOW, TALKING ABOUT THE CANCER
PREDISPOSITION SYNDROME, LFS IS
ONE WHICH I THINK OF AS ONE OF
THE MOST SEVERE.
IT HAS ALMOST 100% PENETRANCE BY
AGE 70.
AND THE NUMBER OF CANCER TYPES
THAT CAN OCCUR ARE A MULTITUDE
AND THIS WILL EXPLAIN WHY WE DO
WHOLE BODY MRI-BASED SCREENING
THAT I'LL TALK ABOUT IN JUST A
MOMENT.
THIS DATA WAS DERIVED FROM THE
GERMLINE P53 DATABASE WHERE WE
LOOKED AT THE NUMBER OF CANCER
SITES THAT WERE LISTED IN OVER
2500 INDIVIDUALS WITH
LI-FRAUMENI SYNDROME AND AS YOU
CAN SEE, THE TOP ONES HERE ARE
THE MOST FREQUENT WITH BREAST
CANCER, EARLY ONSET BREAST
CANCER BEING BY FAR THE MOST
COMMONLY OCCURRING CANCER
INLESS.
IN
LI-FRAUMENI SYNDROME.
BUT THESE TOP FOUR OR FIVE WHICH
ARE EARLY ONSET BREAST CAN SE
SOFT TISSUES, BRAIN, ADRENAL
GLAND AND BONE TUMORS ARE ALSO
WHAT WE CALL THE CORE CANCERS OF
LFS BUT AS YOU SEE, THEY CAN
PRETTY MUCH DEVELOP CANCER
ANYWHERE IN THE BODY.
THERE ARE VERY, VERY FEW CANCERS
THAT WE CONSIDER NOT TO BE PART
OF THE LFS ASSOCIATED CANCER
SPECTRUM.
THE LI-FRAUMENI SYNDROME STUDY
WAS LAUNCHED HERE AT THE NCI
KIND OF AS A REINCARNATION OR
RESURRECTION, IF YOU WILL, OF
THE PREVIOUS STUDY FROM THE
60s AND 70s.
AND EVEN THOUGH WE HAD KNOWN
ABOUT LFS FOR MANY DECADES, UP
UNTIL THE EARLY 2000s,
INVESTIGATORS WERE REALLY
WORKING IN SILOS AND THERE
WASN'T A WHOLE LOT KNOWN MORE
ABOUT OUTSIDE OF WHAT THE CANCER
SPECTRUM MAY BE.
SO WE LAUNCHED THE STUDY UNDER
THE SUPERVISION OF DR. SAVAGE,
WHO IS BOTH MY MENTOR AND
CLINICAL DREG TORE AND SOME OF
THE OBJECTIVES OF THIS
LONGITUDINAL FAMILY STUDY WERE
TO MORE CLEELY DEFINE THE
CLINICAL SPECTRUM, LOOK AT
POTENTIAL RISK MODIFYING FACTORS
BEYOND THE GERMLINE VARIATION IN
P53, ESTABLISH AN EFFECTIVE
CANCER SCREENING PROGRAM,
POSSIBLY OTHER NOVEL CAUSATIVE
GENES FOR LFS, AND I THINK AN
IMPORTANT ASPECT OF THE STUDY IS
TO EVALUATE AND TAKE A DEEP DIVE
INTO THE PSYCHOSOCIAL MENTAL AND
FUNCTIONAL EFFECTS OF HAVING LFS
AND ALSO BEING PART OF A FAMILY
THAT HAS LFS.
TO DATE, WE HAVE ENROLLED OVER
220 FAMILIES AND OVER 900
PARTICIPANTS.
OVER 400 OF WHICH -- OF WHOM
HAVE LFS AND THE OTHER HALF IS
COMPRISED BY UNAFFECTED FAMILY
MEMBERS.
WE HAVE 146 OF THEERS
INDIVITHESE INDIVIDUALSWITH LFSL
CANCER SCREENING PROGRAM WHICH
I'LL TOUCH UPON IN A MOMENT.
TRYING TO UNDERSTAND THE ACTUAL
RISKS OF LFS COMPARED TO THE
GENERAL POPULATION, WE PERFORMED
THIS STUDY WITH ONE OF OUR
FELLOWS WHO IS A POSTDOC FELLOW
OR NOW A RESEARCH FELLOW IN CGB,
COMPARING OUR LFS COHORT AND THE
CANCER INCIDENCE TO THAT OF THE
GENERAL POPULATION USING THE
SEER DATABASE.
WHAT WE FOUND IS THAT
INDIVIDUALS WHO HAVE LFS ARE
OVERALL AT NEARLY 25 TIMES
HIGHER RISK OF DEVELOPING CANCER
THAN THE GENERAL POPULATION, AND
AS YOU CAN SEE FROM THIS GRAPH,
THE HIGHEST COMPARATIVE
INCIDENCE IS FROM CHILDHOOD UP
UNTIL THE AGE OF 30 BUT EVEN BY
THE AGE OF 60, INDIVIDUALS ARE
STILL AT A HIGHER RISK, ALMOST
TENFOLD HIGHER CANCER INCIDENCE
IN LFS COMPARED TO THE GENERAL
POPULATION.
WHEN WE BREAK IT DOWN BY CANCER
TYPES, THIS IS A BUSY SLIDE, BUT
WHAT I'LL DRAW YOUR ATTENTION TO
IS THESE BLACK ARROWS INDICATE
POPULATION-LEVEL RISK, SO WHEN
YOU LOOK AT ALL OF THE DIFFERENT
CANCER TYPES WHICH IS
OSTEOSARCOMA, BREATION CANCER,
BRAIN AND SOFT TISSUE SARCOMAS
AND LUNG CAN SE THESE ARE JUST
SOME OF THE MANY THAT WE
ANALYZED, THE MULTIFOLD
SOMETIMES MULTI-HUNDRED FOLD
HIGHER CANCER INCIDENTS IN LFS
COMPARED TO THE GENERAL
POPULATION JUST INDICATING HOW
MUCH HIGHER THEIR CANCER
DEVELOPMENT RISK IS.
