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Welcome to the Clinical
Center Grand Rounds,

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a weekly series of educational
lectures for physicians and

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health care professionals
broadcast from the Clinical

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Center at the National
Institutes of Health in

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Bethesda, MD.

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The NIH Clinical Center is the
world's largest hospital totally

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dedicated to investigational
research and leads the global

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effort in training today's
investigators and discovering

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tomorrow's cures.

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Learn more by visiting us online
at http://clinicalcenter.nih.gov

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WE START 2023 WITH OUR SPEAKERS,

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DR. PAUL HWANG, A SENIOR

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INVESTIGATOR FOR THE LABORATORY

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OF CARDIOVASCULAR AND CANCER

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GENETICS AT THE NATIONAL HEART,

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BLOOD AND LUNG INSTITUTE AND DRE

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DIVISION OF CANCER EPIDEMIOLOGY

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AND GENETICS AT THE NATIONAL

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CANCER INSTITUTE.

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OUR FIRST SPEAKER, DR. HWANG,

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COMPLETED HIS BACHELOR'S IN

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BIOCHEMISTRY AND CHEMISTRY AT

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THE UNIVERSITY OF KANSAS IN

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1985.

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AS A FULBRIGHT SCHOLAR, GENETICS

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RESEARCH AT THE INSTITUTE OF

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TECHNOLOGY UNIVERSITY OF ZURICH

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FOR A YEAR AFTER WHICH HE CAME

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TO THE JOHNS HOPKINS UNIVERSITY

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SCHOOL OF MEDICINE EARNING BOTH

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HIS M.D. AND PH.D. IN 1993.

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DR. HWANG COMPLETED HIS

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INTERNSHIP AND RESIDENCY IN

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INTERNAL MEDICINE AT THE

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UNIVERSITY OF CALIFORNIA

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SAN FRANCISCO FOLLOWED BY A

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CLINICAL FELLOWSHIP IN

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CARDIOLOGY AND POSTDOCTORAL

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RESEARCH IN ONCOLOGY AT JOHNS

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HOPKINS.

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IN 2001, DR. HWANG JOINED NHLBI

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AS A TENURED TRACK INVESTIGATOR

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IN THE CARDIOVASCULAR BRANCH

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BECOMING A SENIOR INVESTIGATOR

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IN 2011 IN NHLBI'S CENTER.

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DR. HWANG'S WORK ON A TUMOR

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SUPPRESSOR PROTEIN P53

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DEMONSTRATED -- AGAINST

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OXIDATIVE AND OTHER EXPRESSES.

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HIS WORK AS FOCUSED ON THIS LINK

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BETWEEN CANCER AND MITOCHONDRIAL

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METABOLISM WHICH ALSO IMPACTS

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THE CARDIOVASCULAR SYSTEM.

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BY USING MOUSE MODELS AS WELL AS

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PERFORMING TRAN LAITIONAL

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STUDIES IN PATIENTS WITH

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LI-FRAUMENI SYNDROME, A CANCER

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PREDISPOSITION DISORDER CAUSED

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BY DIVERSE GERMLINE MUTATIONS IN

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THE TP53 GENE WITH ACCOMPANYING

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MUTATION SUBTYPE.

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DR. HWANG'S GROUP CONTINUES TO

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STUDY REGULATION OF MITOCHONDRIA

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IN MODEL SYSTEMS, DETERMINING

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RELEVANCE TO HUMAN DISEASES, AND

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HE HAS AUTHORED MANY

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PUBLICATIONS AND SERVED ON

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VARIOUS EDITORIAL BOARDS.

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HE'S AN ELECTED MEMBER AT THE

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AMERICAN SOCIETY FOR CLINICAL

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INVESTIGATION AS A  AS A FELLO N

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CARDIOLOGY.

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OUR SECOND SPEAKER WILL BE

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DR. PAYAL KHINCHA.

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SHE COMPLETED PEDIATRIC

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RESIDENCIES IN MAIMONIDES

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MEDICAL CENTER IN NEW YORK, AND

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THEN A FELLOWSHIP IN PEDIATRIC

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HEMATOLOGY-ONCOLOGY IN

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WASHINGTON, D.C., WHILE ALSO

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EARNING A MASTER'S IN HEALTH

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SCIENCES IN CLINICAL AND

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TRANSLATIONAL RESEARCH AT GEORGE

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WASHINGTON UNIVERSITY.

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IN 2012, DR. KIN  SHE JOINED ASA

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CLINICAL FELLOW IN 2014 AND ROSE

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TO STAFF CLINICIAN IN 2017 AND

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SINCE 2018 HAS BEEN LEADING

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NCI'S STUDY OF LI-FRAUMENI

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SYNDROME AS A PRINCIPAL

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INVESTIGATOR.

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SHE SUCCESSFULLY APPLIED TO

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CLINICAL INVESTIGATOR

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DEVELOPMENT PROGRAM AND HAS BEEN

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AN ASSIST TANT CLINICAL

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INVESTIGATOR SINCE 2020.

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HER RESEARCH FOCUSES ON

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HEREDITARY CANCER PREDISPOSITION

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SYNDROMES, SPECIFICALLY THOSE

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AFFECTING CHILDREN.

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ETIOLOGY, SCREENING, EARLY

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DETECTION, RISK MODIFIERS AND

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PREVENTION OF HEREDITARY CANCER.

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HER RESEARCH AIMS INCLUDE

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CHARACTERIZING CANCER RISK,

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PATTERNS AND GENOTYPE-PHENOTYPE

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CORRELATIONS OF CANCER WITH

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SPECIFIC MUTATION TYPES OR TP53

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AND LI-FRAUMENI SYNDROME.

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ASSESSING SURVEILLANCE ON

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INDIVIDUALS AND FAMILIES WITH

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LFS, AND DETERMINING IF CHANGE

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IN MITOCHONDRIAL FUNCTION IS

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ASSOCIATED WITH CANCER INCIDENCE

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IN THE LFS POPULATION.

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DR. KHINCHA'S WORK HAS LED TO

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IMPORTANT INSIGHTS INTO LFS,

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INCLUDING THE NEED FOR

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COMPREHENSIVE CANCER SCREENING

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IN THESE PATIENTS.

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OF SIGNIFICANCE, HER GROUP WAS

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FIRST TO DESCRIBE THE BENEFICIAL

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EFFECTS OF BREASTFEEDING IN

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WOMEN WITH LFS IN REDUCING

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FUTURE BREAST CANCER RISK.

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SHE HAS PUBLISHED OVER 40 PAPERS

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AND BOOK CHAPTERS IN THE FIELDS

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OF LFS, DYSKERATOSIS CONGENITA

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AND TELOMERE BIOLOGY, AND FOR

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2023, SHE HAS RECEIVED THE NCI

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DIRECTOR'S INNOVATION CLINICAL

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INVESTIGATOR AWARD FOR HER

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PROPOSAL, NOVEL STRIKE THAT STRR

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EARLY DETECTION IN INDIVIDUALS

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WITH LI-FRAUMENI SYNDROME.

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SHE IS BOARD CERTIFIED IN

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PEDIATRICS AND PEDIATRIC

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HEMATOLOGY-ONCOLOGY.

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NOW PLEASE WELCOME OUR SPEAKERS,

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DR. HWANG AND DR. KHINCHA, WHOSE

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PRESENTATION IS ENTITLED

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TARGETING METABOLISM AND CANCER

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PREVENTION IN LI-FRAUMENI

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SYNDROME.

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I'D LIKE TO START OUT BY

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THANKING DR. BURKLOW FOR THIS

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OPPORTUNITY TO PRESENT AT THE

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CLINICAL CENTER GRAND ROUNDS.

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SO IT'S IMPORTANT FOR ME TO

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THANK MEMBERS OF MY LABORATORY

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WHO HAVE DONE ALL THE WORK.

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SO THE LEARNING OBJECTIVE TODAY

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IS FOR ME TO TRY TO GIVE YOU AN

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APPRECIATION OF THE CHANGES IN

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MITOCHONDRIAL METABOLISM THAT

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OCCUR IN A EARLY ONSET

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HEREDITARY CANCER DISORDER KNOWN

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AS LI-FRAUMENI SYNDROME CAUSED

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BY P53 MUTATIONS THAT COULD

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POTENTIALLY BE TARGETED FOR

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CANCER PREVENTION.

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I HAVE NO DISCLOSURES.

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SO I SHOULD MENTION THAT THIS

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BASIC AND TRANSLATIONAL

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PRESENTATION WILL BE FOLLOWED BY

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DR. PAYAL KHINCHA, WHO WILL

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ACTUALLY GO OVER MORE OF THE

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CLINICAL ASPECTS OF LI-FRAUMENI

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SYNDROME, AND A PLANNED CHEMO

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PREVENTION STUDY THAT AGAIN

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DR. KHINCHA WILL GO OVER BASED

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ON SOME OF THESE BASIC

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TRANSLATIONAL WORK.

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SO AS OUTLINED HERE, I'LL TRY TO

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GIVE YOU AN OVERVIEW OF HOW WILD

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TYPE AND MUTANT P53 CAN PROMOTE

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MITOCHONDRIAL METABOLISM AND

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THEN SHARE WITH YOU SOME

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PREVIOUSLY PUBLISHED WORK IN

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WHICH WE HAVE SHOWN THAT BOTH

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THE GENETIC OR PHARMACOLOGIC

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INHIBITION OR DISRUPTION OF

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MITOCHONDRIAL FUNCTION CAN HAVE

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CANCER PREVENTIVE EFFECTS AT

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LEAST IN AN LFS MOUSE MODEL AND

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THAT IT IS ALSO POSSIBLE

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PHARMACOLOGICALLY -- IN LFS

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PATIENTS WITH SIGNALING CHANGES

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THAT APPEAR TO BE CANCER

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PROTECTIVE, AT LEAST IN THE

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MOUSE MODELS.

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AND THEN I'LL FINISH OFF WITH A

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LITTLE BIT MORE RECENT WORK

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WHICH HAS SHOWN THAT INHIBITING

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SPECIFIC ACTIVITY OF THE

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MITOCHONDRIA -- OXIDATION CAN

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ALSO HAVE CANCER-PREVENTIVE

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EFFECTS.

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SO JUST AS A GENERAL

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INTRODUCTION, P53 WHICH IS

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ENCODED BY THE HUMAN TP53 GENE

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IS THE MOST FREQUENTLY MUTATED

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TUMOR SUPPRESSOR GENE IN HUMAN

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CANCERS, INDICATING ITS CRITICAL

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IMPORTANCE IN CANCER FORMATIONS

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IN PATIENTS.

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AND THIS COULD BE BEST DESCRIBED

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AS A TRANSCRIPTION FACTOR THAT

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REGULATES MANY DIFFERENT

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DOWNSTREAM GENES IN CELL CYCLE

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REGULATION, DNA REPAIR OR

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MAINTAINING GENOMIC INTEGRITY.

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SO A NUMBER OF YEARS AGO, WE

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SHOWED THAT BOTH WILD TYPE AND

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MUTANT P53 CAN PROMOTE

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MITOCHONDRIAL FUNCTION AND IT

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DOES SO BY TRANS ACTIVATING A

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NUMBER OF IMPORTANT GENES SUCH

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AS SCO2, AND MITOCHONDRIAL

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TRANSCRIPTION FACTOR -- AS WELL

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AS MUCH MORE THAN WHAT'S

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ACTUALLY LISTED ON THIS SLIDE IN

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THE NUCLEUS, MANY MORE GENES

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HAVE BEEN SHOWN TO BE REGULATED

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BY P53.

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IT ALSO HAS ACTIVITIES DIRECTLY

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IN THE MITOCHONDRIA, ALSO

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IMPORTANT FOR REGULATING THE

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MITOCHONDRIAL GENOME, WHICH IS

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SEPARATE FROM THE NUCLEIC

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GENOME.

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ALL WHICH IMPACT THINGS SUCH AS

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EXERCISE CAPACITY, WHEREBY A

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MUTANT P53 -- MUTANT ALLELE DOSE

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DEPENDENT MANNER INCREASE

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EXERCISE CAPACITY OF MICE IN

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SINGLE POINT MUTATION SO THAT IN

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THE HOMOZYGOUS MUTANT STATE,

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MICE CAN -- MUTANT MICE CAN

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EXERCISE TWICE AS MUCH, RUN

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TWICE AS MUCH AS WILD TYPE

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SIBILITIES.

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SIBLINGS.

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AT THAT TIME, THE IMPACT OF THIS

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MITOCHONDRIAL FUNCTION WAS LESS

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CLEAR ON TUMORIGENESIS, WHICH I

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WILL BE GOING INTO SUBSEQUENTLY.

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SO BESIDES JUST MOUSE MODELS AND

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CELL LINES, WE ALSO WANTED TO

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DETERMINE THE RELEVANCE OF THIS

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ACTIVITY OF P53 IN THE

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MITOCHONDRIA IN HUMANS UNDER

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NORMAL PHYSIOLOGIC CONDITIONS.

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SO AT THAT TIME EARLY ON, WE

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TURNED TO THE LI-FRAUMENI

256
00:10:14,560 --> 00:10:16,200
SYNDROME, AGAIN WHO HAVE

257
00:10:16,200 --> 00:10:18,080
MUTATIONS OF P53 AND BECAUSE

258
00:10:18,080 --> 00:10:22,000
WILD TYPE P53, WE INITIALLY

259
00:10:22,000 --> 00:10:24,560
OBSERVED THAT WILD TYPE P53

260
00:10:24,560 --> 00:10:26,280
PROMOTES MITOCHONDRIAL FUNCTION,

261
00:10:26,280 --> 00:10:28,000
WE SPECULATED THAT MUTATIONS OF

262
00:10:28,000 --> 00:10:28,760
P53, INDIVIDUALS WITH

263
00:10:28,760 --> 00:10:30,160
MUTATIONINGS OF P53 MAY ACTUALLY

264
00:10:30,160 --> 00:10:32,600
HAVE A DEFICIT IN MITOCHONDRIAL

265
00:10:32,600 --> 00:10:34,240
FUNCTION AND MUCH TO OUR

266
00:10:34,240 --> 00:10:36,040
SURPRISE AT THAT TIME, WE

267
00:10:36,040 --> 00:10:39,000
ACTUALLY OBSERVED THAT USING

268
00:10:39,000 --> 00:10:44,000
THIS VERY NONINVASIVE P51MRS

269
00:10:44,000 --> 00:10:46,280
SPECTROSCOPY TECHNIQUE, WE WERE

270
00:10:46,280 --> 00:10:48,280
ABLE TO SHOW AS A MARKER OF

271
00:10:48,280 --> 00:10:49,120
MITOCHONDRIAL FUNCTION, WE WERE

272
00:10:49,120 --> 00:10:51,200
ABLE TO SHOW THAT PATIENTS WITH

273
00:10:51,200 --> 00:10:56,240
P53 MUTATIONS CARRIERS HAVE

274
00:10:56,240 --> 00:10:58,200
FASTER RECOVERY TIME, SUGGEST

275
00:10:58,200 --> 00:11:00,520
THAT IT HAS GREATER OX TAITION

276
00:11:00,520 --> 00:11:01,160
PHOSPHORYLATION CAPACITY

277
00:11:01,160 --> 00:11:02,600
COMPARED TO INDIVIDUALS WHO HAD

278
00:11:02,600 --> 00:11:04,880
WILD TYPE P53.

279
00:11:04,880 --> 00:11:06,840
THIS WAS FURTHER SUBSTANTIATED

280
00:11:06,840 --> 00:11:10,360
IN MOUSE MODELS, NFS MOUSE

281
00:11:10,360 --> 00:11:14,400
MODELS, AS I ALLUDED TO EARLIER,

282
00:11:14,400 --> 00:11:16,240
AND MECHANISTICALLY, WE THINK

283
00:11:16,240 --> 00:11:20,760
THAT THIS INCREASED

284
00:11:20,760 --> 00:11:22,520
MITOCHONDRIAL ACTIVITY OCCURS

285
00:11:22,520 --> 00:11:25,560
THROUGH, FOR EXAMPLE, THE MUTANT

286
00:11:25,560 --> 00:11:29,080
P53 BEING ABLE TO INTERACT

287
00:11:29,080 --> 00:11:36,720
WITH THE TRANSCRIPTION FACTOR

288
00:11:36,720 --> 00:11:37,640
EPS2 TO -- TFAM.

289
00:11:37,640 --> 00:11:39,600
YOU CAN SEE VERY NICELY IN A

290
00:11:39,600 --> 00:11:43,520
MUTANT ALLELE DOSE-DEPENDENT

291
00:11:43,520 --> 00:11:45,600
MANNER, H/H IS THE MUTANT

292
00:11:45,600 --> 00:11:47,120
ALLELE, YOU CAN SEE THIS

293
00:11:47,120 --> 00:11:51,080
INCREASED TFAM MRNA

294
00:11:51,080 --> 00:11:53,040
TRANSCRIPTION, LOSS OF THE

295
00:11:53,040 --> 00:11:54,880
PROTOTYPICAL WILD TYPE P53

296
00:11:54,880 --> 00:11:56,520
TARGET CHAIN P21 THAT'S CRITICAL

297
00:11:56,520 --> 00:11:58,080
FOR CELL CYCLE REGULATION.

298
00:11:58,080 --> 00:12:00,120
SO WITH LOSS OF WILD TYPE

299
00:12:00,120 --> 00:12:01,920
ACTIVITY YOU ACTUALLY SEE A GAIN

300
00:12:01,920 --> 00:12:04,600
OF MITOCHONDRIAL BIOGENESIS AND

301
00:12:04,600 --> 00:12:05,800
WE THINK THROUGH THIS GAIN OF

302
00:12:05,800 --> 00:12:07,680
FUNCTION OF MUTANT P53

303
00:12:07,680 --> 00:12:11,280
TRANSCRIPTION FACTORS.

304
00:12:11,280 --> 00:12:14,240
AND SO WITH THE GROWING EVIDENCE

305
00:12:14,240 --> 00:12:16,200
THAT MITOCHONDRIAL METABOLISM IS

306
00:12:16,200 --> 00:12:19,720
IMPORTANT IN CANCER FORMATION,

307
00:12:19,720 --> 00:12:21,440
WE WONDERED WHAT MIGHT BE THE

308
00:12:21,440 --> 00:12:22,680
EFFECT OF DISRUPTING

309
00:12:22,680 --> 00:12:23,840
MITOCHONDRIAL FUNCTION IN THE

310
00:12:23,840 --> 00:12:26,280
LFS MOUSE MODEL, AND THIS IS

311
00:12:26,280 --> 00:12:30,320
USING THE HUMAN HOT SPOT MUTANT

312
00:12:30,320 --> 00:12:33,160
P53 MODEL, THE 175 MOUSE IN THE

313
00:12:33,160 --> 00:12:33,600
172 POSITION.

314
00:12:33,600 --> 00:12:35,920
AND WE TURNED TO THE THYMUS

315
00:12:35,920 --> 00:12:37,080
TISSUE BECAUSE THAT'S WHERE MOST

316
00:12:37,080 --> 00:12:39,600
OF THE TUMORS THAT T-CELL

317
00:12:39,600 --> 00:12:41,280
INFORMERS DEVELOP IN LFS MOUSE

318
00:12:41,280 --> 00:12:41,560
MODELS.

319
00:12:41,560 --> 00:12:44,360
SO WE WERE ABLE TO SHOW THAT IF

320
00:12:44,360 --> 00:12:49,680
WE CROSS THESE MICE WITH MUTANT

321
00:12:49,680 --> 00:12:54,160
MICE, WE ACTUALLY INTRODUCE --

322
00:12:54,160 --> 00:12:56,400
INTO THE GENOME AND DISRUPT

323
00:12:56,400 --> 00:12:57,560
MITOCHONDRIAL FUNCTION THAT WE

324
00:12:57,560 --> 00:13:01,160
WERE ABLE TO DECREASE

325
00:13:01,160 --> 00:13:01,880
MITOCHONDRIAL -- CONSUMPTION IN

326
00:13:01,880 --> 00:13:03,880
THE THYMUS TISSUE, AGAIN THE

327
00:13:03,880 --> 00:13:06,840
TISSUE WHERE TUMORS DEVELOP IN

328
00:13:06,840 --> 00:13:08,400
THE LFS MOUSE MODELS.

329
00:13:08,400 --> 00:13:10,240
INCREASINGLY THERE'S AN INCREASE

330
00:13:10,240 --> 00:13:12,760
IN BLOOD -- LEVEL -- THERE'S A

331
00:13:12,760 --> 00:13:14,840
TREND THERE.

332
00:13:14,840 --> 00:13:16,360
SUGGESTING THAT THERE MAY BE

333
00:13:16,360 --> 00:13:17,680
COMPENSATORY INCREASE IN

334
00:13:17,680 --> 00:13:18,880
GLYCOLYSIS AND WE'RE ABLE TO

335
00:13:18,880 --> 00:13:21,320
SHOW THAT AT THE BIOGENESIS

336
00:13:21,320 --> 00:13:22,720
LEVEL AS WELL IN THE

337
00:13:22,720 --> 00:13:24,600
MITOCHONDRIAL PROTEINS AS WELL

338
00:13:24,600 --> 00:13:28,400
AS THE GLYCOLYSIS -- IN SKELETAL

339
00:13:28,400 --> 00:13:28,840
MUSCLE.

340
00:13:28,840 --> 00:13:32,240
THE IMPORTANT QUESTION IS,, DOES

341
00:13:32,240 --> 00:13:33,560
MODERATING MITOCHONDRIAL

342
00:13:33,560 --> 00:13:35,080
FUNCTION IN THE THYMUS TISSUE

343
00:13:35,080 --> 00:13:36,080
AFFECT CANCER DEVELOPMENT.

344
00:13:36,080 --> 00:13:37,280
AND THE ANSWER IS YES, WE WERE

345
00:13:37,280 --> 00:13:41,640
ABLE TO ACTUALLY SHOW THAT

346
00:13:41,640 --> 00:13:44,960
COMPARED TO THE LFS GENETIC

347
00:13:44,960 --> 00:13:48,760
BACKGROUND WHICH DEVELOP TUMORS

348
00:13:48,760 --> 00:13:50,840
AND CANCER-FREE SURVIVAL, YOU

349
00:13:50,840 --> 00:13:52,680
CAN SEE THERE WAS A 40% INCREASE

350
00:13:52,680 --> 00:13:56,720
IN CANCER-FREE SURVIVAL IN THE

351
00:13:56,720 --> 00:14:01,240
HETEROZYGOUS MUTANT MICE AND IN

352
00:14:01,240 --> 00:14:02,960
HOMOZYGOUS THERE WAS A -- IN

353
00:14:02,960 --> 00:14:04,000
CANCER SURVIVAL BY INCLUDING

354
00:14:04,000 --> 00:14:04,440
THIS MUTATION.

355
00:14:04,440 --> 00:14:09,360
SOME OF YOU MAY ALREADY KNOW THE

356
00:14:09,360 --> 00:14:10,720
HOMOZYGOUS MUTANT MICE ACTUALLY

357
00:14:10,720 --> 00:14:16,520
HAVE A VERY SEVERE -- THE

358
00:14:16,520 --> 00:14:18,280
HETEROZYGOUS STATE HAS ONLY A

359
00:14:18,280 --> 00:14:19,360
MILD MITOCHONDRIAL EFFECT AND

360
00:14:19,360 --> 00:14:22,560
ACTUALLY HAVE BEEN SHOWN TO HAVE

361
00:14:22,560 --> 00:14:24,520
NO OVERT PHENOTYPE, ACTUALLY

362
00:14:24,520 --> 00:14:25,960
HAVE NORMAL LIFESPAN.

363
00:14:25,960 --> 00:14:27,680
SO INTRODUCING A MILD

364
00:14:27,680 --> 00:14:32,840
MITOCHONDRIAL GENETIC -- MILD

365
00:14:32,840 --> 00:14:34,160
DEFICIENCY MITOCHONDRIA, YOU CAN

366
00:14:34,160 --> 00:14:36,000
SEE THERE WAS A VERY NICE

367
00:14:36,000 --> 00:14:36,320
IMPROVEMENT.

368
00:14:36,320 --> 00:14:38,720
WE ALSO WONDERED ABOUT WHAT

369
00:14:38,720 --> 00:14:39,680
SIGNALING PATHWAYS MIGHT

370
00:14:39,680 --> 00:14:41,240
CONTRIBUTE TO SUCH A PHENOMENON,

371
00:14:41,240 --> 00:14:44,440
SO WE LOOKED AT THYMUS TISSUE

372
00:14:44,440 --> 00:14:46,720
AGAIN AND IT'S KNOWN THAT THE

373
00:14:46,720 --> 00:14:51,440
MUTANT P53 DOWNREGULATES

374
00:14:51,440 --> 00:14:54,280
AUTOPHAGY AND YOU WOULD EXPECT

375
00:14:54,280 --> 00:14:58,320
THAT WITH POLYMER US GAMMA

376
00:14:58,320 --> 00:15:00,200
MUTANT WHERE WE ACTUALLY

377
00:15:00,200 --> 00:15:01,800
INCREASE MITOPHAGY AND AUTOPHAGY

378
00:15:01,800 --> 00:15:04,320
AND INDEED, WE WERE ABLE TO SHOW

379
00:15:04,320 --> 00:15:07,200
THAT IF YOU CROSS AGAIN THE HET

380
00:15:07,200 --> 00:15:14,680
ZYGHETEROZYGOUS STATE INTO THE

381
00:15:14,680 --> 00:15:17,240
BACKGROUND -- IMPORTANTLY, THE

382
00:15:17,240 --> 00:15:18,320
DOWNSTREAM SIGNALING TARGETS

383
00:15:18,320 --> 00:15:24,000
SUCH AS CYCLIN D1, WAS ACTUALLY

384
00:15:24,000 --> 00:15:25,560
DOWN REGULATED IN THYMUS TISSUE.

385
00:15:25,560 --> 00:15:26,840
SO ALTHOUGH WE DO NOT HAVE

386
00:15:26,840 --> 00:15:28,600
EVIDENCE THAT THIS IS THE ONLY

387
00:15:28,600 --> 00:15:32,000
PATHWAY INVOLVED, THIS SORT OF

388
00:15:32,000 --> 00:15:32,880
SIGNALING, ANTIPROLIFERATIVE

389
00:15:32,880 --> 00:15:35,600
SIGNALING PROBABLY CONTRIBUTE TO

390
00:15:35,600 --> 00:15:39,120
THIS CANCER PREVENTIVE EFFECT BY

391
00:15:39,120 --> 00:15:40,840
MILDLY DISRUPTING MITOCHONDRIAL

392
00:15:40,840 --> 00:15:41,200
FUNCTION.

393
00:15:41,200 --> 00:15:42,480
SO AT THIS POINT, THE QUESTION

394
00:15:42,480 --> 00:15:45,280
WAS, IS IT POSSIBLE TO REPRODUCE

395
00:15:45,280 --> 00:15:49,080
THIS GENETIC BENEFIT OF TUMOR

396
00:15:49,080 --> 00:15:51,920
SUPPRESSION BY INHIBITING

397
00:15:51,920 --> 00:15:52,640
MITOCHONDRIA PHARMACOLOGICALLY,

398
00:15:52,640 --> 00:15:53,720
WITH THE IDEA THAT POTENTIALLY

399
00:15:53,720 --> 00:15:59,360
THIS SORT OF STRATEGY COULD BE

400
00:15:59,360 --> 00:16:02,320
USED FOR CHEMO PREVENTION IN

401
00:16:02,320 --> 00:16:02,960
PATIENTS WITH LI-FRAUMENI

402
00:16:02,960 --> 00:16:03,200
SYNDROME.

403
00:16:03,200 --> 00:16:04,480
TO DO THIS, WE TURNED TO

404
00:16:04,480 --> 00:16:05,680
METFORMIN.

405
00:16:05,680 --> 00:16:06,600
METFORMIN, AS MANY OF YOU

406
00:16:06,600 --> 00:16:08,320
ALREADY KNOW, IS A VERY

407
00:16:08,320 --> 00:16:10,280
WELL-KNOWN ANTIDIABETIC DRUG,

408
00:16:10,280 --> 00:16:12,600
VERY GOOD DRUG, HAS A MYRIAD OF

409
00:16:12,600 --> 00:16:13,960
DIFFERENT METABOLIC EFFECTS AND

410
00:16:13,960 --> 00:16:16,960
ONE OF THE EFFECTS IS THAT IT'S

411
00:16:16,960 --> 00:16:20,120
KNOWN TO INHIBIT MITOCHONDRIA

412
00:16:20,120 --> 00:16:21,280
EXPRESSION THROUGH COMPLEX 1.

413
00:16:21,280 --> 00:16:23,520
IT IS A VERY SAFE AND WELL

414
00:16:23,520 --> 00:16:24,840
TOLERATED MEDICATION, AND THE

415
00:16:24,840 --> 00:16:26,160
BEST THING HERE OR ONE OF THE

416
00:16:26,160 --> 00:16:28,760
BEST THINGS HERE IS THAT IT IS

417
00:16:28,760 --> 00:16:30,400
NOT HYPOGLYCEMIC, SO IT CAN BE

418
00:16:30,400 --> 00:16:33,480
TAKEN BY ANY INDIVIDUAL WITHOUT

419
00:16:33,480 --> 00:16:35,360
DIABETES WITHOUT WORRYING ABOUT

420
00:16:35,360 --> 00:16:37,760
HYPOGLYCEMIA.

421
00:16:37,760 --> 00:16:43,000
SO WE DID A EXPERIMENT WITH

422
00:16:43,000 --> 00:16:43,320
MICE.

423
00:16:43,320 --> 00:16:45,240
WE HAD THEM DRINKING METFORMIN

424
00:16:45,240 --> 00:16:48,320
IN DRINKING WATER LONG TERM, AND

425
00:16:48,320 --> 00:16:51,960
THESE WERE DOSES THAT HAD BEEN

426
00:16:51,960 --> 00:16:55,000
SHOWN TO RESULT IN PLASMA LEVELS

427
00:16:55,000 --> 00:16:57,000
OF METFORMIN THAT ARE

428
00:16:57,000 --> 00:16:58,720
THERAPEUTIC, AT LEAST AT THE

429
00:16:58,720 --> 00:16:59,600
HUMAN THERAPEUTIC DOSES.

430
00:16:59,600 --> 00:17:01,920
SO THIS IS NOT USING

431
00:17:01,920 --> 00:17:03,440
SUPERPHYSIOLOGIC DOSES OF

432
00:17:03,440 --> 00:17:05,840
METFORMIN IN MICE, AND WE WERE

433
00:17:05,840 --> 00:17:11,080
ABLE TO SHOW DOSE-DEPENDENT

434
00:17:11,080 --> 00:17:12,720
DECREASE IN OXYGEN CONSUMPTION

435
00:17:12,720 --> 00:17:17,200
IN THE THYMUS TISSUE, INHIBITING

436
00:17:17,200 --> 00:17:19,440
RESPIRATION AND THE CYCLIN D1 IS

437
00:17:19,440 --> 00:17:21,720
ALSO DECREASED COMPARED TO

438
00:17:21,720 --> 00:17:23,880
DRINKING PLAIN WATER.

439
00:17:23,880 --> 00:17:25,640
IMPORTANTLY, WE WERE ABLE TO

440
00:17:25,640 --> 00:17:29,800
SHOW A 25% INCREASE IN

441
00:17:29,800 --> 00:17:30,760
MEDIAN-FREE -- CANCER-FREE

442
00:17:30,760 --> 00:17:32,720
SURVIVAL USING THE

443
00:17:32,720 --> 00:17:33,640
DOSE-DEPENDENT -- USING THE

444
00:17:33,640 --> 00:17:35,040
HIGHER DOSE HERE.

445
00:17:35,040 --> 00:17:36,920
AGAIN, THERAPEUTIC HUMAN

446
00:17:36,920 --> 00:17:41,120
THERAPEUTIC DOSES.

447
00:17:41,120 --> 00:17:42,440
SO ENCOURAGED BY THESE RESULTS,

448
00:17:42,440 --> 00:17:44,520
WE COLLABORATED WITH NCI

449
00:17:44,520 --> 00:17:45,280
INVESTIGATORS WHO WERE

450
00:17:45,280 --> 00:17:47,920
INTERESTED IN LOOKING AT

451
00:17:47,920 --> 00:17:51,400
METFORMIN AS -- LOOKING AT THE

452
00:17:51,400 --> 00:17:53,840
SAFETY OF METFORMIN IN LFS

453
00:17:53,840 --> 00:17:55,560
PATIENTS AND OUR END POINT WAS

454
00:17:55,560 --> 00:17:57,240
TO MEASURE THE MITOCHONDRIAL

455
00:17:57,240 --> 00:17:58,800
FUNCTIONS BEFORE, DURING AND

456
00:17:58,800 --> 00:18:01,600
POST TREATMENT.

457
00:18:01,600 --> 00:18:02,760
AND THIS WAS WORK DONE IN

458
00:18:02,760 --> 00:18:13,760
COLLABORATION INITIALLY WITH DRN

459
00:18:19,800 --> 00:18:24,360
SAVAGE AND DR. KHINCHA.

460
00:18:24,360 --> 00:18:28,600
SO THIS IS A SCHEME OF THE

461
00:18:28,600 --> 00:18:30,560
PILOT, THE LFS PATIENTS WAS

462
00:18:30,560 --> 00:18:31,880
GIVEN METFORMIN AS YOU CAN SEE

463
00:18:31,880 --> 00:18:33,520
HERE, DOSE ESCALATING

464
00:18:33,520 --> 00:18:35,320
500 MILLIGRAMS PER DAY,

465
00:18:35,320 --> 00:18:37,800
INCREASED UP TO A TOTAL OF

466
00:18:37,800 --> 00:18:38,680
2,000 MILLIGRAMS DAILY OVER THE

467
00:18:38,680 --> 00:18:40,200
COURSE OF EIGHT WEEKS AND THIS

468
00:18:40,200 --> 00:18:42,920
IS FDA-APPROVED DOSE OF -- THE

469
00:18:42,920 --> 00:18:43,920
WASHOUT PERIOD OF SIX WEEKS AT

470
00:18:43,920 --> 00:18:45,360
THE END.

471
00:18:45,360 --> 00:18:51,040
AND WE WERE ABLE TO SHOW IN EX

472
00:18:51,040 --> 00:18:53,200
VIVO IS LATED THAT INDEED WE

473
00:18:53,200 --> 00:18:55,200
COULD SHOW MITOCHONDRIAL OXYGEN

474
00:18:55,200 --> 00:18:56,480
CONSUMPTION DECREASE IN THE

475
00:18:56,480 --> 00:18:58,800
BLOOD MONOCYTES OF THIS PATIENT

476
00:18:58,800 --> 00:19:00,240
TAKING THE PEAK DOSES OF

477
00:19:00,240 --> 00:19:02,400
METFORMIN AT 8 WEEKS AND 14

478
00:19:02,400 --> 00:19:05,360
WEEKS, AND WITH WASHOUT AFTER

479
00:19:05,360 --> 00:19:06,480
6 WEEKS OF WASHOUT, THERE WAS

480
00:19:06,480 --> 00:19:11,360
SOME RECOVERY AS SHOWN HERE.

481
00:19:11,360 --> 00:19:12,840
AND IN TERMS OF BIOMARKERS IN

482
00:19:12,840 --> 00:19:14,520
THE BLOOD, WE WERE ABLE TO SHOW

483
00:19:14,520 --> 00:19:16,840
HERE, WE JUST LOOK AT CYCLIN D1,

484
00:19:16,840 --> 00:19:19,040
THAT THERE WAS A DECREASE IN

485
00:19:19,040 --> 00:19:22,320
PSYCYCLIN D1 LEVELS AND THIS IS

486
00:19:22,320 --> 00:19:25,920
WHAT WE OBSERVED IN THE THYMUS

487
00:19:25,920 --> 00:19:28,640
TISSUE IN LFS MICE AS YOU MAY

488
00:19:28,640 --> 00:19:29,320
RECALL.

489
00:19:29,320 --> 00:19:31,840
LASTLY, WE WERE ABLE TO OBTAIN

490
00:19:31,840 --> 00:19:33,880
NONINVASIVE IN VIVO EVIDENCE OF

491
00:19:33,880 --> 00:19:35,320
MITOCHONDRIAL INHIBITION IN

492
00:19:35,320 --> 00:19:38,320
SKELETAL MUSCLE USING P31MR SPEC

493
00:19:38,320 --> 00:19:40,480
TSPECTROSCOPY THAT I MENTIONED

494
00:19:40,480 --> 00:19:40,880
EARLIER.

495
00:19:40,880 --> 00:19:42,440
GENERATION OF THE EXERCISE

496
00:19:42,440 --> 00:19:45,280
DEPLETION AND SO THE FASTER IT

497
00:19:45,280 --> 00:19:47,520
IS, THE GREATER THE CAPACITY, SO

498
00:19:47,520 --> 00:19:50,320
YOU CAN SEE COMPARED TO CONTROL

499
00:19:50,320 --> 00:19:51,520
BASELINE WITHOUT -- BEFORE

500
00:19:51,520 --> 00:19:52,800
METFORMIN TREATMENT THAT THERE'S

501
00:19:52,800 --> 00:19:55,360
AN INCREASE IN RECOVERY TIME

502
00:19:55,360 --> 00:19:57,400
CONSTANT, INDICATING THIS

503
00:19:57,400 --> 00:19:59,480
DECREASE OF OXIDATIVE

504
00:19:59,480 --> 00:20:01,160
PHOSPHORYLATION AT THE TIMES OF

505
00:20:01,160 --> 00:20:03,760
THE -- TREATED TIMES OF 8 WEEKS

506
00:20:03,760 --> 00:20:05,960
AND 14 WEEKS AND THEN AFTER

507
00:20:05,960 --> 00:20:08,800
6 WEEKS OF WASHOUT, WE CAN SEE

508
00:20:08,800 --> 00:20:10,440
THE CHANGE IN TIME CONSTANT

509
00:20:10,440 --> 00:20:12,280
BECOMES NON-SIGNIFICANT.

510
00:20:12,280 --> 00:20:14,360
AND SO THIS AT LEAST WAS VERY

511
00:20:14,360 --> 00:20:17,520
GOOD EVIDENCE FOR US THAT WE

512
00:20:17,520 --> 00:20:19,160
COULD IN VIVO SHOW EVIDENCE OF

513
00:20:19,160 --> 00:20:21,520
DECREASED MITOCHONDRIAL FUNCTION

514
00:20:21,520 --> 00:20:23,600
IN A TISSUE THAT GIVES RISE TO

515
00:20:23,600 --> 00:20:26,160
ONE OF THE PROTOTYPICAL TUMORS

516
00:20:26,160 --> 00:20:28,360
OF LI-FRAUMENI SYNDROME, WHICH

517
00:20:28,360 --> 00:20:35,160
IS RHABDOMYOSARCOMA.

518
00:20:35,160 --> 00:20:40,520
SO BASED ON THIS, DR. KHINCHA

519
00:20:40,520 --> 00:20:43,680
WILL DISCUSS SOME OF THE PLANS

520
00:20:43,680 --> 00:20:47,280
ABOUT POTENTIAL METFORMIN CUOMO

521
00:20:47,280 --> 00:20:48,360
PREVENTION STUDY IN THE NEXT

522
00:20:48,360 --> 00:20:50,560
PART OF THIS GRAND ROUNDS.