LOOKING AT THE CUMULATIVE CANCER
INCIDENCE, YOU'VE GOT THE GRAPH
WITH FEMALES ON THE LEFT AND
MALES ON THE RIGHT, AND AS YOU
CAN SEE IN THE FEMALES, THE
CUMULATIVE CANCER INCIDENCE OF
BREAST CANCER REALLY OVERTAKES
ANYTHING THAT WOMEN GET AND BY
THE AGE OF 75, THERE'S WELL OVER
55% CUMULATIVE INCIDENCE OF
BREAST CANCER FOLLOWED BY ALL OF
THESE OTHER DIFFERENT CANCER
TYPES.
IN THE MALES, THE BRAIN AND SOFT
TISSUE SARCOMAS SEEM TO HAVE THE
HIGHEST CUMULATIVE INCIDENCE OF
CLOSE TO OR RIGHT OVER 20% BY
LATE ADULTHOOD.
IMPORTANT TO NOTE WAS IN
FEMALES, THE MEDIAN AGE AT FIRST
CANCER WAS 33 YEARS, MEANING BY
AGE 33, THEY HAD DEVELOPED AT
LEAST ONE CANCER, AND THE AGE IN
MALES, THE MEDIAN AGE OF FIRST
CANCER WAS 45 YEARS.
THIS DIFFERENCE IS REALLY DRIVEN
BY THE BREAST CANCER RISK IN
LFS.
THE BREAST CANCER RISK IN
ITSELF, THE MEDIAN AGE AT FIRST
BREAST CANCER WAS ALSO IN EARLY
30s, MEANING HALF OF THE WOMEN
ARE DEVELOPING BREAST CANCER IN
THEIR LATE ADOLESCENCE AND EARLY
ADULTHOOD.
LFS IS NOT ONLY A SYNDROME OF
HIGH CANCER RISK BUT ALSO A
SYNDROME WITH HIGH MULTI-CANCER
RISK, MEANING THEY CAN DEVELOP
NOT ONLY ONE BUT MELT PEL
SUBSEQUENT PRIMARIES IN NARE
LIFETIME.
ABOUT 50% OF THOSE THAT SURVIVED
A FIRST CANCER WENT ON TO
DEVELOP A SECOND.
ABOUT 50% OF THOSE WENT ON TO
DEVELOP A THIRD AND FOURTH AND
SO ON.
WE HAVE INDIVIDUALS IN THE STUDY
WHO HAVE DEVELOPED UP TO SEVEN,
EIGHT, NINE PRIMARY CANCERS IN
THEIR LIFETIME.
SO JUST LOOKING BACK AT THE
RISKS AND FEET KNOW TYPES AND
THE HETEROGENEITY OF PHENOTYPES
WITHIN LFS, IT IS VERY HARD TO
PREDICT WHAT IF ANY CANCERS WILL
OCCUR IN AN INDIVIDUAL AND IF
THEY OCCUR, WHAT AGE THAT WILL
BE AND WHAT CANCER THAT WILL BE.
SO LOOKING AT THIS
HETEROGENEITY, IT BECAME VERY
IMPORTANT TO ESTABLISH A
FEASIBLE AND EFFECTIVE CANCER
SCREENING PROGRAM FOR
INDIVIDUALS WITH LFS.
AND THE CURRENT SCREENING
RECOMMENDATIONS THAT ARE PART OF
THE NATIONAL COMPREHENSIVE
CANCER NETWORK OR THE NCCN
GUIDELINES ARE BASED ON WHAT IS
CALLED THE TORONTO PROTOCOL.
THIS IS A PROTOCOL THAT INCLUDED
INTENSE RADIOLOGICAL AND
BIOCHEMICAL SCREENING.
AND IS NOW A -- A VARIANT OF
THIS IS WHAT IS EMPLOYED AT
DIFFERENT INSTITUTES AROUND THE
WORLD THAT DO LFS SCREENING.
HERE I PRESENT TO YOU THE ONLY
LONGITUDINAL CANCER STUDY IN LFS
TO DATE SHOWING IN A MOSTLY
PEDIATRIC POPULATION THAT A
SMALL POPULATION OF 89
INDIVIDUALS, THAT THOSE
INDIVIDUALS WHO CHOSE TO UNDERGO
CANCER SCREENING OR SURVEILLANCE
HAD A STATISTICALLY HIGHER
OVERALL SURVIVAL COMPARED TO
THOSE WHO DID NOT.
AND THIS REALLY JUST HIGHLIGHTS
THE IMPORTANCE OF CANCER
SCREENING NOT ONLY IN EARLY
DETECTION BUT ALSO LONG-TERM
BENEFITS.
SO THE CANCER SCREENING ARM LFS
STUDY WAS LAUNCHED IN 2012,
WHERE WE INVITED A SUBSET OF
THOSE WHO WERE ENROLLED IN OUR
LFS STUDY TO COME TO THE
CLINICAL CENTER FOR ANNUAL
CANCER SCREENING, AND THIS WAS
INDIVIDUALS AND FAMILIES OF ALL
AGE OVER THREE YEARS, GIVEN THE
RESOURCES OF THE CLINICAL
CENTER.
WHAT THIS ENTAILED WAS FOR THE
CHILDREN UNDERGOING ANNUAL WHOLE
BODY MRI WITH AND WITHOUT
CONTRAST, ANNUAL BRAIN MRI,
ABDOMINAL ULTRASOUNDS EVERY FOUR
MONTHS AND BLOOD WORK EVERY FOUR
MONTHS.