523
00:20:50,560 --> 00:20:53,200
IN TERMS OF US BACK IN THE

524
00:20:53,200 --> 00:20:54,160
LABORATORY, A QUESTION THAT

525
00:20:54,160 --> 00:20:56,360
AROSE IS THAT CAN WE INHIBIT

526
00:20:56,360 --> 00:20:58,880
SPECIFIC ACTIVITY OF THE

527
00:20:58,880 --> 00:20:59,760
MITOCHONDRIA RATHER THAN

528
00:20:59,760 --> 00:21:01,080
GLOBALLY INHIBITING

529
00:21:01,080 --> 00:21:02,960
MITOCHONDRIAL RESPIRATION BY

530
00:21:02,960 --> 00:21:04,920
COMPLEX 1 USING METFORMIN, IS

531
00:21:04,920 --> 00:21:07,320
THERE SPECIFIC ACTIVITY THAT CAN

532
00:21:07,320 --> 00:21:09,040
INHIBIT MITOCHONDRIA THAT CAN

533
00:21:09,040 --> 00:21:11,600
ALSO BE PROTECTIVE AGAINST

534
00:21:11,600 --> 00:21:12,120
TUMORIGENESIS.

535
00:21:12,120 --> 00:21:14,520
AND TO DO THIS, WE TURNED TO

536
00:21:14,520 --> 00:21:19,760
FATTY ACID OXIDATION OF THE

537
00:21:19,760 --> 00:21:20,080
MITOCHONDRIA.

538
00:21:20,080 --> 00:21:20,960
THERE'S OBVIOUSLY INCREASING

539
00:21:20,960 --> 00:21:22,120
EVIDENCE IN THE LITERATURE

540
00:21:22,120 --> 00:21:24,280
SHOWING THAT FATTY ACID

541
00:21:24,280 --> 00:21:26,240
METABOLISM CONTRIBUTES TO

542
00:21:26,240 --> 00:21:29,160
TUMORIGENESIS, AND IN FACT, IN A

543
00:21:29,160 --> 00:21:30,280
RECENT MOUSE THAT WE MADE, THIS

544
00:21:30,280 --> 00:21:35,240
IS ANOTHER LFS MUTANT MOUSE, THE

545
00:21:35,240 --> 00:21:35,640
178.

546
00:21:35,640 --> 00:21:39,120
IN HUMANS IT'S 181.

547
00:21:39,120 --> 00:21:44,160
WE ACTUALLY OBSERVED INCREASE

548
00:21:44,160 --> 00:21:47,640
LIPOLYSIS IN WHITE ADIPOSE

549
00:21:47,640 --> 00:21:49,840
TISSUE.

550
00:21:49,840 --> 00:21:50,640
MECHANISTICALLY THIS APPEARS TO

551
00:21:50,640 --> 00:21:55,000
BE WITH THE MUTANT P53 BINDING

552
00:21:55,000 --> 00:21:57,840
TO BINDING SITE OF THE

553
00:21:57,840 --> 00:21:59,480
ADRENERGIC BETA RECEPTOR 3 THAT

554
00:21:59,480 --> 00:22:02,640
SIGNALS DOWNSTREAM TO INCREASE

555
00:22:02,640 --> 00:22:04,920
LIPOLYSIS AND GIVES IT THIS LOW

556
00:22:04,920 --> 00:22:09,960
BODY FAT PHENOTYPE.

557
00:22:09,960 --> 00:22:12,280
IN FACT, EARLY ON IN OUR

558
00:22:12,280 --> 00:22:13,680
STUDIES, WE ACTUALLY OBSERVED

559
00:22:13,680 --> 00:22:16,520
INCREASED FATTY ACID OXIDATION

560
00:22:16,520 --> 00:22:18,240
IN THE HOT SPOT MUTANT MOUSE

561
00:22:18,240 --> 00:22:19,480
THAT WE'RE USING FOR ALL OUR

562
00:22:19,480 --> 00:22:19,920
STUDIES.

563
00:22:19,920 --> 00:22:22,120
IN FACT, IF YOU DO WHOLE BODY

564
00:22:22,120 --> 00:22:23,560
METABOLISM STUDIES, YOU CAN SEE

565
00:22:23,560 --> 00:22:26,080
THAT THE HOMOZYGOUS MUTANT MICE

566
00:22:26,080 --> 00:22:29,080
SHOWN HERE H/H ACTUALLY HAVE A

567
00:22:29,080 --> 00:22:31,880
LOWER RESPIRATORY EXCHANGE

568
00:22:31,880 --> 00:22:35,040
RATIO, CO2 PRODUCTION OF OXYGEN

569
00:22:35,040 --> 00:22:35,320
CONSUMPTION.

570
00:22:35,320 --> 00:22:36,880
THAT'S A MARKER THAT THESE MICE

571
00:22:36,880 --> 00:22:38,840
PREFER TO USE IN FATTY ACIDS

572
00:22:38,840 --> 00:22:41,040
VERSUS CARBOHYDRATES FOR THEIR

573
00:22:41,040 --> 00:22:43,560
OXIDATIVE M METABOLISM.

574
00:22:43,560 --> 00:22:45,520
SO WE WONDERED WHETHER WE COULD

575
00:22:45,520 --> 00:22:48,680
PERHAPS INHIBIT THIS ACTIVITY,

576
00:22:48,680 --> 00:22:49,920
AND WE TOOK ADVANTAGE OF A MOUSE

577
00:22:49,920 --> 00:22:58,440
THAT'S ACTUALLY AVAILABLE TO US,

578
00:22:58,440 --> 00:22:59,520
THE MYOGLOBIN KO MOUSE.

579
00:22:59,520 --> 00:23:02,600
YOU CAN SEE THEY HAVE A

580
00:23:02,600 --> 00:23:04,120
HIGHER -- KNOCKOUT MICE HAVE A

581
00:23:04,120 --> 00:23:06,120
HIGHER RESPIRATORY EXCHANGE

582
00:23:06,120 --> 00:23:06,400
RATIO.

583
00:23:06,400 --> 00:23:09,120
SO IF WE CROSS THESE TWO MICE

584
00:23:09,120 --> 00:23:14,840
THAT HAVE LOW LFS, HIGH RER,

585
00:23:14,840 --> 00:23:15,960
KNOCKOUT, CAN WE NORMALIZE IT,

586
00:23:15,960 --> 00:23:20,000
WITH IWHICH IS A SIMPLE IDEA.

587
00:23:20,000 --> 00:23:21,400
WE WERE ABLE TO SHOW WHEN WE

588
00:23:21,400 --> 00:23:23,160
MADE A DOUBLE MUTANT MOUSE, YOU

589
00:23:23,160 --> 00:23:25,240
CAN SEE THAT THE THYMUS FATTY

590
00:23:25,240 --> 00:23:28,040
ACID THYMUS TISSUE AGAIN WHERE

591
00:23:28,040 --> 00:23:29,480
THE TUMOR DEVELOPS, THE FATTY

592
00:23:29,480 --> 00:23:30,920
ACID OXIDATION WAS ACTUALLY

593
00:23:30,920 --> 00:23:32,320
DECREASED ALMOST TO WILD TYPE

594
00:23:32,320 --> 00:23:32,880
LEVELS.

595
00:23:32,880 --> 00:23:35,400
AND WE WERE ABLE TO SHOW THIS

596
00:23:35,400 --> 00:23:41,720
30% IMPROVEMENT IN CANCER-FREE

597
00:23:41,720 --> 00:23:43,280
SURVIVAL, MEDIAN CANCER-FREE

598
00:23:43,280 --> 00:23:44,480
SURVIVAL IN THE DOUBLE MUTANT

599
00:23:44,480 --> 00:23:49,840
MICE SIMPLY BY DOWNREGULATING

600
00:23:49,840 --> 00:23:51,680
FATTY ACID OXIDATION.

601
00:23:51,680 --> 00:23:55,200
SO FINALLY, WE WANTED TO KNOW,

602
00:23:55,200 --> 00:23:56,840
IS THERE -- RATHER THAN JUST --

603
00:23:56,840 --> 00:23:59,480
SO ONE OF THE REASONS -- WE

604
00:23:59,480 --> 00:24:00,640
BELIEVE THE REASON WHY THIS

605
00:24:00,640 --> 00:24:04,880
INCREASED FATTY ACID OXIDATION

606
00:24:04,880 --> 00:24:10,080
IN THE KNOCKOUT MICE --

607
00:24:10,080 --> 00:24:11,600
DIMINISHED -- AND FATTY ACID

608
00:24:11,600 --> 00:24:13,800
OXIDATION IS A VERY

609
00:24:13,800 --> 00:24:15,440
OXYGEN-INTENSIVE PROCESS AND SO

610
00:24:15,440 --> 00:24:16,120
CARBOHYDRATES ARE PREFERRED

611
00:24:16,120 --> 00:24:17,400
PERHAPS BY THESE MICE.

612
00:24:17,400 --> 00:24:18,480
BUT WE WANTED TO TEST THIS

613
00:24:18,480 --> 00:24:21,120
WHETHER THIS IS A CELL

614
00:24:21,120 --> 00:24:23,080
AUTONOMOUS PROCEDURE, I THINK I

615
00:24:23,080 --> 00:24:24,400
JUMPED ONE SLIDE AHEAD, SORRY.

616
00:24:24,400 --> 00:24:27,600
THIS IS JUST TO SHOW THAT THE

617
00:24:27,600 --> 00:24:30,640
MYOGLOBIN KNOCKOUT CORRECTS THE

618
00:24:30,640 --> 00:24:32,720
SIGNALING IN THE THYMUS TISSUE.

619
00:24:32,720 --> 00:24:37,200
LOOKING HERE AT THE MTOR

620
00:24:37,200 --> 00:24:38,400
SIGNALING TARGET, YOU CAN SEE

621
00:24:38,400 --> 00:24:43,520
THE LFS MICE WITH WILD TYPE --

622
00:24:43,520 --> 00:24:48,920
HAVE INCREASED CELL GROWTH, YOU

623
00:24:48,920 --> 00:24:55,480
CAN SEE WHEN YOU REMOVE THE

624
00:24:55,480 --> 00:24:57,400
MYOGLOBIN, THERE'S DECREASED

625
00:24:57,400 --> 00:24:57,680
SIGNALING.

626
00:24:57,680 --> 00:24:58,760
JUMPING BACK AGAIN, WE WANTED TO

627
00:24:58,760 --> 00:25:00,600
TEST WHETHER THIS DECREASE IN

628
00:25:00,600 --> 00:25:05,080
FATTY ACID OXIDATION BEING

629
00:25:05,080 --> 00:25:06,080
CANCER PROTECTIVE COULD BE

630
00:25:06,080 --> 00:25:07,600
DEMONSTRATED AT THE CELL

631
00:25:07,600 --> 00:25:08,920
AUTONOMOUS LEVEL, SO WE TOOK

632
00:25:08,920 --> 00:25:10,240
ADVANTAGE OF ANOTHER KNOCKOUT

633
00:25:10,240 --> 00:25:10,960
MOUSE AVAILABLE TO US.

634
00:25:10,960 --> 00:25:12,960
THIS IS THE CP T2 KNOCKOUT

635
00:25:12,960 --> 00:25:13,960
MOUSE.

636
00:25:13,960 --> 00:25:16,120
THE CPT2 IS IMPORTANT FOR FATTY

637
00:25:16,120 --> 00:25:17,320
ACID TRANSPORT INTO THE

638
00:25:17,320 --> 00:25:18,640
MITOCHONDRIA FOR ITS OXIDATION,

639
00:25:18,640 --> 00:25:25,360
AND SO WE TOOK A HETEROZYGOUS

640
00:25:25,360 --> 00:25:31,000
MICE WITH THIS AND CROSSED THEM

641
00:25:31,000 --> 00:25:33,400
WITH CD4 CRE MICE, SO THESE MICE

642
00:25:33,400 --> 00:25:37,960
WOULD ONLY HAVE KNOCKOUT OF

643
00:25:37,960 --> 00:25:43,440
FATTY ACID OXIDATION OR

644
00:25:43,440 --> 00:25:44,040
SUFFICIENCY -- IN THE T-CELLS

645
00:25:44,040 --> 00:25:45,720
WHERE THE TUMORS DEVELOP.

646
00:25:45,720 --> 00:25:49,320
AGAIN, JUST SHOWING THAT WE

647
00:25:49,320 --> 00:25:52,080
COULD DECREASE FATTY ACID

648
00:25:52,080 --> 00:25:53,360
OXIDATION MILDLY IN THESE MICE

649
00:25:53,360 --> 00:25:57,520
WHEN CROSSED AGAIN WITH THE

650
00:25:57,520 --> 00:25:58,400
CD4 CRE MICE AND MOST

651
00:25:58,400 --> 00:26:00,160
IMPORTANTLY, WE WERE ABLE TO

652
00:26:00,160 --> 00:26:02,760
SHOW THIS APPROXIMATELY 30%

653
00:26:02,760 --> 00:26:05,520
IMPROVEMENT IN CANCER-FREE

654
00:26:05,520 --> 00:26:07,200
SURVIVAL WITH A SLIGHT DECREASE

655
00:26:07,200 --> 00:26:08,920
IN FATTY ACID OXIDATION.

656
00:26:08,920 --> 00:26:11,400
SO NOT ONLY JUST GLOBALLY

657
00:26:11,400 --> 00:26:12,840
INHIBITING MITOCHONDRIA, BUT

658
00:26:12,840 --> 00:26:15,040
JUST SELECTIVITY INHIBITING ONE

659
00:26:15,040 --> 00:26:16,440
ACTIVITY OF THE MITOCHONDRIA

660
00:26:16,440 --> 00:26:18,760
APPEARS TO BE ABLE TO CONFER

661
00:26:18,760 --> 00:26:20,920
THIS CANCER-PREVENTIVE EFFECT.

662
00:26:20,920 --> 00:26:22,440
SO TO SUMMARIZE, I HOPE I'VE

663
00:26:22,440 --> 00:26:24,000
BEEN ABLE TO SHOW YOU THAT BOTH

664
00:26:24,000 --> 00:26:27,520
BY GENETIC -- INHIBITION OF

665
00:26:27,520 --> 00:26:29,120
MITOCHONDRIAL FUNCTION THAT WE

666
00:26:29,120 --> 00:26:32,080
CAN HAVE CANCER-PREVENTIVE

667
00:26:32,080 --> 00:26:35,360
EFFECTS IN ASSOCIATION WITH THIS

668
00:26:35,360 --> 00:26:37,880
ANTIPROLIFERATION SIGNALING THAT

669
00:26:37,880 --> 00:26:39,320
WE WERE ABLE TO OBSERVE.

670
00:26:39,320 --> 00:26:40,840
AND THAT IT IS ALSO POSSIBLE

671
00:26:40,840 --> 00:26:44,800
USING A VERY BENIGN DRUG SUCH AS

672
00:26:44,800 --> 00:26:46,080
METFORMIN, WELL TOLERATED DRUG,

673
00:26:46,080 --> 00:26:47,720
SO INHIBIT MITOCHONDRIAL

674
00:26:47,720 --> 00:26:51,040
RESPIRATION IN LFS PATIENTS,

675
00:26:51,040 --> 00:26:55,920
WITH, AGAIN, ANTI -- SIGNALING

676
00:26:55,920 --> 00:26:56,920
BIOMARKERS IN THE BLOOD THAT WAS

677
00:26:56,920 --> 00:26:59,240
ASSOCIATED WITH CANCER

678
00:26:59,240 --> 00:27:01,640
PREVENTION IN THE MOUSE MODEL.

679
00:27:01,640 --> 00:27:04,120
AND THIS THEN GIVES WAY TO

680
00:27:04,120 --> 00:27:06,440
CONSIDER METFORMIN

681
00:27:06,440 --> 00:27:07,960
CHEMOPREVENTION STUDY THAT

682
00:27:07,960 --> 00:27:09,360
DR. KHINCHA WILL GO INTO IN THE

683
00:27:09,360 --> 00:27:12,200
NEXT PRESENTATION.

684
00:27:12,200 --> 00:27:15,600
AND IT ALSO POSSIBLE TO DO THIS.

685
00:27:15,600 --> 00:27:17,480
MOST SPECIFICALLY TARGETING

686
00:27:17,480 --> 00:27:19,640
FATTY ACID OXIDATION AND THEY

687
00:27:19,640 --> 00:27:23,840
ARE VERY SPECIFIC FDA-APPROVED

688
00:27:23,840 --> 00:27:26,880
DRUGS OR FATTY ACID OXIDATION

689
00:27:26,880 --> 00:27:27,680
INHIBITORS AVAILABLE THAT ALSO

690
00:27:27,680 --> 00:27:28,200
WE TESTED.

691
00:27:28,200 --> 00:27:35,520
SO I WILL STOP HERE AND END WITH

692
00:27:35,520 --> 00:27:36,400
ACKNOWLEDGING WORK THAT -- THIS

693
00:27:36,400 --> 00:27:37,520
IS WORK THAT REALLY COULDN'T

694
00:27:37,520 --> 00:27:41,880
HAVE BEEN DONE WITHOUT THE

695
00:27:41,880 --> 00:27:44,280
PARTICIPATION OF THE LFS STUDY

696
00:27:44,280 --> 00:27:45,800
PARTICIPANTS, THEIR TIME AND

697
00:27:45,800 --> 00:27:47,800
DEDICATION, MY LAB MEMBERS, BOTH

698
00:27:47,800 --> 00:27:50,000
PAST AND PRESENT MEMBERS, AND

699
00:27:50,000 --> 00:27:52,040
THE MANY COLLABORATORS LISTED

700
00:27:52,040 --> 00:27:54,640
HERE THAT HAVE CONTRIBUTED TO

701
00:27:54,640 --> 00:27:58,040
THE STUDY OVER THE YEARS AND

702
00:27:58,040 --> 00:28:00,040
ESPECIALLY DR. KHINCHA AND

703
00:28:00,040 --> 00:28:03,480
DR. SAVAGE AND ANNUNZIATA.

704
00:28:03,480 --> 00:28:06,160
THANK YOU.

705
00:28:06,160 --> 00:28:07,360
DR. HWANG, THANK YOU SO MUCH FOR

706
00:28:07,360 --> 00:28:07,800
THAT PRESENTATION.

707
00:28:07,800 --> 00:28:09,240
THAT WILL HOPEFULLY SEGUE WELL

708
00:28:09,240 --> 00:28:10,960
INTO WHAT I'M TALKING ABOUT.

709
00:28:10,960 --> 00:28:12,920
AND I WILL BE TALKING MORE ABOUT

710
00:28:12,920 --> 00:28:15,240
THE CLINICAL ASPECTS, TAKING A

711
00:28:15,240 --> 00:28:16,440
LITTLE BIT OF A SWITCH, TALKING

712
00:28:16,440 --> 00:28:19,000
ABOUT THE CLINICAL ASPECTS OF

713
00:28:19,000 --> 00:28:20,120
LI-FRAUMENI SYNDROME, A BIT

714
00:28:20,120 --> 00:28:21,160
ABOUT THE PHENOTYPES, WHAT'S

715
00:28:21,160 --> 00:28:22,360
AVAILABLE FOR PRIMARY AND

716
00:28:22,360 --> 00:28:24,280
SECONDARY CANCER PREVENTION, AND

717
00:28:24,280 --> 00:28:25,400
HOPEFULLY END WITH SHARING WITH

718
00:28:25,400 --> 00:28:27,240
YOU WHY THE WORK OF DR. HWANG

719
00:28:27,240 --> 00:28:30,640
AND SO MANY OF HIS LAB MEMBERS

720
00:28:30,640 --> 00:28:31,640
AND COLLABORATORS IS SO

721
00:28:31,640 --> 00:28:35,040
IMPORTANT IN THIS SIN CHROME.

722
00:28:35,040 --> 00:28:35,480
 -- SYNDROME.

723
00:28:35,480 --> 00:28:37,880
I HAVE NO DISCLOSURES FOR

724
00:28:37,880 --> 00:28:38,440
TODAY'S TALK.

725
00:28:38,440 --> 00:28:39,840
SO IN THE CLINICAL GENETICS

726
00:28:39,840 --> 00:28:40,960
BRANCH, WE STUDY RARE DISEASE

727
00:28:40,960 --> 00:28:42,280
AND SPECIFICALLY WE STUDY RARE

728
00:28:42,280 --> 00:28:44,200
DISEASE THAT LEAD TO AN

729
00:28:44,200 --> 00:28:45,200
INCREASED RISK OF CANCER.

730
00:28:45,200 --> 00:28:47,080
MOST OF THE WORK THAT WE DO

731
00:28:47,080 --> 00:28:49,480
SPANS THE SPECTRUM FROM ETIOLOGY

732
00:28:49,480 --> 00:28:52,320
IN PHENOTYPE THROUGH EARLY

733
00:28:52,320 --> 00:28:53,760
DETECTION IN CANCER SCREENING,

734
00:28:53,760 --> 00:28:54,920
IMPACT MANAGEMENT, PREVENTION

735
00:28:54,920 --> 00:28:57,560
AND POPULATION IMPACT OF THESE

736
00:28:57,560 --> 00:28:58,000
SYNDROMES.

737
00:28:58,000 --> 00:28:59,200
AND I'LL BE TOUCHING UPON MOST

738
00:28:59,200 --> 00:29:01,480
OF THESE TODAY AS I TRY TO GIVE

739
00:29:01,480 --> 00:29:04,560
YOU A WHIRLWIND TOUR OF WHAT LFS

740
00:29:04,560 --> 00:29:05,320
ENTAILS AND SOME OF THE WORK

741
00:29:05,320 --> 00:29:08,160
WE'RE DOING IN LFS.

742
00:29:08,160 --> 00:29:09,480
SO LI-FRAUMENI SYNDROME OR LFS

743
00:29:09,480 --> 00:29:11,560
WAS FIRST DESCRIBED IN 1969 HERE

744
00:29:11,560 --> 00:29:13,200
AT THE NIH IN THE NATIONAL

745
00:29:13,200 --> 00:29:20,440
CANCER INSTITUTE BY DRS. LI AND

746
00:29:20,440 --> 00:29:22,280
FRAUMENI, FIRST AS EARLY ONSET

747
00:29:22,280 --> 00:29:24,360
IN BREAST CANCERS.

748
00:29:24,360 --> 00:29:27,200
WHAT YOU SEE IS MULTIPLE

749
00:29:27,200 --> 00:29:28,080
GENERATIONS, MULTIPLE FAMILY

750
00:29:28,080 --> 00:29:29,040
MEMBERS AFFECTED WITH A NUMBER

751
00:29:29,040 --> 00:29:30,720
OF DIFFERENT CANCER TYPES.

752
00:29:30,720 --> 00:29:32,680
WHILE IT WAS DESCRIBED IN 1969,

753
00:29:32,680 --> 00:29:36,200
IT WASN'T UNTIL 1990, WHEN

754
00:29:36,200 --> 00:29:37,840
GERMLINE -- AND I UNDERLINED

755
00:29:37,840 --> 00:29:40,440
GERMLINE BECAUSE AS DR. HWANG

756
00:29:40,440 --> 00:29:41,840
MENTIONED, P53 IS THE MOST

757
00:29:41,840 --> 00:29:44,280
COMMONLY MUTATED GENE IN HUMAN

758
00:29:44,280 --> 00:29:44,920
CANCER, BUT LI-FRAUMENI SYNDROME

759
00:29:44,920 --> 00:29:47,000
IS SPECIFICALLY ASSOCIATED WITH

760
00:29:47,000 --> 00:29:48,480
GERMLINE P53 VARIATION THAT WAS

761
00:29:48,480 --> 00:29:50,160
FIRST ASSOCIATED IN 1990.

762
00:29:50,160 --> 00:29:53,120
AND TO DATE, P53 VARIANTS REMAIN

763
00:29:53,120 --> 00:29:55,120
THE ONLY KNOWN GENETIC CAUSE OF

764
00:29:55,120 --> 00:29:56,840
LFS AND ACCOUNT FOR BETWEEN 70

765
00:29:56,840 --> 00:29:59,360
TO 80% OF THOSE CLASSIC

766
00:29:59,360 --> 00:30:00,280
CANCER-RIDDLED PEDIGREES THAT I

767
00:30:00,280 --> 00:30:02,640
SHOWED YOU EARLIER, AND IT IS

768
00:30:02,640 --> 00:30:04,960
INHERITED IN AUTOSOMAL DOMINANT

769
00:30:04,960 --> 00:30:05,480
FASHION.

770
00:30:05,480 --> 00:30:06,600
NOW OVER THE YEARS AS WE'VE

771
00:30:06,600 --> 00:30:09,520
LEARNED MORE AND MORE ABOUT LFS

772
00:30:09,520 --> 00:30:11,040
AND AS GENE PANEL TESTING HAS

773
00:30:11,040 --> 00:30:13,360
BECOME MORE AND MORE THE NORM IN

774
00:30:13,360 --> 00:30:15,240
ONCOLOGY CLINICS, WE SEE THAT AS

775
00:30:15,240 --> 00:30:17,400
MANY OF THE HERITABLE CANCER

776
00:30:17,400 --> 00:30:19,000
SYNDROMES, LFS HAS A SPECTRUM

777
00:30:19,000 --> 00:30:21,240
THAT SPANS FROM THE VERY SEVERE

778
00:30:21,240 --> 00:30:22,640
CANCER RIDDLED PEDIGREES ALL THE

779
00:30:22,640 --> 00:30:24,640
WAY DOWN TO INCIDENTAL CARRIERS

780
00:30:24,640 --> 00:30:26,920
WHERE P53 IS FOUND ON A GENETIC

781
00:30:26,920 --> 00:30:29,120
TESTING STUDY, BUT THEY DON'T

782
00:30:29,120 --> 00:30:31,160
REALLY HAVE THE CLASSIC CANCER

783
00:30:31,160 --> 00:30:32,600
OR FAMILY HISTORY AND WHAT THIS

784
00:30:32,600 --> 00:30:33,480
SPECTRUM REALLY MEANS IS

785
00:30:33,480 --> 00:30:34,360
SOMETHING WE'RE TRYING TO

786
00:30:34,360 --> 00:30:37,520
UNDERSTAND MORE.

787
00:30:37,520 --> 00:30:39,800
NOW, TALKING ABOUT THE CANCER

788
00:30:39,800 --> 00:30:41,320
PREDISPOSITION SYNDROME, LFS IS

789
00:30:41,320 --> 00:30:42,680
ONE WHICH I THINK OF AS ONE OF

790
00:30:42,680 --> 00:30:44,000
THE MOST SEVERE.

791
00:30:44,000 --> 00:30:47,600
IT HAS ALMOST 100% PENETRANCE BY

792
00:30:47,600 --> 00:30:48,080
AGE 70.

793
00:30:48,080 --> 00:30:49,560
AND THE NUMBER OF CANCER TYPES

794
00:30:49,560 --> 00:30:51,640
THAT CAN OCCUR ARE A MULTITUDE

795
00:30:51,640 --> 00:30:53,600
AND THIS WILL EXPLAIN WHY WE DO

796
00:30:53,600 --> 00:30:56,560
WHOLE BODY MRI-BASED SCREENING

797
00:30:56,560 --> 00:30:57,880
THAT I'LL TALK ABOUT IN JUST A

798
00:30:57,880 --> 00:30:58,640
MOMENT.

799
00:30:58,640 --> 00:31:01,720
THIS DATA WAS DERIVED FROM THE

800
00:31:01,720 --> 00:31:04,440
GERMLINE P53 DATABASE WHERE WE

801
00:31:04,440 --> 00:31:06,520
LOOKED AT THE NUMBER OF CANCER

802
00:31:06,520 --> 00:31:09,560
SITES THAT WERE LISTED IN OVER

803
00:31:09,560 --> 00:31:10,040
2500 INDIVIDUALS WITH

804
00:31:10,040 --> 00:31:10,920
LI-FRAUMENI SYNDROME AND AS YOU

805
00:31:10,920 --> 00:31:13,600
CAN SEE, THE TOP ONES HERE ARE

806
00:31:13,600 --> 00:31:15,280
THE MOST FREQUENT WITH BREAST

807
00:31:15,280 --> 00:31:16,800
CANCER, EARLY ONSET BREAST

808
00:31:16,800 --> 00:31:18,000
CANCER BEING BY FAR THE MOST

809
00:31:18,000 --> 00:31:20,200
COMMONLY OCCURRING CANCER

810
00:31:20,200 --> 00:31:22,400
INLESS.

811
00:31:22,400 --> 00:31:22,560
 IN

812
00:31:22,560 --> 00:31:23,040
LI-FRAUMENI SYNDROME.

813
00:31:23,040 --> 00:31:25,240
BUT THESE TOP FOUR OR FIVE WHICH

814
00:31:25,240 --> 00:31:26,600
ARE EARLY ONSET BREAST CAN SE

815
00:31:26,600 --> 00:31:29,680
SOFT TISSUES, BRAIN, ADRENAL

816
00:31:29,680 --> 00:31:31,360
GLAND AND BONE TUMORS ARE ALSO

817
00:31:31,360 --> 00:31:33,760
WHAT WE CALL THE CORE CANCERS OF

818
00:31:33,760 --> 00:31:35,640
LFS BUT AS YOU SEE, THEY CAN

819
00:31:35,640 --> 00:31:36,600
PRETTY MUCH DEVELOP CANCER

820
00:31:36,600 --> 00:31:37,400
ANYWHERE IN THE BODY.

821
00:31:37,400 --> 00:31:39,360
THERE ARE VERY, VERY FEW CANCERS

822
00:31:39,360 --> 00:31:40,880
THAT WE CONSIDER NOT TO BE PART

823
00:31:40,880 --> 00:31:42,440
OF THE LFS ASSOCIATED CANCER

824
00:31:42,440 --> 00:31:43,680
SPECTRUM.

825
00:31:43,680 --> 00:31:44,400
THE LI-FRAUMENI SYNDROME STUDY

826
00:31:44,400 --> 00:31:46,000
WAS LAUNCHED HERE AT THE NCI

827
00:31:46,000 --> 00:31:48,800
KIND OF AS A REINCARNATION OR

828
00:31:48,800 --> 00:31:49,640
RESURRECTION, IF YOU WILL, OF

829
00:31:49,640 --> 00:31:51,200
THE PREVIOUS STUDY FROM THE

830
00:31:51,200 --> 00:31:52,240
60s AND 70s.

831
00:31:52,240 --> 00:31:53,800
AND EVEN THOUGH WE HAD KNOWN

832
00:31:53,800 --> 00:31:55,760
ABOUT LFS FOR MANY DECADES, UP

833
00:31:55,760 --> 00:31:58,200
UNTIL THE EARLY 2000s,

834
00:31:58,200 --> 00:31:59,080
INVESTIGATORS WERE REALLY

835
00:31:59,080 --> 00:32:00,160
WORKING IN SILOS AND THERE

836
00:32:00,160 --> 00:32:01,880
WASN'T A WHOLE LOT KNOWN MORE

837
00:32:01,880 --> 00:32:03,440
ABOUT OUTSIDE OF WHAT THE CANCER

838
00:32:03,440 --> 00:32:05,080
SPECTRUM MAY BE.

839
00:32:05,080 --> 00:32:06,600
SO WE LAUNCHED THE STUDY UNDER

840
00:32:06,600 --> 00:32:08,760
THE SUPERVISION OF DR. SAVAGE,

841
00:32:08,760 --> 00:32:11,080
WHO IS BOTH MY MENTOR AND

842
00:32:11,080 --> 00:32:12,640
CLINICAL DREG TORE AND SOME OF

843
00:32:12,640 --> 00:32:14,360
THE OBJECTIVES OF THIS

844
00:32:14,360 --> 00:32:15,240
LONGITUDINAL FAMILY STUDY WERE

845
00:32:15,240 --> 00:32:16,800
TO MORE CLEELY DEFINE THE

846
00:32:16,800 --> 00:32:18,320
CLINICAL SPECTRUM, LOOK AT

847
00:32:18,320 --> 00:32:19,600
POTENTIAL RISK MODIFYING FACTORS

848
00:32:19,600 --> 00:32:22,120
BEYOND THE GERMLINE VARIATION IN

849
00:32:22,120 --> 00:32:23,240
P53, ESTABLISH AN EFFECTIVE

850
00:32:23,240 --> 00:32:25,640
CANCER SCREENING PROGRAM,

851
00:32:25,640 --> 00:32:27,040
POSSIBLY OTHER NOVEL CAUSATIVE

852
00:32:27,040 --> 00:32:29,240
GENES FOR LFS, AND I THINK AN

853
00:32:29,240 --> 00:32:31,520
IMPORTANT ASPECT OF THE STUDY IS

854
00:32:31,520 --> 00:32:35,040
TO EVALUATE AND TAKE A DEEP DIVE

855
00:32:35,040 --> 00:32:38,880
INTO THE PSYCHOSOCIAL MENTAL AND

856
00:32:38,880 --> 00:32:40,840
FUNCTIONAL EFFECTS OF HAVING LFS

857
00:32:40,840 --> 00:32:42,520
AND ALSO BEING PART OF A FAMILY

858
00:32:42,520 --> 00:32:43,360
THAT HAS LFS.

859
00:32:43,360 --> 00:32:45,520
TO DATE, WE HAVE ENROLLED OVER

860
00:32:45,520 --> 00:32:47,800
220 FAMILIES AND OVER 900

861
00:32:47,800 --> 00:32:48,600
PARTICIPANTS.

862
00:32:48,600 --> 00:32:50,280
OVER 400 OF WHICH -- OF WHOM

863
00:32:50,280 --> 00:32:53,120
HAVE LFS AND THE OTHER HALF IS

864
00:32:53,120 --> 00:32:54,200
COMPRISED BY UNAFFECTED FAMILY

865
00:32:54,200 --> 00:32:54,760
MEMBERS.

866
00:32:54,760 --> 00:32:55,960
WE HAVE 146 OF THEERS

867
00:32:55,960 --> 00:33:01,240
INDIVITHESE INDIVIDUALSWITH LFSL

868
00:33:01,240 --> 00:33:02,400
CANCER SCREENING PROGRAM WHICH

869
00:33:02,400 --> 00:33:03,840
I'LL TOUCH UPON IN A MOMENT.

870
00:33:03,840 --> 00:33:05,280
TRYING TO UNDERSTAND THE ACTUAL

871
00:33:05,280 --> 00:33:06,480
RISKS OF LFS COMPARED TO THE

872
00:33:06,480 --> 00:33:07,680
GENERAL POPULATION, WE PERFORMED

873
00:33:07,680 --> 00:33:09,960
THIS STUDY WITH ONE OF OUR

874
00:33:09,960 --> 00:33:12,040
FELLOWS WHO IS A POSTDOC FELLOW

875
00:33:12,040 --> 00:33:14,760
OR NOW A RESEARCH FELLOW IN CGB,

876
00:33:14,760 --> 00:33:16,560
COMPARING OUR LFS COHORT AND THE

877
00:33:16,560 --> 00:33:17,720
CANCER INCIDENCE TO THAT OF THE

878
00:33:17,720 --> 00:33:19,760
GENERAL POPULATION USING THE

879
00:33:19,760 --> 00:33:20,360
SEER DATABASE.

880
00:33:20,360 --> 00:33:22,320
WHAT WE FOUND IS THAT

881
00:33:22,320 --> 00:33:24,840
INDIVIDUALS WHO HAVE LFS ARE

882
00:33:24,840 --> 00:33:26,600
OVERALL AT NEARLY 25 TIMES

883
00:33:26,600 --> 00:33:27,920
HIGHER RISK OF DEVELOPING CANCER

884
00:33:27,920 --> 00:33:31,040
THAN THE GENERAL POPULATION, AND

885
00:33:31,040 --> 00:33:32,600
AS YOU CAN SEE FROM THIS GRAPH,

886
00:33:32,600 --> 00:33:34,440
THE HIGHEST COMPARATIVE

887
00:33:34,440 --> 00:33:35,960
INCIDENCE IS FROM CHILDHOOD UP

888
00:33:35,960 --> 00:33:37,240
UNTIL THE AGE OF 30 BUT EVEN BY

889
00:33:37,240 --> 00:33:38,600
THE AGE OF 60, INDIVIDUALS ARE

890
00:33:38,600 --> 00:33:40,480
STILL AT A HIGHER RISK, ALMOST

891
00:33:40,480 --> 00:33:42,440
TENFOLD HIGHER CANCER INCIDENCE

892
00:33:42,440 --> 00:33:43,520
IN LFS COMPARED TO THE GENERAL

893
00:33:43,520 --> 00:33:44,120
POPULATION.

894
00:33:44,120 --> 00:33:45,920
WHEN WE BREAK IT DOWN BY CANCER

895
00:33:45,920 --> 00:33:48,040
TYPES, THIS IS A BUSY SLIDE, BUT

896
00:33:48,040 --> 00:33:49,360
WHAT I'LL DRAW YOUR ATTENTION TO

897
00:33:49,360 --> 00:33:52,800
IS THESE BLACK ARROWS INDICATE

898
00:33:52,800 --> 00:33:53,560
POPULATION-LEVEL RISK, SO WHEN

899
00:33:53,560 --> 00:33:55,480
YOU LOOK AT ALL OF THE DIFFERENT

900
00:33:55,480 --> 00:33:57,200
CANCER TYPES WHICH IS

901
00:33:57,200 --> 00:33:58,840
OSTEOSARCOMA, BREATION CANCER,

902
00:33:58,840 --> 00:34:00,800
BRAIN AND SOFT TISSUE SARCOMAS

903
00:34:00,800 --> 00:34:02,000
AND LUNG CAN SE THESE ARE JUST

904
00:34:02,000 --> 00:34:05,960
SOME OF THE MANY THAT WE

905
00:34:05,960 --> 00:34:07,920
ANALYZED, THE MULTIFOLD

906
00:34:07,920 --> 00:34:09,120
SOMETIMES MULTI-HUNDRED FOLD

907
00:34:09,120 --> 00:34:11,000
HIGHER CANCER INCIDENTS IN LFS

908
00:34:11,000 --> 00:34:12,080
COMPARED TO THE GENERAL

909
00:34:12,080 --> 00:34:13,600
POPULATION JUST INDICATING HOW

910
00:34:13,600 --> 00:34:14,920
MUCH HIGHER THEIR CANCER

911
00:34:14,920 --> 00:34:17,480
DEVELOPMENT RISK IS.

912
00:34:17,480 --> 00:34:19,200
LOOKING AT THE CUMULATIVE CANCER

913
00:34:19,200 --> 00:34:20,120
INCIDENCE, YOU'VE GOT THE GRAPH

914
00:34:20,120 --> 00:34:21,320
WITH FEMALES ON THE LEFT AND

915
00:34:21,320 --> 00:34:22,360
MALES ON THE RIGHT, AND AS YOU

916
00:34:22,360 --> 00:34:25,000
CAN SEE IN THE FEMALES, THE

917
00:34:25,000 --> 00:34:26,120
CUMULATIVE CANCER INCIDENCE OF

918
00:34:26,120 --> 00:34:27,400
BREAST CANCER REALLY OVERTAKES

919
00:34:27,400 --> 00:34:28,960
ANYTHING THAT WOMEN GET AND BY

920
00:34:28,960 --> 00:34:32,800
THE AGE OF 75, THERE'S WELL OVER

921
00:34:32,800 --> 00:34:34,520
55% CUMULATIVE INCIDENCE OF

922
00:34:34,520 --> 00:34:35,760
BREAST CANCER FOLLOWED BY ALL OF

923
00:34:35,760 --> 00:34:36,640
THESE OTHER DIFFERENT CANCER

924
00:34:36,640 --> 00:34:37,600
TYPES.

925
00:34:37,600 --> 00:34:39,480
IN THE MALES, THE BRAIN AND SOFT

926
00:34:39,480 --> 00:34:41,400
TISSUE SARCOMAS SEEM TO HAVE THE

927
00:34:41,400 --> 00:34:42,760
HIGHEST CUMULATIVE INCIDENCE OF

928
00:34:42,760 --> 00:34:45,400
CLOSE TO OR RIGHT OVER 20% BY

929
00:34:45,400 --> 00:34:46,600
LATE ADULTHOOD.