THE ADULTS ALSO UNDERWENT ANNUAL
WHOLE BODY MRI, BRAIN PLAI, THEY
ALSO DID COLONOSCOPY SCREENING,
ENDOSCOPY HAS BEEN ADDED TO
THESE GUIDELINES.
FOR THE FEMALES WHO HAD NOT
UNDERGOB RISK REDUCING
MASTECTOMIES, THEY UNDERWENT
ANNUAL BREAST MRI STARTING AGE
20 OR YOUNGER DEPENDING ON THE
FAMILY HISTORY AND ANNUAL
MAMMOGRAPHY STARTING AT AGE 40,
AND THIS HAS NOW BEEN BROUGHT
DOWN TO AGE 30, GIVEN THE CANCER
RISKS.
TO DATE, WE HAVE SCREENED 146
INDIVIDUALS AT THE CLINICAL
CENTER AT LEAST ONCE, AND THESE
INDIVIDUALS RANGE FROM 3 TO 78
YEARS.
WE'VE HAD FAMILIES WHO COME BACK
FOR THEIR TENTH ANNUAL SCREENING
AND SOME WHO HAVE COME FOR FEW
FEWER.
WITH THE RESOURCES OF THE
CLINICAL CENTER AND THE
WONDERFUL COLLABORATION WITH
RADIOLOGY AND IMAGING
DEPARTMENT, WE'VE CREATED A
WEALTH OF RESOURCE FOR LEARNING
ABOUT SCREENING IN LFS, HAVING
DONE WELL OVER 775 ANNUAL
SCREENING VISITS TO DATE, WHICH
MEANS THAT THERE'S DATA ON WELL
OVER 700 WHOLE BODY AND BRAIN
MRIS THAT WE CONTINUE TO LEARN
FROM.
THE CANCER DETECTION RATE,
MEANING THE DETECTION OF
ASYMPTOMATIC PRIMARY
MALIGNANCIES HAS REMAINED
BETWEEN 2 TO 6% PER YEAR, AND
THIS IS NOT ACCOUNTING FOR THE
INTERVAL CANCERS THEY GET
BETWEEN THE TWO ANNUAL SCREENING
VISITS, SO THIS IS JUST LOOKING
AT WHAT WAS DIAGNOSED AT THEIR
SCREENING VISIT, AND OUR FORMAL
ANALYSIS IS CURRENTLY UNDERWAY
LOOKING AT LONG TERM BENEFITS
AND OTHER OUTCOMES FROM THIS
STUDY.
NOW WHEN YOU TALK ABOUT WHOLE
BODY MRI, I WANTED TO IMPRESS
UPON YOU THAT THIS REALLY IS
WHOLE BODY MRI.
WE DO SCANS ON THE MACHINES THAT
LOOK FROM HEAD TO TOE, AND AS
YOU CAN IMAGINE, THIS IS JUST
ONE OF MANY SEQUENCES THAT WE
GET AS PART OF THE STUDY.
LOOKING AT THESE LESIONS IS NO
EASY FEAT, BUT IT COMES WITH THE
BENEFIT OF PICKING UP SOME
REALLY EARLY CANCERS.
FOR EXAMPLE, I'M SHOWING YOU
HERE A SUBCOUNCILM SUBCENTIMETET
TURNED OUT TO BE A CARCINOMA
THAT WAS ADEQUATELY TREATED,
THIS INDIVIDUAL HAS HAD TWO
FURTHER PRIMARY MALIGNANCIES.
SO THE BENEFIT IS THERE, WITH
COST.
DR. SAVAGE LED A META-ANALYSIS
OF LOOKING AT INDIVIDUALS OF ALL
AGES WHO RECEIVED THEIR BASELINE
WHOLE BODY MRI AND TO REALLY
ESTABLISH WHAT THE DETECTION
WAS, AND WHAT THE FALSE
POSITIVITY WAS.
SO THIS STUDY HAD THE
PARTICIPATION OF 13 CENTERS FROM
FOUR CONTINENTS AROUND THE
WORLD, WHERE WE LOOKED AT 578
INDIVIDUALS OF ALL AGES WHO HAD
LFS, AND WITH THEIR DATA JUST AT
THE FIRST WHOLE BODY MRI, ENDED
UP WITH DETECTION OF 42 CANCERS.
THESE ARE 42 PRIMARY CANCERS IN
39 INDIVIDUALS, ALL OF WHICH
WERE TREATED WITH CURATIVE
INTENT.
AND WE HAVE A LIST OF THE
CENTERS ON THE LEFT BUT IF YOU
LOOK ACROSS THE STUDIES, 7% OF
THE INDIVIDUALS WHO UNDERWENT
WHOLE BODY MRI, BASELINE WHOLE
BODY MRI HAD AN ASYMPTOMATIC
PRIMARY MALIGNANCY DIAGNOSED.
SO IN SUMMARY, THERE WAS A 7%
DETECTION RATE FOR NEW LOCALIZED
MALIGNANCIES BY THE WHOLE BODY
BASELINE MRI.
THERE WAS DEFINITELY A FALSE
POSITIVE RATE THAT WAS VERY HIGH
IF YOU CAN IMAGINE LOOKING AT
THESE MULTIPLE SEQUENCES, I
ALWAYS TALK ABOUT LFS SCREENING
AS WHERE EVERY LESION IS GUILTY
UNTIL PROVEN INNOCENT.
MANY OF THESE LESIONS HAD TO
UNDERGO FOLLOW-UP EVALUATIONS,
SOME OF WHICH TURNED OUT TO BE
CANCER AND SOME OF WHICH DIDN'T.
BUT AS I SAID, ALL
SCREEN-DETECTED NEW CANCERS WERE
TREATED WITH CURATIVE INTENT.