930
00:34:46,600 --> 00:34:48,480
IMPORTANT TO NOTE WAS IN

931
00:34:48,480 --> 00:34:50,520
FEMALES, THE MEDIAN AGE AT FIRST

932
00:34:50,520 --> 00:34:56,560
CANCER WAS 33 YEARS, MEANING BY

933
00:34:56,560 --> 00:34:58,080
AGE 33, THEY HAD DEVELOPED AT

934
00:34:58,080 --> 00:34:59,960
LEAST ONE CANCER, AND THE AGE IN

935
00:34:59,960 --> 00:35:01,800
MALES, THE MEDIAN AGE OF FIRST

936
00:35:01,800 --> 00:35:03,640
CANCER WAS 45 YEARS.

937
00:35:03,640 --> 00:35:05,640
THIS DIFFERENCE IS REALLY DRIVEN

938
00:35:05,640 --> 00:35:06,840
BY THE BREAST CANCER RISK IN

939
00:35:06,840 --> 00:35:07,800
LFS.

940
00:35:07,800 --> 00:35:09,360
THE BREAST CANCER RISK IN

941
00:35:09,360 --> 00:35:11,240
ITSELF, THE MEDIAN AGE AT FIRST

942
00:35:11,240 --> 00:35:13,200
BREAST CANCER WAS ALSO IN EARLY

943
00:35:13,200 --> 00:35:14,240
30s, MEANING HALF OF THE WOMEN

944
00:35:14,240 --> 00:35:15,800
ARE DEVELOPING BREAST CANCER IN

945
00:35:15,800 --> 00:35:17,560
THEIR LATE ADOLESCENCE AND EARLY

946
00:35:17,560 --> 00:35:20,400
ADULTHOOD.

947
00:35:20,400 --> 00:35:21,920
LFS IS NOT ONLY A SYNDROME OF

948
00:35:21,920 --> 00:35:24,760
HIGH CANCER RISK BUT ALSO A

949
00:35:24,760 --> 00:35:26,320
SYNDROME WITH HIGH MULTI-CANCER

950
00:35:26,320 --> 00:35:27,600
RISK, MEANING THEY CAN DEVELOP

951
00:35:27,600 --> 00:35:29,920
NOT ONLY ONE BUT MELT PEL

952
00:35:29,920 --> 00:35:31,560
SUBSEQUENT PRIMARIES IN NARE

953
00:35:31,560 --> 00:35:32,560
LIFETIME.

954
00:35:32,560 --> 00:35:34,840
ABOUT 50% OF THOSE THAT SURVIVED

955
00:35:34,840 --> 00:35:36,400
A FIRST CANCER WENT ON TO

956
00:35:36,400 --> 00:35:37,640
DEVELOP A SECOND.

957
00:35:37,640 --> 00:35:39,800
ABOUT 50% OF THOSE WENT ON TO

958
00:35:39,800 --> 00:35:40,920
DEVELOP A THIRD AND FOURTH AND

959
00:35:40,920 --> 00:35:41,400
SO ON.

960
00:35:41,400 --> 00:35:42,640
WE HAVE INDIVIDUALS IN THE STUDY

961
00:35:42,640 --> 00:35:45,240
WHO HAVE DEVELOPED UP TO SEVEN,

962
00:35:45,240 --> 00:35:46,120
EIGHT, NINE PRIMARY CANCERS IN

963
00:35:46,120 --> 00:35:47,320
THEIR LIFETIME.

964
00:35:47,320 --> 00:35:49,200
SO JUST LOOKING BACK AT THE

965
00:35:49,200 --> 00:35:52,360
RISKS AND FEET KNOW TYPES AND

966
00:35:52,360 --> 00:35:54,640
THE HETEROGENEITY OF PHENOTYPES

967
00:35:54,640 --> 00:35:56,240
WITHIN LFS, IT IS VERY HARD TO

968
00:35:56,240 --> 00:35:57,400
PREDICT WHAT IF ANY CANCERS WILL

969
00:35:57,400 --> 00:35:58,920
OCCUR IN AN INDIVIDUAL AND IF

970
00:35:58,920 --> 00:36:00,040
THEY OCCUR, WHAT AGE THAT WILL

971
00:36:00,040 --> 00:36:01,680
BE AND WHAT CANCER THAT WILL BE.

972
00:36:01,680 --> 00:36:03,320
SO LOOKING AT THIS

973
00:36:03,320 --> 00:36:04,760
HETEROGENEITY, IT BECAME VERY

974
00:36:04,760 --> 00:36:06,840
IMPORTANT TO ESTABLISH A

975
00:36:06,840 --> 00:36:08,680
FEASIBLE AND EFFECTIVE CANCER

976
00:36:08,680 --> 00:36:09,680
SCREENING PROGRAM FOR

977
00:36:09,680 --> 00:36:12,520
INDIVIDUALS WITH LFS.

978
00:36:12,520 --> 00:36:13,800
AND THE CURRENT SCREENING

979
00:36:13,800 --> 00:36:16,640
RECOMMENDATIONS THAT ARE PART OF

980
00:36:16,640 --> 00:36:17,880
THE NATIONAL COMPREHENSIVE

981
00:36:17,880 --> 00:36:19,640
CANCER NETWORK OR THE NCCN

982
00:36:19,640 --> 00:36:21,840
GUIDELINES ARE BASED ON WHAT IS

983
00:36:21,840 --> 00:36:23,160
CALLED THE TORONTO PROTOCOL.

984
00:36:23,160 --> 00:36:25,120
THIS IS A PROTOCOL THAT INCLUDED

985
00:36:25,120 --> 00:36:26,800
INTENSE RADIOLOGICAL AND

986
00:36:26,800 --> 00:36:28,200
BIOCHEMICAL SCREENING.

987
00:36:28,200 --> 00:36:30,520
AND IS NOW A -- A VARIANT OF

988
00:36:30,520 --> 00:36:31,920
THIS IS WHAT IS EMPLOYED AT

989
00:36:31,920 --> 00:36:33,120
DIFFERENT INSTITUTES AROUND THE

990
00:36:33,120 --> 00:36:34,320
WORLD THAT DO LFS SCREENING.

991
00:36:34,320 --> 00:36:36,640
HERE I PRESENT TO YOU THE ONLY

992
00:36:36,640 --> 00:36:37,760
LONGITUDINAL CANCER STUDY IN LFS

993
00:36:37,760 --> 00:36:40,360
TO DATE SHOWING IN A MOSTLY

994
00:36:40,360 --> 00:36:41,240
PEDIATRIC POPULATION THAT A

995
00:36:41,240 --> 00:36:43,280
SMALL POPULATION OF 89

996
00:36:43,280 --> 00:36:44,120
INDIVIDUALS, THAT THOSE

997
00:36:44,120 --> 00:36:47,200
INDIVIDUALS WHO CHOSE TO UNDERGO

998
00:36:47,200 --> 00:36:48,480
CANCER SCREENING OR SURVEILLANCE

999
00:36:48,480 --> 00:36:50,560
HAD A STATISTICALLY HIGHER

1000
00:36:50,560 --> 00:36:51,560
OVERALL SURVIVAL COMPARED TO

1001
00:36:51,560 --> 00:36:52,520
THOSE WHO DID NOT.

1002
00:36:52,520 --> 00:36:56,600
AND THIS REALLY JUST HIGHLIGHTS

1003
00:36:56,600 --> 00:36:58,000
THE IMPORTANCE OF CANCER

1004
00:36:58,000 --> 00:36:59,240
SCREENING NOT ONLY IN EARLY

1005
00:36:59,240 --> 00:37:00,720
DETECTION BUT ALSO LONG-TERM

1006
00:37:00,720 --> 00:37:03,160
BENEFITS.

1007
00:37:03,160 --> 00:37:06,760
SO THE CANCER SCREENING ARM LFS

1008
00:37:06,760 --> 00:37:08,400
STUDY WAS LAUNCHED IN 2012,

1009
00:37:08,400 --> 00:37:09,720
WHERE WE INVITED A SUBSET OF

1010
00:37:09,720 --> 00:37:11,480
THOSE WHO WERE ENROLLED IN OUR

1011
00:37:11,480 --> 00:37:13,360
LFS STUDY TO COME TO THE

1012
00:37:13,360 --> 00:37:14,240
CLINICAL CENTER FOR ANNUAL

1013
00:37:14,240 --> 00:37:15,640
CANCER SCREENING, AND THIS WAS

1014
00:37:15,640 --> 00:37:16,840
INDIVIDUALS AND FAMILIES OF ALL

1015
00:37:16,840 --> 00:37:18,920
AGE OVER THREE YEARS, GIVEN THE

1016
00:37:18,920 --> 00:37:19,920
RESOURCES OF THE CLINICAL

1017
00:37:19,920 --> 00:37:20,160
CENTER.

1018
00:37:20,160 --> 00:37:22,000
WHAT THIS ENTAILED WAS FOR THE

1019
00:37:22,000 --> 00:37:24,840
CHILDREN UNDERGOING ANNUAL WHOLE

1020
00:37:24,840 --> 00:37:26,280
BODY MRI WITH AND WITHOUT

1021
00:37:26,280 --> 00:37:28,360
CONTRAST, ANNUAL BRAIN MRI,

1022
00:37:28,360 --> 00:37:30,000
ABDOMINAL ULTRASOUNDS EVERY FOUR

1023
00:37:30,000 --> 00:37:31,720
MONTHS AND BLOOD WORK EVERY FOUR

1024
00:37:31,720 --> 00:37:32,280
MONTHS.

1025
00:37:32,280 --> 00:37:35,360
THE ADULTS ALSO UNDERWENT ANNUAL

1026
00:37:35,360 --> 00:37:38,680
WHOLE BODY MRI, BRAIN PLAI, THEY

1027
00:37:38,680 --> 00:37:42,720
ALSO DID COLONOSCOPY SCREENING,

1028
00:37:42,720 --> 00:37:43,560
ENDOSCOPY HAS BEEN ADDED TO

1029
00:37:43,560 --> 00:37:45,240
THESE GUIDELINES.

1030
00:37:45,240 --> 00:37:47,560
FOR THE FEMALES WHO HAD NOT

1031
00:37:47,560 --> 00:37:49,520
UNDERGOB RISK REDUCING

1032
00:37:49,520 --> 00:37:51,800
MASTECTOMIES, THEY UNDERWENT

1033
00:37:51,800 --> 00:37:53,600
ANNUAL BREAST MRI STARTING AGE

1034
00:37:53,600 --> 00:37:56,000
20 OR YOUNGER DEPENDING ON THE

1035
00:37:56,000 --> 00:37:57,520
FAMILY HISTORY AND ANNUAL

1036
00:37:57,520 --> 00:37:58,600
MAMMOGRAPHY STARTING AT AGE 40,

1037
00:37:58,600 --> 00:38:00,480
AND THIS HAS NOW BEEN BROUGHT

1038
00:38:00,480 --> 00:38:02,120
DOWN TO AGE 30, GIVEN THE CANCER

1039
00:38:02,120 --> 00:38:03,080
RISKS.

1040
00:38:03,080 --> 00:38:05,640
TO DATE, WE HAVE SCREENED 146

1041
00:38:05,640 --> 00:38:06,720
INDIVIDUALS AT THE CLINICAL

1042
00:38:06,720 --> 00:38:10,360
CENTER AT LEAST ONCE, AND THESE

1043
00:38:10,360 --> 00:38:12,120
INDIVIDUALS RANGE FROM 3 TO 78

1044
00:38:12,120 --> 00:38:12,400
YEARS.

1045
00:38:12,400 --> 00:38:13,960
WE'VE HAD FAMILIES WHO COME BACK

1046
00:38:13,960 --> 00:38:15,120
FOR THEIR TENTH ANNUAL SCREENING

1047
00:38:15,120 --> 00:38:18,200
AND SOME WHO HAVE COME FOR FEW

1048
00:38:18,200 --> 00:38:18,560
FEWER.

1049
00:38:18,560 --> 00:38:19,760
WITH THE RESOURCES OF THE

1050
00:38:19,760 --> 00:38:20,880
CLINICAL CENTER AND THE

1051
00:38:20,880 --> 00:38:21,640
WONDERFUL COLLABORATION WITH

1052
00:38:21,640 --> 00:38:23,040
RADIOLOGY AND IMAGING

1053
00:38:23,040 --> 00:38:23,720
DEPARTMENT, WE'VE CREATED A

1054
00:38:23,720 --> 00:38:25,040
WEALTH OF RESOURCE FOR LEARNING

1055
00:38:25,040 --> 00:38:27,240
ABOUT SCREENING IN LFS, HAVING

1056
00:38:27,240 --> 00:38:29,760
DONE WELL OVER 775 ANNUAL

1057
00:38:29,760 --> 00:38:31,200
SCREENING VISITS TO DATE, WHICH

1058
00:38:31,200 --> 00:38:33,920
MEANS THAT THERE'S DATA ON WELL

1059
00:38:33,920 --> 00:38:35,440
OVER 700 WHOLE BODY AND BRAIN

1060
00:38:35,440 --> 00:38:36,360
MRIS THAT WE CONTINUE TO LEARN

1061
00:38:36,360 --> 00:38:37,000
FROM.

1062
00:38:37,000 --> 00:38:38,280
THE CANCER DETECTION RATE,

1063
00:38:38,280 --> 00:38:41,640
MEANING THE DETECTION OF

1064
00:38:41,640 --> 00:38:42,600
ASYMPTOMATIC PRIMARY

1065
00:38:42,600 --> 00:38:44,120
MALIGNANCIES HAS REMAINED

1066
00:38:44,120 --> 00:38:47,000
BETWEEN 2 TO 6% PER YEAR, AND

1067
00:38:47,000 --> 00:38:48,200
THIS IS NOT ACCOUNTING FOR THE

1068
00:38:48,200 --> 00:38:48,960
INTERVAL CANCERS THEY GET

1069
00:38:48,960 --> 00:38:50,840
BETWEEN THE TWO ANNUAL SCREENING

1070
00:38:50,840 --> 00:38:52,160
VISITS, SO THIS IS JUST LOOKING

1071
00:38:52,160 --> 00:38:54,920
AT WHAT WAS DIAGNOSED AT THEIR

1072
00:38:54,920 --> 00:38:56,640
SCREENING VISIT, AND OUR FORMAL

1073
00:38:56,640 --> 00:38:58,000
ANALYSIS IS CURRENTLY UNDERWAY

1074
00:38:58,000 --> 00:38:59,280
LOOKING AT LONG TERM BENEFITS

1075
00:38:59,280 --> 00:39:00,480
AND OTHER OUTCOMES FROM THIS

1076
00:39:00,480 --> 00:39:03,560
STUDY.

1077
00:39:03,560 --> 00:39:05,000
NOW WHEN YOU TALK ABOUT WHOLE

1078
00:39:05,000 --> 00:39:06,240
BODY MRI, I WANTED TO IMPRESS

1079
00:39:06,240 --> 00:39:07,640
UPON YOU THAT THIS REALLY IS

1080
00:39:07,640 --> 00:39:08,240
WHOLE BODY MRI.

1081
00:39:08,240 --> 00:39:11,120
WE DO SCANS ON THE MACHINES THAT

1082
00:39:11,120 --> 00:39:14,320
LOOK FROM HEAD TO TOE, AND AS

1083
00:39:14,320 --> 00:39:15,720
YOU CAN IMAGINE, THIS IS JUST

1084
00:39:15,720 --> 00:39:16,720
ONE OF MANY SEQUENCES THAT WE

1085
00:39:16,720 --> 00:39:18,040
GET AS PART OF THE STUDY.

1086
00:39:18,040 --> 00:39:20,760
LOOKING AT THESE LESIONS IS NO

1087
00:39:20,760 --> 00:39:22,000
EASY FEAT, BUT IT COMES WITH THE

1088
00:39:22,000 --> 00:39:24,400
BENEFIT OF PICKING UP SOME

1089
00:39:24,400 --> 00:39:25,280
REALLY EARLY CANCERS.

1090
00:39:25,280 --> 00:39:27,160
FOR EXAMPLE, I'M SHOWING YOU

1091
00:39:27,160 --> 00:39:31,000
HERE A SUBCOUNCILM SUBCENTIMETET

1092
00:39:31,000 --> 00:39:35,000
TURNED OUT TO BE A CARCINOMA

1093
00:39:35,000 --> 00:39:39,000
THAT WAS ADEQUATELY TREATED,

1094
00:39:39,000 --> 00:39:41,920
THIS INDIVIDUAL HAS HAD TWO

1095
00:39:41,920 --> 00:39:44,680
FURTHER PRIMARY MALIGNANCIES.

1096
00:39:44,680 --> 00:39:48,840
SO THE BENEFIT IS THERE, WITH

1097
00:39:48,840 --> 00:39:49,840
COST.

1098
00:39:49,840 --> 00:39:52,240
DR. SAVAGE LED A META-ANALYSIS

1099
00:39:52,240 --> 00:39:55,880
OF LOOKING AT INDIVIDUALS OF ALL

1100
00:39:55,880 --> 00:39:58,560
AGES WHO RECEIVED THEIR BASELINE

1101
00:39:58,560 --> 00:39:59,920
WHOLE BODY MRI AND TO REALLY

1102
00:39:59,920 --> 00:40:01,120
ESTABLISH WHAT THE DETECTION

1103
00:40:01,120 --> 00:40:03,000
WAS, AND WHAT THE FALSE

1104
00:40:03,000 --> 00:40:05,280
POSITIVITY WAS.

1105
00:40:05,280 --> 00:40:06,600
SO THIS STUDY HAD THE

1106
00:40:06,600 --> 00:40:08,000
PARTICIPATION OF 13 CENTERS FROM

1107
00:40:08,000 --> 00:40:09,120
FOUR CONTINENTS AROUND THE

1108
00:40:09,120 --> 00:40:11,400
WORLD, WHERE WE LOOKED AT 578

1109
00:40:11,400 --> 00:40:14,920
INDIVIDUALS OF ALL AGES WHO HAD

1110
00:40:14,920 --> 00:40:16,360
LFS, AND WITH THEIR DATA JUST AT

1111
00:40:16,360 --> 00:40:18,880
THE FIRST WHOLE BODY MRI, ENDED

1112
00:40:18,880 --> 00:40:21,080
UP WITH DETECTION OF 42 CANCERS.

1113
00:40:21,080 --> 00:40:23,520
THESE ARE 42 PRIMARY CANCERS IN

1114
00:40:23,520 --> 00:40:24,720
39 INDIVIDUALS, ALL OF WHICH

1115
00:40:24,720 --> 00:40:27,520
WERE TREATED WITH CURATIVE

1116
00:40:27,520 --> 00:40:27,760
INTENT.

1117
00:40:27,760 --> 00:40:29,960
AND WE HAVE A LIST OF THE

1118
00:40:29,960 --> 00:40:31,160
CENTERS ON THE LEFT BUT IF YOU

1119
00:40:31,160 --> 00:40:34,040
LOOK ACROSS THE STUDIES, 7% OF

1120
00:40:34,040 --> 00:40:35,560
THE INDIVIDUALS WHO UNDERWENT

1121
00:40:35,560 --> 00:40:38,600
WHOLE BODY MRI, BASELINE WHOLE

1122
00:40:38,600 --> 00:40:41,040
BODY MRI HAD AN ASYMPTOMATIC

1123
00:40:41,040 --> 00:40:41,800
PRIMARY MALIGNANCY DIAGNOSED.

1124
00:40:41,800 --> 00:40:43,880
SO IN SUMMARY, THERE WAS A 7%

1125
00:40:43,880 --> 00:40:46,440
DETECTION RATE FOR NEW LOCALIZED

1126
00:40:46,440 --> 00:40:48,040
MALIGNANCIES BY THE WHOLE BODY

1127
00:40:48,040 --> 00:40:48,480
BASELINE MRI.