THIS WAS REALLY ONE BIG STUDY
THAT ESTABLISHED THE IMPORTANCE
AND CLINICAL UTILITY OF WHOLE
BODY MRI IN MANAGEMENT OF CANCER
RISK AND EARLY DETECTION IN
INDIVIDUALS IN THE P53
MUTATIONS.
BUT AS I SAID, SCREENING AND LFS
COMES WITH A COST.
THERE ARE PHYSICAL, EMOTIONAL,
SOCIAL, MENTAL AND FINANCIAL
BURDENS WITH LFS AND LFS
SCREENING.
TO DESCRIBE THIS IN SOME OF THE
PARTICIPANTS' WORDS, AS I SAID,
WE HAVE A VERY ROBUST AND
COLLABORATIVE PSYCHOSOCIAL AND
BEHAVIORAL RESEARCH GROUP THAT
HAS BEEN DOING SOME WONDERFUL
RESEARCH, AND SOME OF THESE
WORDS HAVE COME FROM THOSE
STUDIES.
THIS IS ACTUALLY FROM AN
INDIVIDUAL WHO IS A PARTNER WHO
SOMEONE WHO HAS LFS, SO THIS
PERSON THEMSELF DOES NOT HAVE
LFS BUT IS THE SPOUSE OF SOMEONE
WHO HAS LFS AND SAID, WE'RE BOTH
JUST KIND OF WORRIED.
YOU'VE SEEN IT HAPPEN, YOU'VE
SEEN IT HAPPEN TO HER, HER
FATHER, HER SISTER, YOU KNOW
WHERE YOU FINISH THE RACE.
YOU JUST DON'T KNOW WHEN YOU'RE
FINISHING THE RACE.
WHEN TALKING ABOUT SCREENING AND
THE ANNUAL CANCER SCREENING THAT
HAS BEEN RECOMMENDED, ONE
PARTICIPANT SAID, WE PLAY
RUSSIAN ROULETTE ONCE A YEAR.
BUT THE GAME IS NEVER OVER.
AND TO QUOTE ANOTHER PARTICIPANT
WHO TALKED ABOUT JUST THE IMPACT
OF LFS, TALKING TO MY
ONCOLOGIST, I SAID THERE'S
CERTAIN THINGS YOU SHOULD KNOW,
AND ONE OF THEM SHOULD BE THAT
YOU'RE CERTAINLY GOING TO DIE OF
CANCER, BECAUSE THEN EVERY
LITTLE PAIN YOU GET IN YOUR
SIDE, YOU'RE LIKE, OH, THIS MUST
BE CANCER.
SO THIS IS JUST A VERY, VERY
SMALL SNAPSHOT INTO THE IMPACTS
OF HAVING LFS, BEING PART OF A
FAMILY THAT HAS LFS, AND
UNDERGOING CANCER SCREENING.
SO JUST LOOKING AT THE
HETEROGENEITY OF THE CANCER
RISKS, THE BENEFITS OF SCREENING
BUT ALSO THE CHALLENGES, IT
BECAME REALLY IMPORTANT FOR US
TO THINK FURTHER ABOUT NOT JUST
SECONDARY PREVENTION WITH EARLY
DETECTION, BUT ALSO PRIMARY
PREVENTION.
WHAT ARE SOME THINGS THAT WE CAN
EMPLOY LEVERAGE TO LOOK AT
PRIMARY CANCER PREVENTION IN
THESE INDIVIDUALS?
CURRENTLY THE ONLY OPTION THEY
HAVE FOR PRIMARY CANCER
PREVENTION IS REALLY
RISK-REDUCING BILATERAL
MASTECTOMY, AND WE START TALKING
ABOUT THIS TO REDUCE BREAST
CANCER RISK TO WOMEN AS YOUNG AT
17, 18 YEARS OLD, SO IMAGINE
HAVING THIS CLINIC WHERE YOU'RE
TALKING TO TEENAGERS AND YOUNG
ADULTS WHO HAVEN'T REALLY HAD
MANY LIFE EXPERIENCES YET,
ABOUT, YOU KNOW, INVASIVE
SURGERY TO REDUCE BREAST CANCER
RISK, BUT ALSO IMPRESSING UPON
THEM THAT THAT DOES NOT REDUCE
RISK OF OTHER CANCERS THAT CAN
OCCUR ACROSS THE BODY.
SO REALLY WE HAD TO DIG DEEP AND
SEE WHAT OF THE WORK THAT HAS
BEEN DONE SO FAR WERE REALLY
LEVERAGED INTO PRIMARY REVENGS.
PREVENTION.
THIS IS WHERE DR. HWANG'S WORK
HAS BEEN SO IMPORTANT.
I WON'T REHASH EVERYTHING HE
SAID BUT JUST TO POINT OUT THAT
P53 HAD MANY KNOWN FUNCTIONS IN
THE BODY AND ONE OF THOSE IS THE
DAMPENING METABOLIC
REPROGRAMMING.
SO LEMPLING LEVERAGING ALL THE L
WORK DR. HWANG AND HIS
COLLEAGUES HAD DONE, WE THOUGHT
ABOUT THIS AS AN INTERPLAY
BETWEEN METABOLISM AND ME METFON
THAT IS KNOWN TO INTERACT WITH
BOTH.
REALLY WHERE WE ARE NOW IS BASED
ON THE SUCCESS OF THE PILOT
STUDY, WE'RE DEVELOPING A PHASE
2 PHARMACOPREVENTIVE TRIAL OF
METFORMIN AND LFS.
THIS TRIAL IS CURRENTLY UNDER
SCIENTIFIC REVIEW AND IS BEING
DESIGNED AS A RANDOMIZED
NON-PLACEBO CONTROL TRIAL WITH A
FIVE-YEAR END POINT LOOKING AT
CANCER INCIDENCE.