1128
00:40:48,480 --> 00:40:49,920
THERE WAS DEFINITELY A FALSE

1129
00:40:49,920 --> 00:40:50,920
POSITIVE RATE THAT WAS VERY HIGH

1130
00:40:50,920 --> 00:40:52,240
IF YOU CAN IMAGINE LOOKING AT

1131
00:40:52,240 --> 00:40:53,240
THESE MULTIPLE SEQUENCES, I

1132
00:40:53,240 --> 00:40:55,080
ALWAYS TALK ABOUT LFS SCREENING

1133
00:40:55,080 --> 00:40:56,880
AS WHERE EVERY LESION IS GUILTY

1134
00:40:56,880 --> 00:40:57,720
UNTIL PROVEN INNOCENT.

1135
00:40:57,720 --> 00:40:59,480
MANY OF THESE LESIONS HAD TO

1136
00:40:59,480 --> 00:41:01,280
UNDERGO FOLLOW-UP EVALUATIONS,

1137
00:41:01,280 --> 00:41:02,440
SOME OF WHICH TURNED OUT TO BE

1138
00:41:02,440 --> 00:41:04,400
CANCER AND SOME OF WHICH DIDN'T.

1139
00:41:04,400 --> 00:41:07,600
BUT AS I SAID, ALL

1140
00:41:07,600 --> 00:41:08,680
SCREEN-DETECTED NEW CANCERS WERE

1141
00:41:08,680 --> 00:41:10,160
TREATED WITH CURATIVE INTENT.

1142
00:41:10,160 --> 00:41:12,000
THIS WAS REALLY ONE BIG STUDY

1143
00:41:12,000 --> 00:41:13,760
THAT ESTABLISHED THE IMPORTANCE

1144
00:41:13,760 --> 00:41:16,240
AND CLINICAL UTILITY OF WHOLE

1145
00:41:16,240 --> 00:41:17,960
BODY MRI IN MANAGEMENT OF CANCER

1146
00:41:17,960 --> 00:41:20,360
RISK AND EARLY DETECTION IN

1147
00:41:20,360 --> 00:41:23,440
INDIVIDUALS IN THE P53

1148
00:41:23,440 --> 00:41:23,960
MUTATIONS.

1149
00:41:23,960 --> 00:41:25,840
BUT AS I SAID, SCREENING AND LFS

1150
00:41:25,840 --> 00:41:26,600
COMES WITH A COST.

1151
00:41:26,600 --> 00:41:29,240
THERE ARE PHYSICAL, EMOTIONAL,

1152
00:41:29,240 --> 00:41:31,720
SOCIAL, MENTAL AND FINANCIAL

1153
00:41:31,720 --> 00:41:34,160
BURDENS WITH LFS AND LFS

1154
00:41:34,160 --> 00:41:34,800
SCREENING.

1155
00:41:34,800 --> 00:41:36,680
TO DESCRIBE THIS IN SOME OF THE

1156
00:41:36,680 --> 00:41:37,760
PARTICIPANTS' WORDS, AS I SAID,

1157
00:41:37,760 --> 00:41:40,080
WE HAVE A VERY ROBUST AND

1158
00:41:40,080 --> 00:41:41,160
COLLABORATIVE PSYCHOSOCIAL AND

1159
00:41:41,160 --> 00:41:42,040
BEHAVIORAL RESEARCH GROUP THAT

1160
00:41:42,040 --> 00:41:43,720
HAS BEEN DOING SOME WONDERFUL

1161
00:41:43,720 --> 00:41:45,360
RESEARCH, AND SOME OF THESE

1162
00:41:45,360 --> 00:41:48,080
WORDS HAVE COME FROM THOSE

1163
00:41:48,080 --> 00:41:48,360
STUDIES.

1164
00:41:48,360 --> 00:41:49,440
THIS IS ACTUALLY FROM AN

1165
00:41:49,440 --> 00:41:50,680
INDIVIDUAL WHO IS A PARTNER WHO

1166
00:41:50,680 --> 00:41:53,960
SOMEONE WHO HAS LFS, SO THIS

1167
00:41:53,960 --> 00:41:55,040
PERSON THEMSELF DOES NOT HAVE

1168
00:41:55,040 --> 00:41:56,480
LFS BUT IS THE SPOUSE OF SOMEONE

1169
00:41:56,480 --> 00:41:58,240
WHO HAS LFS AND SAID, WE'RE BOTH

1170
00:41:58,240 --> 00:42:01,280
JUST KIND OF WORRIED.

1171
00:42:01,280 --> 00:42:02,480
YOU'VE SEEN IT HAPPEN, YOU'VE

1172
00:42:02,480 --> 00:42:03,840
SEEN IT HAPPEN TO HER, HER

1173
00:42:03,840 --> 00:42:04,720
FATHER, HER SISTER, YOU KNOW

1174
00:42:04,720 --> 00:42:05,800
WHERE YOU FINISH THE RACE.

1175
00:42:05,800 --> 00:42:07,280
YOU JUST DON'T KNOW WHEN YOU'RE

1176
00:42:07,280 --> 00:42:09,320
FINISHING THE RACE.

1177
00:42:09,320 --> 00:42:10,880
WHEN TALKING ABOUT SCREENING AND

1178
00:42:10,880 --> 00:42:12,360
THE ANNUAL CANCER SCREENING THAT

1179
00:42:12,360 --> 00:42:13,960
HAS BEEN RECOMMENDED, ONE

1180
00:42:13,960 --> 00:42:15,280
PARTICIPANT SAID, WE PLAY

1181
00:42:15,280 --> 00:42:16,800
RUSSIAN ROULETTE ONCE A YEAR.

1182
00:42:16,800 --> 00:42:19,080
BUT THE GAME IS NEVER OVER.

1183
00:42:19,080 --> 00:42:20,720
AND TO QUOTE ANOTHER PARTICIPANT

1184
00:42:20,720 --> 00:42:22,960
WHO TALKED ABOUT JUST THE IMPACT

1185
00:42:22,960 --> 00:42:26,000
OF LFS, TALKING TO MY

1186
00:42:26,000 --> 00:42:27,120
ONCOLOGIST, I SAID THERE'S

1187
00:42:27,120 --> 00:42:28,320
CERTAIN THINGS YOU SHOULD KNOW,

1188
00:42:28,320 --> 00:42:29,520
AND ONE OF THEM SHOULD BE THAT

1189
00:42:29,520 --> 00:42:30,760
YOU'RE CERTAINLY GOING TO DIE OF

1190
00:42:30,760 --> 00:42:31,960
CANCER, BECAUSE THEN EVERY

1191
00:42:31,960 --> 00:42:33,160
LITTLE PAIN YOU GET IN YOUR

1192
00:42:33,160 --> 00:42:34,480
SIDE, YOU'RE LIKE, OH, THIS MUST

1193
00:42:34,480 --> 00:42:34,800
BE CANCER.

1194
00:42:34,800 --> 00:42:36,720
SO THIS IS JUST A VERY, VERY

1195
00:42:36,720 --> 00:42:38,560
SMALL SNAPSHOT INTO THE IMPACTS

1196
00:42:38,560 --> 00:42:40,320
OF HAVING LFS, BEING PART OF A

1197
00:42:40,320 --> 00:42:43,080
FAMILY THAT HAS LFS, AND

1198
00:42:43,080 --> 00:42:47,120
UNDERGOING CANCER SCREENING.

1199
00:42:47,120 --> 00:42:49,760
SO JUST LOOKING AT THE

1200
00:42:49,760 --> 00:42:50,640
HETEROGENEITY OF THE CANCER

1201
00:42:50,640 --> 00:42:51,760
RISKS, THE BENEFITS OF SCREENING

1202
00:42:51,760 --> 00:42:52,960
BUT ALSO THE CHALLENGES, IT

1203
00:42:52,960 --> 00:42:54,200
BECAME REALLY IMPORTANT FOR US

1204
00:42:54,200 --> 00:42:56,160
TO THINK FURTHER ABOUT NOT JUST

1205
00:42:56,160 --> 00:42:57,360
SECONDARY PREVENTION WITH EARLY

1206
00:42:57,360 --> 00:42:59,240
DETECTION, BUT ALSO PRIMARY

1207
00:42:59,240 --> 00:42:59,840
PREVENTION.

1208
00:42:59,840 --> 00:43:02,840
WHAT ARE SOME THINGS THAT WE CAN

1209
00:43:02,840 --> 00:43:04,040
EMPLOY LEVERAGE TO LOOK AT

1210
00:43:04,040 --> 00:43:05,120
PRIMARY CANCER PREVENTION IN

1211
00:43:05,120 --> 00:43:07,480
THESE INDIVIDUALS?

1212
00:43:07,480 --> 00:43:08,520
CURRENTLY THE ONLY OPTION THEY

1213
00:43:08,520 --> 00:43:10,120
HAVE FOR PRIMARY CANCER

1214
00:43:10,120 --> 00:43:11,920
PREVENTION IS REALLY

1215
00:43:11,920 --> 00:43:13,280
RISK-REDUCING BILATERAL

1216
00:43:13,280 --> 00:43:14,160
MASTECTOMY, AND WE START TALKING

1217
00:43:14,160 --> 00:43:15,560
ABOUT THIS TO REDUCE BREAST

1218
00:43:15,560 --> 00:43:18,000
CANCER RISK TO WOMEN AS YOUNG AT

1219
00:43:18,000 --> 00:43:19,360
17, 18 YEARS OLD, SO IMAGINE

1220
00:43:19,360 --> 00:43:20,960
HAVING THIS CLINIC WHERE YOU'RE

1221
00:43:20,960 --> 00:43:23,280
TALKING TO TEENAGERS AND YOUNG

1222
00:43:23,280 --> 00:43:24,200
ADULTS WHO HAVEN'T REALLY HAD

1223
00:43:24,200 --> 00:43:26,000
MANY LIFE EXPERIENCES YET,

1224
00:43:26,000 --> 00:43:27,440
ABOUT, YOU KNOW, INVASIVE

1225
00:43:27,440 --> 00:43:29,000
SURGERY TO REDUCE BREAST CANCER

1226
00:43:29,000 --> 00:43:30,560
RISK, BUT ALSO IMPRESSING UPON

1227
00:43:30,560 --> 00:43:32,280
THEM THAT THAT DOES NOT REDUCE

1228
00:43:32,280 --> 00:43:33,760
RISK OF OTHER CANCERS THAT CAN

1229
00:43:33,760 --> 00:43:36,160
OCCUR ACROSS THE BODY.

1230
00:43:36,160 --> 00:43:37,880
SO REALLY WE HAD TO DIG DEEP AND

1231
00:43:37,880 --> 00:43:38,880
SEE WHAT OF THE WORK THAT HAS

1232
00:43:38,880 --> 00:43:41,880
BEEN DONE SO FAR WERE REALLY

1233
00:43:41,880 --> 00:43:43,320
LEVERAGED INTO PRIMARY REVENGS.

1234
00:43:43,320 --> 00:43:45,920
PREVENTION.

1235
00:43:45,920 --> 00:43:47,720
THIS IS WHERE DR. HWANG'S WORK

1236
00:43:47,720 --> 00:43:48,920
HAS BEEN SO IMPORTANT.

1237
00:43:48,920 --> 00:43:51,000
I WON'T REHASH EVERYTHING HE

1238
00:43:51,000 --> 00:43:53,320
SAID BUT JUST TO POINT OUT THAT

1239
00:43:53,320 --> 00:43:54,680
P53 HAD MANY KNOWN FUNCTIONS IN

1240
00:43:54,680 --> 00:43:57,080
THE BODY AND ONE OF THOSE IS THE

1241
00:43:57,080 --> 00:43:57,720
DAMPENING METABOLIC

1242
00:43:57,720 --> 00:43:58,040
REPROGRAMMING.

1243
00:43:58,040 --> 00:44:01,800
SO LEMPLING LEVERAGING ALL THE L

1244
00:44:01,800 --> 00:44:03,240
WORK DR. HWANG AND HIS

1245
00:44:03,240 --> 00:44:04,440
COLLEAGUES HAD DONE, WE THOUGHT

1246
00:44:04,440 --> 00:44:07,600
ABOUT THIS AS AN INTERPLAY

1247
00:44:07,600 --> 00:44:09,960
BETWEEN METABOLISM AND ME METFON

1248
00:44:09,960 --> 00:44:11,480
THAT IS KNOWN TO INTERACT WITH

1249
00:44:11,480 --> 00:44:12,000
BOTH.

1250
00:44:12,000 --> 00:44:13,280
REALLY WHERE WE ARE NOW IS BASED

1251
00:44:13,280 --> 00:44:15,520
ON THE SUCCESS OF THE PILOT

1252
00:44:15,520 --> 00:44:19,720
STUDY, WE'RE DEVELOPING A PHASE

1253
00:44:19,720 --> 00:44:21,120
2 PHARMACOPREVENTIVE TRIAL OF

1254
00:44:21,120 --> 00:44:21,800
METFORMIN AND LFS.

1255
00:44:21,800 --> 00:44:23,680
THIS TRIAL IS CURRENTLY UNDER

1256
00:44:23,680 --> 00:44:26,280
SCIENTIFIC REVIEW AND IS BEING

1257
00:44:26,280 --> 00:44:29,280
DESIGNED AS A RANDOMIZED

1258
00:44:29,280 --> 00:44:30,920
NON-PLACEBO CONTROL TRIAL WITH A

1259
00:44:30,920 --> 00:44:32,240
FIVE-YEAR END POINT LOOKING AT

1260
00:44:32,240 --> 00:44:33,360
CANCER INCIDENCE.

1261
00:44:33,360 --> 00:44:34,200
RANDOMIZATION WILL BE BETWEEN

1262
00:44:34,200 --> 00:44:35,560
SCREENING AS WE CURRENTLY

1263
00:44:35,560 --> 00:44:37,160
RECOMMEND IT VERSUS SCREENING

1264
00:44:37,160 --> 00:44:39,480
AND METFORMIN TO COMPARE THE

1265
00:44:39,480 --> 00:44:40,360
CANCER INCIDENCE BETWEEN THESE

1266
00:44:40,360 --> 00:44:42,640
TWO ARMS IN INDIVIDUALS WHO HAVE

1267
00:44:42,640 --> 00:44:46,280
KNOWN PATH GENIC OR LIKE LEGAL

1268
00:44:46,280 --> 00:44:52,320
PATHOGENIC GERMLINE P53 MUTATION

1269
00:44:52,320 --> 00:44:57,160
AND HAVE NOT HAD METFORMIN USE

1270
00:44:57,160 --> 00:44:57,560
IN SIX MONTHS.

1271
00:44:57,560 --> 00:45:00,120
THIS WILL NOT ONLY PROVIDE AN

1272
00:45:00,120 --> 00:45:01,680
INFRASTRUCTURE FOR FURTHER SUCH

1273
00:45:01,680 --> 00:45:03,080
RESEARCH WITH PHARMACOPREVENTION

1274
00:45:03,080 --> 00:45:04,080
OR AGENTS OTHERWISE BUT ALSO

1275
00:45:04,080 --> 00:45:05,160
BUILD UPON THAT FOUNDATION THAT

1276
00:45:05,160 --> 00:45:06,520
WILL HELP US UNDERSTAND

1277
00:45:06,520 --> 00:45:08,160
UNDERLYING BIOLOGY AND

1278
00:45:08,160 --> 00:45:09,880
CARCINOGENESIS IN LFS LOOK AT

1279
00:45:09,880 --> 00:45:12,120
BIOMARKERS, METABOLIC PROFILING,

1280
00:45:12,120 --> 00:45:13,280
ALTERNATIVE SCREENING STRATEGIES

1281
00:45:13,280 --> 00:45:17,600
AND A NUMBER OF OTHER ITEMS THAT

1282
00:45:17,600 --> 00:45:20,040
WE'RE HOPING TO DO.

1283
00:45:20,040 --> 00:45:21,120
IMPORTANT TO NOTE AS WELL, WE

1284
00:45:21,120 --> 00:45:22,800
TALK ABOUT THIS STUDY HERE AT

1285
00:45:22,800 --> 00:45:24,200
THE NCI, WE'RE REALLY AT THE

1286
00:45:24,200 --> 00:45:25,640
FOREFRONT OF AN INTERNATIONAL

1287
00:45:25,640 --> 00:45:28,800
DISCUSSION THAT I SPEARHEADED

1288
00:45:28,800 --> 00:45:34,280
BETWEEN THE SITES IN U.K. AT

1289
00:45:34,280 --> 00:45:37,600
OXFORD, TORONTO, AND GERMANY,

1290
00:45:37,600 --> 00:45:38,880
WHERE WE SPENT THE BETTER PART

1291
00:45:38,880 --> 00:45:40,400
OF THE PANDEMIC COMING UP WITH A

1292
00:45:40,400 --> 00:45:45,600
SHARED PROTOCOL TO LAUNCH THE

1293
00:45:45,600 --> 00:45:46,440
SAME PHARMACOPREVENTIVE TRIAL AT

1294
00:45:46,440 --> 00:45:50,240
EACH OF THESE SN TERES.

1295
00:45:50,240 --> 00:45:50,800
 THESE CENTERS.

1296
00:45:50,800 --> 00:45:52,280
THE IDEA IS EACH CENTER WILL

1297
00:45:52,280 --> 00:45:53,640
HAVE INDEPENDENT STUDY USING THE

1298
00:45:53,640 --> 00:45:56,400
SAME SHARED PROTOCOL, THE SAME

1299
00:45:56,400 --> 00:45:56,720
BIOSTATISTICS.

1300
00:45:56,720 --> 00:45:58,120
THE U.K. IS ALREADY FUNDED AND

1301
00:45:58,120 --> 00:45:59,720
THEY'RE HOPING TO BE UP AND

1302
00:45:59,720 --> 00:46:01,320
RUNNING IN THE NEXT COUPLE OF

1303
00:46:01,320 --> 00:46:03,560
MONTHS, AND CANADA AND GERMANY

1304
00:46:03,560 --> 00:46:05,200
ARE WAITING TO HEAR BACK FROM

1305
00:46:05,200 --> 00:46:07,080
FUNDING AGENCIES.

1306
00:46:07,080 --> 00:46:08,480
BUT THE IDEA IS, AT THE END OF

1307
00:46:08,480 --> 00:46:09,920
THIS FIVE YEARS, TO BE ABLE TO

1308
00:46:09,920 --> 00:46:12,800
PULL ALL OF THIS DATA TOGETHER

1309
00:46:12,800 --> 00:46:14,760
WITH WELL OVER 700 PARTICIPANTS,

1310
00:46:14,760 --> 00:46:16,000
EVERYTHING GOING WELL, AND

1311
00:46:16,000 --> 00:46:17,320
PERFORM A META-ANALYSIS, THAT

1312
00:46:17,320 --> 00:46:20,400
WILL HELP US DIVE MUCH DEEPER

1313
00:46:20,400 --> 00:46:22,880
INTO THE POTENTIAL EFFECTS OF

1314
00:46:22,880 --> 00:46:24,680
METFORMIN AS A POTENTIAL

1315
00:46:24,680 --> 00:46:28,720
PHARMACOPREVENTIVE AGENT IN LFS.

1316
00:46:28,720 --> 00:46:30,360
THE NCI STUDY ITSELF THAT I'M

1317
00:46:30,360 --> 00:46:32,040
LEADING IS BASED ON THE

1318
00:46:32,040 --> 00:46:32,920
WONDERFUL COLLABORATIVE

1319
00:46:32,920 --> 00:46:35,520
INFRASTRUCTURE THAT THE NIH

1320
00:46:35,520 --> 00:46:35,920
OFFERS.

1321
00:46:35,920 --> 00:46:38,600
WITH US IN DCEG HAVING EXPERTISE

1322
00:46:38,600 --> 00:46:40,360
IN LFS AND P53 WITH FIELD AND

1323
00:46:40,360 --> 00:46:42,360
FAMILY STUDIES, PARTICIPATION,

1324
00:46:42,360 --> 00:46:45,440
ENGAGEMENT AND TRACKING AND

1325
00:46:45,440 --> 00:46:47,600
REMOTE BIOSPECIMEN COLLECTION,

1326
00:46:47,600 --> 00:46:48,840
THAT THEY'VE DONE SUCCESSFULLY

1327
00:46:48,840 --> 00:46:50,240
FOR DECADES NOW, LEVERAGING THE

1328
00:46:50,240 --> 00:46:54,120
EXPERTISE OF CCR WITH EXPERTISE

1329
00:46:54,120 --> 00:47:00,360
IN CLINICAL TRIALS, WITH OTHERS,

1330
00:47:00,360 --> 00:47:02,280
AND ALSO THE WONDERFUL RESOURCES

1331
00:47:02,280 --> 00:47:04,440
OF THE CLINICAL CENTER.

1332
00:47:04,440 --> 00:47:05,720
ALSO BRINGING IN THE EXPERTISE

1333
00:47:05,720 --> 00:47:07,080
OF THE DIVISION OF CANCER

1334
00:47:07,080 --> 00:47:09,080
PREVENTION WITH INVOLVEMENT FROM

1335
00:47:09,080 --> 00:47:11,800
DR. PHIL CASSELL AND DR. HOWARD

1336
00:47:11,800 --> 00:47:13,120
PARNES WITH CANCER PREVENTION

1337
00:47:13,120 --> 00:47:14,800
STUDY EXPERTISE AND ALSO THE

1338
00:47:14,800 --> 00:47:16,160
NEWLY MINTED CANCER PREVENTION

1339
00:47:16,160 --> 00:47:18,440
CLINIC THAT MAY BE A WONDERFUL

1340
00:47:18,440 --> 00:47:19,280
INFRASTRUCTURE FOR THIS STUDY TO

1341
00:47:19,280 --> 00:47:21,320
BE LAUNCHED ON.

1342
00:47:21,320 --> 00:47:22,840
AND AS I MENTIONED, WE WILL BE

1343
00:47:22,840 --> 00:47:24,040
LOOKING NOT ONLY AS THE

1344
00:47:24,040 --> 00:47:26,400
POTENTIAL OF METFORMIN TO REDUCE

1345
00:47:26,400 --> 00:47:28,480
CANCER RISK IN LFS OR PREVENT

1346
00:47:28,480 --> 00:47:30,120
CANCERS FROM OCCURRING, BUT ALSO

1347
00:47:30,120 --> 00:47:31,120
PROVIDE THE OPPORTUNITY TO LOOK

1348
00:47:31,120 --> 00:47:33,760
AT MANY DIFFERENT UNDERLYING

1349
00:47:33,760 --> 00:47:35,160
BIOLOGICAL PHENOMENON IN LFS,

1350
00:47:35,160 --> 00:47:37,080
ONE OF WHICH IS METABOLOMICS

1351
00:47:37,080 --> 00:47:39,040
STUDIES, WE CURRENTLY HAVE

1352
00:47:39,040 --> 00:47:40,920
ONGOING BASELINE AND

1353
00:47:40,920 --> 00:47:42,280
LONGITUDINAL METABOLOMICS

1354
00:47:42,280 --> 00:47:43,480
STUDIES JUST BASED ON THE

1355
00:47:43,480 --> 00:47:45,120
RESULTS IN THE PILOT STUDY THAT

1356
00:47:45,120 --> 00:47:46,960
DR. HWANG MENTIONED WE DID

1357
00:47:46,960 --> 00:47:48,000
COLLABORATIVELY WITH THEM, AND

1358
00:47:48,000 --> 00:47:49,320
THIS WILL, I THINK, REALLY FORM

1359
00:47:49,320 --> 00:47:50,560
THE BASIS OF WHAT WE'RE ABLE TO

1360
00:47:50,560 --> 00:47:52,000
DO WITHIN THE METFORMIN TRIAL,

1361
00:47:52,000 --> 00:47:53,520
LOOK AT METABOLOMICS DIFFERENCES

1362
00:47:53,520 --> 00:47:54,720
BETWEEN THOSE WHO ARE TREATED

1363
00:47:54,720 --> 00:47:57,600
AND UNTREATED WITH METFORMIN,

1364
00:47:57,600 --> 00:47:59,240
LOOK SPECIFICALLY AT DIFFERENT

1365
00:47:59,240 --> 00:48:00,600
MECHANISMS OF ACTION OF

1366
00:48:00,600 --> 00:48:01,760
METFORMIN IN THESE INDIVIDUALS,

1367
00:48:01,760 --> 00:48:04,640
AND, OF COURSE, IDENTIFY

1368
00:48:04,640 --> 00:48:06,000
POTENTIAL NOVEL TARGET FOR

1369
00:48:06,000 --> 00:48:08,280
FUTURE INTERVENTION SUCH AS THE

1370
00:48:08,280 --> 00:48:11,240
FATTY ACID OXIDATION THAT

1371
00:48:11,240 --> 00:48:13,800
DR. HWANG MENTIONED, BUT ALSO

1372
00:48:13,800 --> 00:48:17,400
DELVING INTO OTHER -- BRANCH

1373
00:48:17,400 --> 00:48:18,600
CHAIN AMINO ACIDS, ET CETERA.

1374
00:48:18,600 --> 00:48:20,120
WHAT THIS TRIAL WILL ALSO DO IS,

1375
00:48:20,120 --> 00:48:21,840
AS I'VE TALKED ABOUT CANCER

1376
00:48:21,840 --> 00:48:23,400
SCREENING AND THE RIGOR OF

1377
00:48:23,400 --> 00:48:24,360
CANCER SCREENING AND ALSO SOME

1378
00:48:24,360 --> 00:48:26,200
OF ITS IMPACTS, LOOK AT

1379
00:48:26,200 --> 00:48:28,240
ALTERNATIVE SCREENING REGIMENTS

1380
00:48:28,240 --> 00:48:28,880
THEMSELVES, ONE OF WHICH OF

1381
00:48:28,880 --> 00:48:31,240
COURSE IS VERY WIDELY DISCUSSED

1382
00:48:31,240 --> 00:48:34,200
NOW, THE CELL FREE DNA OR LIQUID

1383
00:48:34,200 --> 00:48:36,920
BIOPSY ASSAYS, THAT PRESUME

1384
00:48:36,920 --> 00:48:38,040
CANCER CELLS WILL SHED DNA AND

1385
00:48:38,040 --> 00:48:39,920
THIS CAN BE DIFFERENTIATED FROM

1386
00:48:39,920 --> 00:48:41,680
NON-CAN RUSS CELL-FREE DNA.

1387
00:48:41,680 --> 00:48:43,000
THERE ARE MULTIPLE TECHNOLOGIES

1388
00:48:43,000 --> 00:48:45,000
THAT ARE BEING STUDIED AND

1389
00:48:45,000 --> 00:48:47,080
RESEARCHED FOR CELL CIRCULATING

1390
00:48:47,080 --> 00:48:50,480
TUMOR DNA ASSAYS INCLUDING WHOLE

1391
00:48:50,480 --> 00:48:53,920
GENOME SEQUENCING, METHYLATION

1392
00:48:53,920 --> 00:48:56,320
PATTERNS IN DNA FRAGMENT LENGTH,

1393
00:48:56,320 --> 00:48:58,080
AND ALONG WITH OUR ESTABLISHED

1394
00:48:58,080 --> 00:49:00,600
COLLABORATIONS WITH OTHER

1395
00:49:00,600 --> 00:49:01,960
EXPERTS IN LFS AND ALSO OUR

1396
00:49:01,960 --> 00:49:03,160
INDUSTRY PARTNERS, I THINK THIS

1397
00:49:03,160 --> 00:49:04,560
STUDY WILL REALLY -- THIS TRIAL

1398
00:49:04,560 --> 00:49:06,360
WILL REALLY GIVE US THE

1399
00:49:06,360 --> 00:49:09,640
OPPORTUNITY TO PE PROSPECTIVELY

1400
00:49:09,640 --> 00:49:12,840
LOOK AT THE UNITS THAT SCREENING

1401
00:49:12,840 --> 00:49:15,480
MAY OFFER TO THOSE WITH LFS.

1402
00:49:15,480 --> 00:49:16,800
ANOTHER ASPECT I THINK THAT IS

1403
00:49:16,800 --> 00:49:18,240
VERY IMPORTANT GIVEN THE CURRENT

1404
00:49:18,240 --> 00:49:19,920
BURDENS OF LFS SCREENING IS

1405
00:49:19,920 --> 00:49:22,120
LOOKING AT SCREENING ASSOCIATED

1406
00:49:22,120 --> 00:49:22,520
DISTRESS.

1407
00:49:22,520 --> 00:49:24,400
AND OUR HOPE IS TO BE ABLE TO

1408
00:49:24,400 --> 00:49:26,200
CHARACTERIZE THE PATTERNS AND

1409
00:49:26,200 --> 00:49:27,560
TIMING OF SCREENING ASSOCIATED

1410
00:49:27,560 --> 00:49:29,720
DISTRESS AND TO UNDERSTAND THE

1411
00:49:29,720 --> 00:49:31,600
COPING MECHANISMS EMPLOYED AS

1412
00:49:31,600 --> 00:49:33,440
YOU MAY IMAGINE, NOT EVERYTHING

1413
00:49:33,440 --> 00:49:34,880
DEALS WITH THIS THE SAME.

1414
00:49:34,880 --> 00:49:36,960
BUT NOT ONLY TO LOOK AT

1415
00:49:36,960 --> 00:49:38,720
INDIVIDUALS WHO HAVE LFS AND HOW

1416
00:49:38,720 --> 00:49:40,040
THEY DEAL WITH THEIR OWN

1417
00:49:40,040 --> 00:49:41,040
SCREENING, BUT ALSO HOW THEY

1418
00:49:41,040 --> 00:49:42,600
DEAL WITH SCREENING OF THEIR

1419
00:49:42,600 --> 00:49:44,400
FAMILY MEMBERS, SUCH AT

1420
00:49:44,400 --> 00:49:46,040
CHILDREN, PARENTS, SIBLINGS, ET

1421
00:49:46,040 --> 00:49:46,360
CETERA.

1422
00:49:46,360 --> 00:49:48,120
WE HAVE AN ONGOING QUALITATIVE

1423
00:49:48,120 --> 00:49:50,000
PILOT STUDY TO SET US UP FOR THE

1424
00:49:50,000 --> 00:49:50,560
METFORMIN TRIAL.

1425
00:49:50,560 --> 00:49:52,880
WE'RE LOOKING AT DATA GIVEN BY

1426
00:49:52,880 --> 00:49:53,920
ABOUT 20 INDIVIDUALS THAT HAS

1427
00:49:53,920 --> 00:49:55,640
ALREADY BEEN VERY RICH AND

1428
00:49:55,640 --> 00:49:56,600
INFORMATIVE, AND WE'RE HOPING TO

1429
00:49:56,600 --> 00:49:58,720
LAUNCH A MIXED METHOD STUDY WITH

1430
00:49:58,720 --> 00:49:59,960
QUANTITATIVE AND QUALITATIVE

1431
00:49:59,960 --> 00:50:01,720
ASPECT WITH THE METFORMIN TRIAL.

1432
00:50:01,720 --> 00:50:03,440
AND THE OVERARCHING GOAL WITH

1433
00:50:03,440 --> 00:50:06,120
THE EXPERTISE OF DR. PAUL HAAN

1434
00:50:06,120 --> 00:50:10,920
AND OUR FELLOWS, IS TO DEVELOP

1435
00:50:10,920 --> 00:50:11,680
INTEGRATIVE INTERVENTIONS FOR

1436
00:50:11,680 --> 00:50:13,120
THE MANAGEMENT AND GUIDELINES OF

1437
00:50:13,120 --> 00:50:14,800
BOTH PATIENTS AND PROVIDERS

1438
00:50:14,800 --> 00:50:16,240
BECAUSE WE ALL HOPE THAT

1439
00:50:16,240 --> 00:50:17,880
METFORMIN WILL BE THAT EUREKA

1440
00:50:17,880 --> 00:50:19,320
MOMENT, BUT UNTIL WE GET THERE,

1441
00:50:19,320 --> 00:50:20,760
SCREENING IS THE BEST WE HAVE TO

1442
00:50:20,760 --> 00:50:21,880
OFFER AND WE WANT TO MAKE SURE

1443
00:50:21,880 --> 00:50:23,760
THAT WE'RE DOING THE BEST WE CAN

1444
00:50:23,760 --> 00:50:26,280
FOR THESE FAMILIES.

1445
00:50:26,280 --> 00:50:28,800
SO IN SUMMARY, I KNOW THIS WAS

1446
00:50:28,800 --> 00:50:32,120
VERY WHIRLWIND QUICK TOUR, BUT I

1447
00:50:32,120 --> 00:50:33,400
HOPE I'VE IMPRESSED UPON YOU

1448
00:50:33,400 --> 00:50:37,480
THAT LFS HAS VERY HIGH CANCER

1449
00:50:37,480 --> 00:50:38,840
RISK OF MULTIPLE PRIMARY

1450
00:50:38,840 --> 00:50:39,520
CANCERS.

1451
00:50:39,520 --> 00:50:40,360
CANCER SCREENING COMES WITH THE

1452
00:50:40,360 --> 00:50:41,600
BENEFIT OF EARLY CANCER

1453
00:50:41,600 --> 00:50:43,400
DETECTION BUT IS RIGOROUS

1454
00:50:43,400 --> 00:50:44,880
EMOTIONALLY AND PHYSICALLY

1455
00:50:44,880 --> 00:50:45,520
BURDENSOME.

1456
00:50:45,520 --> 00:50:46,760
THERE ARE VERY, VERY FEW OPTIONS

1457
00:50:46,760 --> 00:50:48,240
FOR PRIMARY CANCER PREVENTION

1458
00:50:48,240 --> 00:50:50,880
LEADING US TO REALLY NEED TO

1459
00:50:50,880 --> 00:50:52,480
LOOK AT -- LOOK BEYOND

1460
00:50:52,480 --> 00:50:54,040
MULTI-CANCER DETECTION AT

1461
00:50:54,040 --> 00:50:54,960
PRIMARY CANCER PREVENTION, AND

1462
00:50:54,960 --> 00:50:57,360
WE HOPE THAT THE STUDY OF

1463
00:50:57,360 --> 00:50:59,000
METFORMIN IN LFS, WHICH WILL

1464
00:50:59,000 --> 00:51:01,960
FORGE A COLLABORATIVE PATH, LEAD

1465
00:51:01,960 --> 00:51:03,320
A FOUNDATION FOR PREVENTION

1466
00:51:03,320 --> 00:51:03,840
RESEARCH AS WELL AS

1467
00:51:03,840 --> 00:51:05,720
UNDERSTANDING THE UNDERLYING LFS

1468
00:51:05,720 --> 00:51:08,200
BIOLOGY AND CARCINOGENESIS.

1469
00:51:08,200 --> 00:51:10,400
AND AS ALL OF THE WORK THAT WE

1470
00:51:10,400 --> 00:51:13,480
COULDO, THIS IS NEVER AN INDIVIL

1471
00:51:13,480 --> 00:51:14,360
EFFORT, THIS IS VERY MUCH A TEAM

1472
00:51:14,360 --> 00:51:14,720
EFFORT.

1473
00:51:14,720 --> 00:51:16,720
I HAVE A WONDERFUL, WONDERFUL

1474
00:51:16,720 --> 00:51:18,240
TEAM WORKING BACK WITH ME BUT

1475
00:51:18,240 --> 00:51:19,800
VERY IMPORTANTLY, WE ALSO HAVE

1476
00:51:19,800 --> 00:51:21,720
VERY STRONG PARTNERSHIPS WITH

1477
00:51:21,720 --> 00:51:23,960
OUR FAMILY -- OUR PATIENT

1478
00:51:23,960 --> 00:51:25,240
ADVOCACY GROUPS INCLUDING THE

1479
00:51:25,240 --> 00:51:26,040
LI-FRAUMENI SYNDROME ASSOCIATION

1480
00:51:26,040 --> 00:51:27,800
AND LIVING LFS, AS YOU CAN SEE

1481
00:51:27,800 --> 00:51:31,800
HERE, THIS IS DR. FRAUMENI AT

1482
00:51:31,800 --> 00:51:32,920
THE SIXTH INTERNATIONAL

1483
00:51:32,920 --> 00:51:35,520
SYMPOSIUM WE HOSTED HERE AT

1484
00:51:35,520 --> 00:51:36,600
SHADY GROVE IN OCTOBER WHICH IS

1485
00:51:36,600 --> 00:51:40,160
A VERY UNIQUE MIX, SCIENTISTS,

1486
00:51:40,160 --> 00:51:41,400
CLINICIANS AND RESEARCHERS AND

1487
00:51:41,400 --> 00:51:42,520
THE OTHER HALF BEING ACTUALLY

1488
00:51:42,520 --> 00:51:43,360
FAMILY MEMBERS AND INDIVIDUALS

1489
00:51:43,360 --> 00:51:44,160
WHO HAVE LFS.

1490
00:51:44,160 --> 00:51:46,000
AND OF COURSE OUR COLLABORATORS

1491
00:51:46,000 --> 00:51:48,120
NEAR AND FAR ACROSS THE GLOBE

1492
00:51:48,120 --> 00:51:49,800
WHO HELP US ANSWER THESE

1493
00:51:49,800 --> 00:51:51,080
QUESTIONS, AND WE REALLY WORK

1494
00:51:51,080 --> 00:51:52,880
TOGETHER VERY WELL ANSWERING

1495
00:51:52,880 --> 00:51:53,760
QUESTIONS  THAT WILL BRING

1496
00:51:53,760 --> 00:51:54,520
BENEFITS HOPEFULLY TO THE

1497
00:51:54,520 --> 00:51:56,240
PATIENTS AND FAMILIES SOON.

1498
00:51:56,240 --> 00:51:57,960
WITH THAT, AGAIN, I'M VERY

1499
00:51:57,960 --> 00:51:59,160
GRATEFUL FOR THE OPPORTUNITY TO

1500
00:51:59,160 --> 00:52:00,680
PRESENT HERE, AND I'M HAPPY TO

1501
00:52:00,680 --> 00:52:01,320
ANSWER QUESTIONS.

1502
00:52:01,320 --> 00:52:09,800
THANK YOU.

1503
00:52:09,800 --> 00:52:12,120
>>THANK YOU, DR. KHINCHA,
AND

1504
00:52:12,120 --> 00:52:13,080
THANK YOU, DR. HWANG.

1505
00:52:13,080 --> 00:52:14,760
AND FOR THE EXCELLENT

1506
00:52:14,760 --> 00:52:20,200
PRESENTATIONS, AND FOR SHARING

1507
00:52:20,200 --> 00:52:21,680
YOUR COLLABORATIVE WORK,

1508
00:52:21,680 --> 00:52:23,320
OBVIOUSLY ILLUSTRATING THE BASIC

1509
00:52:23,320 --> 00:52:25,280
SCIENCE TO THE CLINICAL

1510
00:52:25,280 --> 00:52:31,680
APPLICATIONS AND THIS -- CANCER

1511
00:52:31,680 --> 00:52:34,800
PREVENTION IN A CHALLENGING --

1512
00:52:34,800 --> 00:52:35,320
WITH LI-FRAUMENI SYNDROME.

1513
00:52:35,320 --> 00:52:36,480
WE HAVE SEVERAL QUESTIONS COMING

1514
00:52:36,480 --> 00:52:38,000
IN, I THINK WE HAVE SOME TIME

1515
00:52:38,000 --> 00:52:38,320
HERE.

1516
00:52:38,320 --> 00:52:40,840
SO I'LL START OFF, THIS IS

1517
00:52:40,840 --> 00:52:41,480
ACTUALLY FOR DR. HWANG.

1518
00:52:41,480 --> 00:52:43,520
DO YOU THINK THE INCREASED

1519
00:52:43,520 --> 00:52:45,560
MITOCHONDRIAL FUNCTION AS IN THE

1520
00:52:45,560 --> 00:52:49,080
LFS MU TAN P53 STATE IS --

1521
00:52:49,080 --> 00:52:51,080
DERIVED CANCER PREVENTION

1522
00:52:51,080 --> 00:52:51,880
BENEFITS, MITOCHONDRIAL

1523
00:52:51,880 --> 00:52:53,840
INHIBITION USING METFORMIN?