RANDOMIZATION WILL BE BETWEEN
SCREENING AS WE CURRENTLY
RECOMMEND IT VERSUS SCREENING
AND METFORMIN TO COMPARE THE
CANCER INCIDENCE BETWEEN THESE
TWO ARMS IN INDIVIDUALS WHO HAVE
KNOWN PATH GENIC OR LIKE LEGAL
PATHOGENIC GERMLINE P53 MUTATION
AND HAVE NOT HAD METFORMIN USE
IN SIX MONTHS.
THIS WILL NOT ONLY PROVIDE AN
INFRASTRUCTURE FOR FURTHER SUCH
RESEARCH WITH PHARMACOPREVENTION
OR AGENTS OTHERWISE BUT ALSO
BUILD UPON THAT FOUNDATION THAT
WILL HELP US UNDERSTAND
UNDERLYING BIOLOGY AND
CARCINOGENESIS IN LFS LOOK AT
BIOMARKERS, METABOLIC PROFILING,
ALTERNATIVE SCREENING STRATEGIES
AND A NUMBER OF OTHER ITEMS THAT
WE'RE HOPING TO DO.
IMPORTANT TO NOTE AS WELL, WE
TALK ABOUT THIS STUDY HERE AT
THE NCI, WE'RE REALLY AT THE
FOREFRONT OF AN INTERNATIONAL
DISCUSSION THAT I SPEARHEADED
BETWEEN THE SITES IN U.K. AT
OXFORD, TORONTO, AND GERMANY,
WHERE WE SPENT THE BETTER PART
OF THE PANDEMIC COMING UP WITH A
SHARED PROTOCOL TO LAUNCH THE
SAME PHARMACOPREVENTIVE TRIAL AT
EACH OF THESE SN TERES.
THESE CENTERS.
THE IDEA IS EACH CENTER WILL
HAVE INDEPENDENT STUDY USING THE
SAME SHARED PROTOCOL, THE SAME
BIOSTATISTICS.
THE U.K. IS ALREADY FUNDED AND
THEY'RE HOPING TO BE UP AND
RUNNING IN THE NEXT COUPLE OF
MONTHS, AND CANADA AND GERMANY
ARE WAITING TO HEAR BACK FROM
FUNDING AGENCIES.
BUT THE IDEA IS, AT THE END OF
THIS FIVE YEARS, TO BE ABLE TO
PULL ALL OF THIS DATA TOGETHER
WITH WELL OVER 700 PARTICIPANTS,
EVERYTHING GOING WELL, AND
PERFORM A META-ANALYSIS, THAT
WILL HELP US DIVE MUCH DEEPER
INTO THE POTENTIAL EFFECTS OF
METFORMIN AS A POTENTIAL
PHARMACOPREVENTIVE AGENT IN LFS.
THE NCI STUDY ITSELF THAT I'M
LEADING IS BASED ON THE
WONDERFUL COLLABORATIVE
INFRASTRUCTURE THAT THE NIH
OFFERS.
WITH US IN DCEG HAVING EXPERTISE
IN LFS AND P53 WITH FIELD AND
FAMILY STUDIES, PARTICIPATION,
ENGAGEMENT AND TRACKING AND
REMOTE BIOSPECIMEN COLLECTION,
THAT THEY'VE DONE SUCCESSFULLY
FOR DECADES NOW, LEVERAGING THE
EXPERTISE OF CCR WITH EXPERTISE
IN CLINICAL TRIALS, WITH OTHERS,
AND ALSO THE WONDERFUL RESOURCES
OF THE CLINICAL CENTER.
ALSO BRINGING IN THE EXPERTISE
OF THE DIVISION OF CANCER
PREVENTION WITH INVOLVEMENT FROM
DR. PHIL CASSELL AND DR. HOWARD
PARNES WITH CANCER PREVENTION
STUDY EXPERTISE AND ALSO THE
NEWLY MINTED CANCER PREVENTION
CLINIC THAT MAY BE A WONDERFUL
INFRASTRUCTURE FOR THIS STUDY TO
BE LAUNCHED ON.
AND AS I MENTIONED, WE WILL BE
LOOKING NOT ONLY AS THE
POTENTIAL OF METFORMIN TO REDUCE
CANCER RISK IN LFS OR PREVENT
CANCERS FROM OCCURRING, BUT ALSO
PROVIDE THE OPPORTUNITY TO LOOK
AT MANY DIFFERENT UNDERLYING
BIOLOGICAL PHENOMENON IN LFS,
ONE OF WHICH IS METABOLOMICS
STUDIES, WE CURRENTLY HAVE
ONGOING BASELINE AND
LONGITUDINAL METABOLOMICS
STUDIES JUST BASED ON THE
RESULTS IN THE PILOT STUDY THAT
DR. HWANG MENTIONED WE DID
COLLABORATIVELY WITH THEM, AND
THIS WILL, I THINK, REALLY FORM
THE BASIS OF WHAT WE'RE ABLE TO
DO WITHIN THE METFORMIN TRIAL,
LOOK AT METABOLOMICS DIFFERENCES
BETWEEN THOSE WHO ARE TREATED
AND UNTREATED WITH METFORMIN,
LOOK SPECIFICALLY AT DIFFERENT
MECHANISMS OF ACTION OF
METFORMIN IN THESE INDIVIDUALS,
AND, OF COURSE, IDENTIFY
POTENTIAL NOVEL TARGET FOR
FUTURE INTERVENTION SUCH AS THE
FATTY ACID OXIDATION THAT
DR. HWANG MENTIONED, BUT ALSO
DELVING INTO OTHER -- BRANCH
CHAIN AMINO ACIDS, ET CETERA.
WHAT THIS TRIAL WILL ALSO DO IS,
AS I'VE TALKED ABOUT CANCER
SCREENING AND THE RIGOR OF
CANCER SCREENING AND ALSO SOME
OF ITS IMPACTS, LOOK AT
ALTERNATIVE SCREENING REGIMENTS
THEMSELVES, ONE OF WHICH OF
COURSE IS VERY WIDELY DISCUSSED
NOW, THE CELL FREE DNA OR LIQUID
BIOPSY ASSAYS, THAT PRESUME
CANCER CELLS WILL SHED DNA AND
THIS CAN BE DIFFERENTIATED FROM
NON-CAN RUSS CELL-FREE DNA.
THERE ARE MULTIPLE TECHNOLOGIES
THAT ARE BEING STUDIED AND
RESEARCHED FOR CELL CIRCULATING
TUMOR DNA ASSAYS INCLUDING WHOLE
GENOME SEQUENCING, METHYLATION
PATTERNS IN DNA FRAGMENT LENGTH,
AND ALONG WITH OUR ESTABLISHED
COLLABORATIONS WITH OTHER
EXPERTS IN LFS AND ALSO OUR
INDUSTRY PARTNERS, I THINK THIS
STUDY WILL REALLY -- THIS TRIAL
WILL REALLY GIVE US THE
OPPORTUNITY TO PE PROSPECTIVELY
LOOK AT THE UNITS THAT SCREENING
MAY OFFER TO THOSE WITH LFS.
ANOTHER ASPECT I THINK THAT IS
VERY IMPORTANT GIVEN THE CURRENT
BURDENS OF LFS SCREENING IS
LOOKING AT SCREENING ASSOCIATED
DISTRESS.
AND OUR HOPE IS TO BE ABLE TO
CHARACTERIZE THE PATTERNS AND
TIMING OF SCREENING ASSOCIATED
DISTRESS AND TO UNDERSTAND THE
COPING MECHANISMS EMPLOYED AS
YOU MAY IMAGINE, NOT EVERYTHING
DEALS WITH THIS THE SAME.
BUT NOT ONLY TO LOOK AT
INDIVIDUALS WHO HAVE LFS AND HOW
THEY DEAL WITH THEIR OWN
SCREENING, BUT ALSO HOW THEY
DEAL WITH SCREENING OF THEIR
FAMILY MEMBERS, SUCH AT
CHILDREN, PARENTS, SIBLINGS, ET
CETERA.
WE HAVE AN ONGOING QUALITATIVE
PILOT STUDY TO SET US UP FOR THE
METFORMIN TRIAL.
WE'RE LOOKING AT DATA GIVEN BY
ABOUT 20 INDIVIDUALS THAT HAS
ALREADY BEEN VERY RICH AND
INFORMATIVE, AND WE'RE HOPING TO
LAUNCH A MIXED METHOD STUDY WITH
QUANTITATIVE AND QUALITATIVE
ASPECT WITH THE METFORMIN TRIAL.
AND THE OVERARCHING GOAL WITH
THE EXPERTISE OF DR. PAUL HAAN
AND OUR FELLOWS, IS TO DEVELOP
INTEGRATIVE INTERVENTIONS FOR
THE MANAGEMENT AND GUIDELINES OF
BOTH PATIENTS AND PROVIDERS
BECAUSE WE ALL HOPE THAT
METFORMIN WILL BE THAT EUREKA
MOMENT, BUT UNTIL WE GET THERE,
SCREENING IS THE BEST WE HAVE TO
OFFER AND WE WANT TO MAKE SURE
THAT WE'RE DOING THE BEST WE CAN
FOR THESE FAMILIES.
SO IN SUMMARY, I KNOW THIS WAS
VERY WHIRLWIND QUICK TOUR, BUT I
HOPE I'VE IMPRESSED UPON YOU
THAT LFS HAS VERY HIGH CANCER
RISK OF MULTIPLE PRIMARY
CANCERS.
CANCER SCREENING COMES WITH THE
BENEFIT OF EARLY CANCER
DETECTION BUT IS RIGOROUS
EMOTIONALLY AND PHYSICALLY
BURDENSOME.
THERE ARE VERY, VERY FEW OPTIONS
FOR PRIMARY CANCER PREVENTION
LEADING US TO REALLY NEED TO
LOOK AT -- LOOK BEYOND
MULTI-CANCER DETECTION AT
PRIMARY CANCER PREVENTION, AND
WE HOPE THAT THE STUDY OF
METFORMIN IN LFS, WHICH WILL
FORGE A COLLABORATIVE PATH, LEAD
A FOUNDATION FOR PREVENTION
RESEARCH AS WELL AS
UNDERSTANDING THE UNDERLYING LFS
BIOLOGY AND CARCINOGENESIS.
AND AS ALL OF THE WORK THAT WE
COULDO, THIS IS NEVER AN INDIVIL
EFFORT, THIS IS VERY MUCH A TEAM
EFFORT.
I HAVE A WONDERFUL, WONDERFUL
TEAM WORKING BACK WITH ME BUT
VERY IMPORTANTLY, WE ALSO HAVE
VERY STRONG PARTNERSHIPS WITH
OUR FAMILY -- OUR PATIENT
ADVOCACY GROUPS INCLUDING THE
LI-FRAUMENI SYNDROME ASSOCIATION
AND LIVING LFS, AS YOU CAN SEE
HERE, THIS IS DR. FRAUMENI AT
THE SIXTH INTERNATIONAL
SYMPOSIUM WE HOSTED HERE AT
SHADY GROVE IN OCTOBER WHICH IS
A VERY UNIQUE MIX, SCIENTISTS,
CLINICIANS AND RESEARCHERS AND
THE OTHER HALF BEING ACTUALLY
FAMILY MEMBERS AND INDIVIDUALS
WHO HAVE LFS.
AND OF COURSE OUR COLLABORATORS
NEAR AND FAR ACROSS THE GLOBE
WHO HELP US ANSWER THESE
QUESTIONS, AND WE REALLY WORK
TOGETHER VERY WELL ANSWERING
QUESTIONS THAT WILL BRING
BENEFITS HOPEFULLY TO THE
PATIENTS AND FAMILIES SOON.
WITH THAT, AGAIN, I'M VERY
GRATEFUL FOR THE OPPORTUNITY TO
PRESENT HERE, AND I'M HAPPY TO
ANSWER QUESTIONS.
THANK YOU.
>>THANK YOU, DR. KHINCHA, AND
THANK YOU, DR. HWANG.
AND FOR THE EXCELLENT
PRESENTATIONS, AND FOR SHARING
YOUR COLLABORATIVE WORK,
OBVIOUSLY ILLUSTRATING THE BASIC
SCIENCE TO THE CLINICAL
APPLICATIONS AND THIS -- CANCER
PREVENTION IN A CHALLENGING --
WITH LI-FRAUMENI SYNDROME.
WE HAVE SEVERAL QUESTIONS COMING
IN, I THINK WE HAVE SOME TIME
HERE.
SO I'LL START OFF, THIS IS
ACTUALLY FOR DR. HWANG.
DO YOU THINK THE INCREASED
MITOCHONDRIAL FUNCTION AS IN THE
LFS MU TAN P53 STATE IS --
DERIVED CANCER PREVENTION
BENEFITS, MITOCHONDRIAL
INHIBITION USING METFORMIN?
>>THAT'S A GREAT QUESTION.
ACTUALLY, IT HIGHLIGHTS ONE OF
THE CRITICAL THINGS HERE IS THAT
AS I SHOWED YOU WITH A MUTANT
STATE WHO HAVE INCREASED
MITOCHONDRIAL METABOLISM, SO IS
THE MODERATION OF THE ACTIVITY
WHAT IS DRIVING THE CANCER
PREVENTION EFFECT, AND WE REALLY
HAVEN'T DONE THE EXPERIMENT
BECAUSE THE P53 NULL MICE, NOT
THE KNOCK-IN MOUSE, WHICH IS LFS
MUTATION STATE BUT THE NULL
MICE, WHO HAVEN'T LOOKED AT
THOSE MICE, BUT WITHOUT
SPECULATING, I WOULD GUESS THAT
EVEN THE NULL STATE WHERE YOU
DON'T HAVE THE INCREASED
MITOCHONDRIAL FUNCTION MAY HAVE
SIMILAR BENEFIT OF CANCER
PREVENTION.
AND I THINK THAT IS MAINLY
BECAUSE OF THE CELL METABOLISM
STRESS THAT THE CELLS -- THAT
THE BODY MIGHT BE FEELING THAT
GIVES THIS PROTECTIVE EFFECT
AGAINST CANCER -- ON THE OTHER
HAND, I THINK IT'S ALSO TRUE
THAT THE INCREASE IN
MITOCHONDRIAL METABOLISM IS
CRITICAL FOR CANCER CELL
SURVIVAL AND METASTASES, AND SO
CLEARLY THAT ALSO HAS A ROLE IN
IT, BUT IT'S A GOOD THING, I
THINK, BECAUSE IT PREDICTS THAT
EVEN INDIVIDUALS -- BECAUSE
LI-FRAUMENI SYNDROME IS VERY
HETEROGENEOUS SOME MUTATIONS
HAVE MORE MITOCHONDRIAL
ACTIVITY, SOME HAVE LESS, SOME
HAVE NONE.
SO I THINK IT'S GOOD NEWS THAT
AT LEAST IN MY MIND, THAT THESE
INDIVIDUALS WHO DON'T HAVE THIS
BOOST IN MITOCHONDRIAL ACTIVITY
MAY ALSO BENEFIT FROM METFORMIN.
>>THANK YOU.
NEXT QUESTION, DR. KHINCHA,
COULD YOU ELABORATE ON LFS IN
CHILDREN AND THE IMPACT OF
SCREENING.
YOUR PROTOCOL SCREENING BEGINS
AT AGE 3.
DOES THE CANCER PROFILE DIFFER
FROM ADULTS, AND DOES THE
OUTCOME DATA DIFFER FROM THE
NON-LFS PEDIATRIC PATIENTS WITH
SIMILAR CANCERS?
>>THAT'S GREAT QUESTIONS AND
I'LL TRY TO ANSWER THEM ONE BY
ONE.
SO SPECIFICALLY FOR OUR
PROTOCOL, AGE 3 WAS BASED ON
CLINICAL CENTER RESOURCES WITH
SEDATION, ANESTHESIA, RESOURCES
AVAILABLE FOR CHILDREN YOUNGER.
BUT NO, IT DOES NOT START AT 3.
SO INDIVIDUALS, CHILDREN WITH
LFS START SCREENING BASICALLY
WHEN THEY'RE DIAGNOSED EVEN IN
INFANCY.
SO THEY DO START GETTING WHOLE
BODY AND BRAIN MRI AS SOON AS
THEY'RE DIAGNOSED, UNDERSTANDING
THE CANCER RISK.
BECAUSE IF YOU LOOK AT SOME OF
THE LFS CURVES WHICH I DIDN'T
SHOW TODAY, THE RISK OF CANCER
REALLY IS HIGHEST IN CHILDHOOD.
THE TUMOR PROFILES THEMSELVES
ARE DIFFERENT, AS YOU WOULD
IMAGINE, BETWEEN CHILDREN AND
ADULTS EVEN IN THE GENERAL
POPULATION.
SO CANCERS SUCH AS
ADRENOCORTICAL CARCINOMAS, CORY
PLEX IS CARCINOMAS,
RHABDOMYOSARCOSIS IS GENERALLY
CANCERS OF CHILDREN, OCCUR MORE
SO IN CHILDHOOD. SO WHEN YOU
START SCREENING AT 3, I WILL
ACKNOWLEDGE IT'S VERY MUCH A
MAJORITY ADULT, BUT WITH OUR
COLLABORATORS ACROSS A WORLD WHO
HAVE PEDIATRIC CENTERS SUCH AS
SICK KIDS, WE DEFINITELY SEE
THAT DIFFERENCE IN PHENOTYPE.
AS FAR AS OUT COME DATA, THAT'S
A WONDERFUL QUESTION.
WE ACTUALLY DON'T HAVE VERY GOOD
OUTCOME DATA LOOKING AT THINGS
LIKE SURVIVAL, AND WE'RE
STARTING TO DO SOME OF THAT NOW.
WE THINK OF CANCERS AND LFS, WE
TREAT THEM WITH STANDARD
PROTOCOL, SO THERE'S NO REAL
LFS-SPECIFIC PROTOCOL FOR
TREATMENT OTHER THAN AVOIDING
IONIZING RADIATION WHEN
POSSIBLE, BUT THEY UNDERGO
BASICALLY THE STANDARD TREATMENT
THAT ANY CANCER OF THAT
MORPHOLOGY WOULD, THEY JUST
OCCUR MUCH MORE FREQUENTLY, AND
WE HAVEN'T SEEN AT LEAST
ANECDOTALLY OR IN CASE THEER
EASE, WE HAVEN'T SEEN ANY
DIFFERENCES IN OUTCOME.
I THINK THE BIG DIFFERENCE S
THEY'RE JUST GENETICALLY AT A
MUCH HIGHER RISK OF DEVELOPING
SUBSEQUENT CANCERS, AND I THINK
THE GENOTOXIC THERAPIES LIKE
CHEMO AND RADIATION MAY ONLY
COMPOUND THAT AND WE'RE ACTUALLY
PART OF A MULTI-INSTITUTIONAL
STUDY THAT IS LOOKING AT TREAT M
EFFECTS AND RISK OF SUBSEQUENT
CANCER.
BUT FROM THE SPECIFIC CANCER
OUTCOME AS A POPULATION, I DON'T
THINK WE HAVE ENOUGH DATA TO
ANSWER THAT.
>>THANK YOU VERY MUCH.
A LOT OF QUESTIONS ON METFORMIN.
I'M GOING TO -- SO THIS TELLS
ABOUT THE SIDE EFFECT OF
METFORMIN USE AND POSITIVE
NEGATIVE INTERACTIONS OF --
NEGATIVE INTERACTIONS OF
METFORMIN USE.
IS THERE ANYTHING ELSE BESIDES
METFORMIN THAT MIGHT BE ABLE TO
ACCOMPLISH THE SAME?
>>THAT'S A GREAT QUESTION.
SO WITH THE PILOT STUDY WHERE WE
LOOKED AT SAFETY AND FEASIBILITY
THAT DR. HWANG IS ALSO A PART
OF, THE METFORMIN ADVERSE EVENT
PROFILE IS PRETTY MUCH THE SAME
AS WHAT IT IS IN THE GENERAL
POPULATION.
SO A LOT OF G.I. SIDE EFFECTS
SUCH AS NAUSEA, BLOATING, VERY
FEW -- WAS THERE ANYTHING
SPECIFIC TO LFS THAT WAS NOT
KNOWN ABOUT METFORMIN, AND
THANKFULLY THERE WASN'T, WHICH
IS WHY WE'RE MOVING AHEAD.
AS FAR AS WHY METFORMIN, CAN ANY
OTHER AGENT DO IT, I THINK THAT
SOME OF THAT IS GOING TO DEPEND
ON THE WORK OF DR. HWANG AND
OTHER COLLABORATORS LOOKING AT
DIFFERENT AGENTS AND DIFFERENT
SPECIFIC ACTIONS OF METFORMIN.
BUT THE REASON WE CHOSE
METFORMIN IS, ONE, YOU KNOW,
WE'VE GOT SOME VERY STRONG
FOUNDATIONAL DATA FROM
DR. HWANG'S WORK.
IT'S ALSO A DRUG THAT'S BEEN
AROUND FOR DECADES, WELL
TOLERATED, EASILY AVAILABLE, AND
EASILY DEPLOYED TO LARGE --
RELATIVELY LARGE POPULATIONS IN
RARE DISEASE AS WE LIKE TO CALL
THEM.
TO BE ABLE TO STUDY.
THE IDEA WITH SETTING THIS TRIAL
AND THIS INFRASTRUCTURE UP WAS
TO REALLY BE ABLE TO ADAPT TO
OTHER AGENTS IF WE NEEDED TO, TO
LOOK AT SOME MORE EFFECT, SO FOR
EXAMPLE, IF WE WANTED TO LOOK AT
FATTY ACID OXIDATION IN THE
FUTURE, WE WOULD BE ABLE TO USE
THE SAME INFRASTRUCTURE AND THE
SAME FOUNDATION REALLY TO STUDY
THAT IN THE FUTURE.
AND THIS IS REALLY JUST THE
FIRST STEP WE'RE TAKING INTO
PREVENTION, SO I THINK THIS IS
JUST THE STARTING OF WHAT I HOPE
WILL BE A VERY ROBUST AND
FRUITFUL EFFORT.
>>THANK YOU, DR. KHINCHA.
DR. HWANG, THIS TAKES US UP TO
THE HOUR.
AGAIN, I WANT TO THANK YOU
PERSONALLY FOR EXCEPTIONAL
TALKS, WITH THE CLARITY OF SOME
VERY ROBUST SCIENCE AND
POTENTIALLY A VERY BRIGHT FUTURE
FOR THIS POPULATION.
SO THANK YOU VERY MUCH, AND TO
THE NIH COMMUNITY, THANK YOU FOR
JOINING US, AND WE WILL SEE
EVERYONE NEXT WEEK.
THANK YOU AGAIN.
HAVE A GOOD DAY.
>>ALL RIGHT, THANK YOU.
>>THANK YOU.