1524
00:52:53,840 --> 00:52:58,760
>>THAT'S A GREAT
QUESTION.

1525
00:52:58,760 --> 00:53:00,040
ACTUALLY, IT HIGHLIGHTS ONE OF

1526
00:53:00,040 --> 00:53:02,640
THE CRITICAL THINGS HERE IS THAT

1527
00:53:02,640 --> 00:53:05,640
AS I SHOWED YOU WITH A MUTANT

1528
00:53:05,640 --> 00:53:07,280
STATE WHO HAVE INCREASED

1529
00:53:07,280 --> 00:53:08,280
MITOCHONDRIAL METABOLISM, SO IS

1530
00:53:08,280 --> 00:53:10,520
THE MODERATION OF THE ACTIVITY

1531
00:53:10,520 --> 00:53:12,240
WHAT IS DRIVING THE CANCER

1532
00:53:12,240 --> 00:53:15,320
PREVENTION EFFECT, AND WE REALLY

1533
00:53:15,320 --> 00:53:16,080
HAVEN'T DONE THE EXPERIMENT

1534
00:53:16,080 --> 00:53:18,280
BECAUSE THE P53 NULL MICE, NOT

1535
00:53:18,280 --> 00:53:20,640
THE KNOCK-IN MOUSE, WHICH IS LFS

1536
00:53:20,640 --> 00:53:23,160
MUTATION STATE BUT THE NULL

1537
00:53:23,160 --> 00:53:24,920
MICE, WHO HAVEN'T LOOKED AT

1538
00:53:24,920 --> 00:53:28,400
THOSE MICE, BUT WITHOUT

1539
00:53:28,400 --> 00:53:29,560
SPECULATING, I WOULD GUESS THAT

1540
00:53:29,560 --> 00:53:31,000
EVEN THE NULL STATE WHERE YOU

1541
00:53:31,000 --> 00:53:34,800
DON'T HAVE THE INCREASED

1542
00:53:34,800 --> 00:53:36,120
MITOCHONDRIAL FUNCTION MAY HAVE

1543
00:53:36,120 --> 00:53:39,280
SIMILAR BENEFIT OF CANCER

1544
00:53:39,280 --> 00:53:40,120
PREVENTION.

1545
00:53:40,120 --> 00:53:41,440
AND I THINK THAT IS MAINLY

1546
00:53:41,440 --> 00:53:42,960
BECAUSE OF THE CELL METABOLISM

1547
00:53:42,960 --> 00:53:45,000
STRESS THAT THE CELLS -- THAT

1548
00:53:45,000 --> 00:53:46,440
THE BODY MIGHT BE FEELING THAT

1549
00:53:46,440 --> 00:53:50,240
GIVES THIS PROTECTIVE EFFECT

1550
00:53:50,240 --> 00:53:51,080
AGAINST CANCER -- ON THE OTHER

1551
00:53:51,080 --> 00:53:53,240
HAND, I THINK IT'S ALSO TRUE

1552
00:53:53,240 --> 00:53:55,760
THAT THE INCREASE IN

1553
00:53:55,760 --> 00:53:56,760
MITOCHONDRIAL METABOLISM IS

1554
00:53:56,760 --> 00:53:58,400
CRITICAL FOR CANCER CELL

1555
00:53:58,400 --> 00:54:01,520
SURVIVAL AND METASTASES, AND SO

1556
00:54:01,520 --> 00:54:06,560
CLEARLY THAT ALSO HAS A ROLE IN

1557
00:54:06,560 --> 00:54:08,520
IT, BUT IT'S A GOOD THING, I

1558
00:54:08,520 --> 00:54:12,680
THINK, BECAUSE IT PREDICTS THAT

1559
00:54:12,680 --> 00:54:14,720
EVEN INDIVIDUALS -- BECAUSE

1560
00:54:14,720 --> 00:54:17,120
LI-FRAUMENI SYNDROME IS VERY

1561
00:54:17,120 --> 00:54:18,000
HETEROGENEOUS SOME MUTATIONS

1562
00:54:18,000 --> 00:54:19,520
HAVE MORE MITOCHONDRIAL

1563
00:54:19,520 --> 00:54:20,720
ACTIVITY, SOME HAVE LESS, SOME

1564
00:54:20,720 --> 00:54:21,120
HAVE NONE.

1565
00:54:21,120 --> 00:54:23,960
SO I THINK IT'S GOOD NEWS THAT

1566
00:54:23,960 --> 00:54:26,880
AT LEAST IN MY MIND, THAT THESE

1567
00:54:26,880 --> 00:54:28,640
INDIVIDUALS WHO DON'T HAVE THIS

1568
00:54:28,640 --> 00:54:30,280
BOOST IN MITOCHONDRIAL ACTIVITY

1569
00:54:30,280 --> 00:54:35,520
MAY ALSO BENEFIT FROM METFORMIN.

1570
00:54:35,520 --> 00:54:37,560
>>THANK YOU.

1571
00:54:37,560 --> 00:54:39,840
NEXT QUESTION, DR. KHINCHA,

1572
00:54:39,840 --> 00:54:41,640
COULD YOU ELABORATE ON LFS IN

1573
00:54:41,640 --> 00:54:44,080
CHILDREN AND THE IMPACT OF

1574
00:54:44,080 --> 00:54:44,680
SCREENING.

1575
00:54:44,680 --> 00:54:47,160
YOUR PROTOCOL SCREENING BEGINS

1576
00:54:47,160 --> 00:54:47,800
AT AGE 3.

1577
00:54:47,800 --> 00:54:49,480
DOES THE CANCER PROFILE DIFFER

1578
00:54:49,480 --> 00:54:54,320
FROM ADULTS, AND DOES THE

1579
00:54:54,320 --> 00:54:57,280
OUTCOME DATA DIFFER FROM THE

1580
00:54:57,280 --> 00:54:59,720
NON-LFS PEDIATRIC PATIENTS WITH

1581
00:54:59,720 --> 00:55:00,960
SIMILAR CANCERS?

1582
00:55:00,960 --> 00:55:03,440
>>THAT'S GREAT QUESTIONS
AND

1583
00:55:03,440 --> 00:55:05,440
I'LL TRY TO ANSWER THEM ONE BY

1584
00:55:05,440 --> 00:55:05,760
ONE.

1585
00:55:05,760 --> 00:55:10,200
SO SPECIFICALLY FOR OUR

1586
00:55:10,200 --> 00:55:11,840
PROTOCOL, AGE 3 WAS BASED ON

1587
00:55:11,840 --> 00:55:13,800
CLINICAL CENTER RESOURCES WITH

1588
00:55:13,800 --> 00:55:15,440
SEDATION, ANESTHESIA, RESOURCES

1589
00:55:15,440 --> 00:55:16,280
AVAILABLE FOR CHILDREN YOUNGER.

1590
00:55:16,280 --> 00:55:18,640
BUT NO, IT DOES NOT START AT 3.

1591
00:55:18,640 --> 00:55:21,440
SO INDIVIDUALS, CHILDREN WITH

1592
00:55:21,440 --> 00:55:22,680
LFS START SCREENING BASICALLY

1593
00:55:22,680 --> 00:55:24,120
WHEN THEY'RE DIAGNOSED EVEN IN

1594
00:55:24,120 --> 00:55:27,280
INFANCY.

1595
00:55:27,280 --> 00:55:28,800
SO THEY DO START GETTING WHOLE

1596
00:55:28,800 --> 00:55:30,560
BODY AND BRAIN MRI AS SOON AS

1597
00:55:30,560 --> 00:55:31,560
THEY'RE DIAGNOSED, UNDERSTANDING

1598
00:55:31,560 --> 00:55:32,480
THE CANCER RISK.

1599
00:55:32,480 --> 00:55:33,560
BECAUSE IF YOU LOOK AT SOME OF

1600
00:55:33,560 --> 00:55:34,840
THE LFS CURVES WHICH I DIDN'T

1601
00:55:34,840 --> 00:55:36,480
SHOW TODAY, THE RISK OF CANCER

1602
00:55:36,480 --> 00:55:41,400
REALLY IS HIGHEST IN CHILDHOOD.

1603
00:55:41,400 --> 00:55:42,760
THE TUMOR PROFILES THEMSELVES

1604
00:55:42,760 --> 00:55:43,880
ARE DIFFERENT, AS YOU WOULD

1605
00:55:43,880 --> 00:55:44,840
IMAGINE, BETWEEN CHILDREN AND

1606
00:55:44,840 --> 00:55:45,640
ADULTS EVEN IN THE GENERAL

1607
00:55:45,640 --> 00:55:46,440
POPULATION.

1608
00:55:46,440 --> 00:55:49,040
SO CANCERS SUCH AS

1609
00:55:49,040 --> 00:55:52,360
ADRENOCORTICAL CARCINOMAS, CORY

1610
00:55:52,360 --> 00:55:56,880
PLEX IS CARCINOMAS,

1611
00:55:56,880 --> 00:55:58,640
RHABDOMYOSARCOSIS IS GENERALLY

1612
00:55:58,640 --> 00:55:59,720
CANCERS OF CHILDREN, OCCUR MORE

1613
00:55:59,720 --> 00:56:01,720
SO IN CHILDHOOD.  SO WHEN YOU

1614
00:56:01,720 --> 00:56:05,240
START SCREENING AT 3, I WILL

1615
00:56:05,240 --> 00:56:06,360
ACKNOWLEDGE IT'S VERY MUCH A

1616
00:56:06,360 --> 00:56:07,960
MAJORITY ADULT, BUT WITH OUR

1617
00:56:07,960 --> 00:56:08,800
COLLABORATORS ACROSS A WORLD WHO

1618
00:56:08,800 --> 00:56:11,000
HAVE PEDIATRIC CENTERS SUCH AS

1619
00:56:11,000 --> 00:56:12,680
SICK KIDS, WE DEFINITELY SEE

1620
00:56:12,680 --> 00:56:18,200
THAT DIFFERENCE IN PHENOTYPE.

1621
00:56:18,200 --> 00:56:19,240
AS FAR AS OUT COME DATA, THAT'S

1622
00:56:19,240 --> 00:56:19,920
A WONDERFUL QUESTION.

1623
00:56:19,920 --> 00:56:21,840
WE ACTUALLY DON'T HAVE VERY GOOD

1624
00:56:21,840 --> 00:56:26,280
OUTCOME DATA LOOKING AT THINGS

1625
00:56:26,280 --> 00:56:27,480
LIKE SURVIVAL, AND WE'RE

1626
00:56:27,480 --> 00:56:30,520
STARTING TO DO SOME OF THAT NOW.

1627
00:56:30,520 --> 00:56:31,960
WE THINK OF CANCERS AND LFS, WE

1628
00:56:31,960 --> 00:56:33,160
TREAT THEM WITH STANDARD

1629
00:56:33,160 --> 00:56:35,400
PROTOCOL, SO THERE'S NO REAL

1630
00:56:35,400 --> 00:56:37,960
LFS-SPECIFIC PROTOCOL FOR

1631
00:56:37,960 --> 00:56:39,680
TREATMENT OTHER THAN AVOIDING

1632
00:56:39,680 --> 00:56:40,880
IONIZING RADIATION WHEN

1633
00:56:40,880 --> 00:56:42,760
POSSIBLE, BUT THEY UNDERGO

1634
00:56:42,760 --> 00:56:43,800
BASICALLY THE STANDARD TREATMENT

1635
00:56:43,800 --> 00:56:45,000
THAT ANY CANCER OF THAT

1636
00:56:45,000 --> 00:56:46,000
MORPHOLOGY WOULD, THEY JUST

1637
00:56:46,000 --> 00:56:47,480
OCCUR MUCH MORE FREQUENTLY, AND

1638
00:56:47,480 --> 00:56:49,320
WE HAVEN'T SEEN AT LEAST

1639
00:56:49,320 --> 00:56:51,960
ANECDOTALLY OR IN CASE THEER

1640
00:56:51,960 --> 00:56:53,160
EASE, WE HAVEN'T SEEN ANY

1641
00:56:53,160 --> 00:56:54,120
DIFFERENCES IN OUTCOME.

1642
00:56:54,120 --> 00:56:55,440
I THINK THE BIG DIFFERENCE S

1643
00:56:55,440 --> 00:56:57,720
THEY'RE JUST GENETICALLY AT A

1644
00:56:57,720 --> 00:56:59,440
MUCH HIGHER RISK OF DEVELOPING

1645
00:56:59,440 --> 00:57:00,640
SUBSEQUENT CANCERS, AND I THINK

1646
00:57:00,640 --> 00:57:02,720
THE GENOTOXIC THERAPIES LIKE

1647
00:57:02,720 --> 00:57:04,040
CHEMO AND RADIATION MAY ONLY

1648
00:57:04,040 --> 00:57:05,520
COMPOUND THAT AND WE'RE ACTUALLY

1649
00:57:05,520 --> 00:57:06,920
PART OF A MULTI-INSTITUTIONAL

1650
00:57:06,920 --> 00:57:08,360
STUDY THAT IS LOOKING AT TREAT M

1651
00:57:08,360 --> 00:57:09,880
EFFECTS AND RISK OF SUBSEQUENT

1652
00:57:09,880 --> 00:57:10,640
CANCER.

1653
00:57:10,640 --> 00:57:14,360
BUT FROM THE SPECIFIC CANCER

1654
00:57:14,360 --> 00:57:15,440
OUTCOME AS A POPULATION, I DON'T

1655
00:57:15,440 --> 00:57:16,640
THINK WE HAVE ENOUGH DATA TO

1656
00:57:16,640 --> 00:57:18,440
ANSWER THAT.

1657
00:57:18,440 --> 00:57:19,600
>>THANK YOU VERY MUCH.

1658
00:57:19,600 --> 00:57:23,280
A LOT OF QUESTIONS ON METFORMIN.

1659
00:57:23,280 --> 00:57:30,120
I'M GOING TO -- SO THIS TELLS

1660
00:57:30,120 --> 00:57:31,480
ABOUT THE SIDE EFFECT OF

1661
00:57:31,480 --> 00:57:33,520
METFORMIN USE AND POSITIVE

1662
00:57:33,520 --> 00:57:36,760
NEGATIVE INTERACTIONS OF --

1663
00:57:36,760 --> 00:57:37,720
NEGATIVE INTERACTIONS OF

1664
00:57:37,720 --> 00:57:38,120
METFORMIN USE.

1665
00:57:38,120 --> 00:57:39,760
IS THERE ANYTHING ELSE BESIDES

1666
00:57:39,760 --> 00:57:41,000
METFORMIN THAT MIGHT BE ABLE TO

1667
00:57:41,000 --> 00:57:42,440
ACCOMPLISH THE SAME?

1668
00:57:42,440 --> 00:57:45,360
>>THAT'S A GREAT
QUESTION.

1669
00:57:45,360 --> 00:57:47,000
SO WITH THE PILOT STUDY WHERE WE

1670
00:57:47,000 --> 00:57:48,840
LOOKED AT SAFETY AND FEASIBILITY

1671
00:57:48,840 --> 00:57:50,240
THAT DR. HWANG IS ALSO A PART

1672
00:57:50,240 --> 00:57:52,000
OF, THE METFORMIN ADVERSE EVENT

1673
00:57:52,000 --> 00:57:53,680
PROFILE IS PRETTY MUCH THE SAME

1674
00:57:53,680 --> 00:57:54,480
AS WHAT IT IS IN THE GENERAL

1675
00:57:54,480 --> 00:57:54,800
POPULATION.

1676
00:57:54,800 --> 00:57:59,840
SO A LOT OF G.I. SIDE EFFECTS

1677
00:57:59,840 --> 00:58:04,400
SUCH AS NAUSEA, BLOATING, VERY

1678
00:58:04,400 --> 00:58:05,920
FEW -- WAS THERE ANYTHING

1679
00:58:05,920 --> 00:58:07,040
SPECIFIC TO LFS THAT WAS NOT

1680
00:58:07,040 --> 00:58:08,520
KNOWN ABOUT METFORMIN, AND

1681
00:58:08,520 --> 00:58:09,480
THANKFULLY THERE WASN'T, WHICH

1682
00:58:09,480 --> 00:58:13,200
IS WHY WE'RE MOVING AHEAD.

1683
00:58:13,200 --> 00:58:15,400
AS FAR AS WHY METFORMIN, CAN ANY

1684
00:58:15,400 --> 00:58:16,760
OTHER AGENT DO IT, I THINK THAT

1685
00:58:16,760 --> 00:58:17,960
SOME OF THAT IS GOING TO DEPEND

1686
00:58:17,960 --> 00:58:19,280
ON THE WORK OF DR. HWANG AND

1687
00:58:19,280 --> 00:58:21,360
OTHER COLLABORATORS LOOKING AT

1688
00:58:21,360 --> 00:58:24,320
DIFFERENT AGENTS AND DIFFERENT

1689
00:58:24,320 --> 00:58:25,600
SPECIFIC ACTIONS OF METFORMIN.

1690
00:58:25,600 --> 00:58:27,440
BUT THE REASON WE CHOSE

1691
00:58:27,440 --> 00:58:29,160
METFORMIN IS, ONE, YOU KNOW,

1692
00:58:29,160 --> 00:58:31,240
WE'VE GOT SOME VERY STRONG

1693
00:58:31,240 --> 00:58:32,760
FOUNDATIONAL DATA FROM

1694
00:58:32,760 --> 00:58:33,320
DR. HWANG'S WORK.

1695
00:58:33,320 --> 00:58:34,520
IT'S ALSO A DRUG THAT'S BEEN

1696
00:58:34,520 --> 00:58:37,880
AROUND FOR DECADES, WELL

1697
00:58:37,880 --> 00:58:40,400
TOLERATED, EASILY AVAILABLE, AND

1698
00:58:40,400 --> 00:58:42,800
EASILY DEPLOYED TO LARGE --

1699
00:58:42,800 --> 00:58:44,080
RELATIVELY LARGE POPULATIONS IN

1700
00:58:44,080 --> 00:58:45,160
RARE DISEASE AS WE LIKE TO CALL

1701
00:58:45,160 --> 00:58:45,920
THEM.

1702
00:58:45,920 --> 00:58:50,720
TO BE ABLE TO STUDY.

1703
00:58:50,720 --> 00:58:53,120
THE IDEA WITH SETTING THIS TRIAL

1704
00:58:53,120 --> 00:58:54,080
AND THIS INFRASTRUCTURE UP WAS

1705
00:58:54,080 --> 00:58:58,240
TO REALLY BE ABLE TO ADAPT TO

1706
00:58:58,240 --> 00:58:59,720
OTHER AGENTS IF WE NEEDED TO, TO

1707
00:58:59,720 --> 00:59:01,920
LOOK AT SOME MORE EFFECT, SO FOR

1708
00:59:01,920 --> 00:59:03,720
EXAMPLE, IF WE WANTED TO LOOK AT

1709
00:59:03,720 --> 00:59:04,720
FATTY ACID OXIDATION IN THE

1710
00:59:04,720 --> 00:59:06,040
FUTURE, WE WOULD BE ABLE TO USE

1711
00:59:06,040 --> 00:59:07,360
THE SAME INFRASTRUCTURE AND THE

1712
00:59:07,360 --> 00:59:08,520
SAME FOUNDATION REALLY TO STUDY

1713
00:59:08,520 --> 00:59:09,400
THAT IN THE FUTURE.

1714
00:59:09,400 --> 00:59:11,480
AND THIS IS REALLY JUST THE

1715
00:59:11,480 --> 00:59:12,920
FIRST STEP WE'RE TAKING INTO

1716
00:59:12,920 --> 00:59:14,600
PREVENTION, SO I THINK THIS IS

1717
00:59:14,600 --> 00:59:15,680
JUST THE STARTING OF WHAT I HOPE

1718
00:59:15,680 --> 00:59:17,760
WILL BE A VERY ROBUST AND

1719
00:59:17,760 --> 00:59:21,400
FRUITFUL EFFORT.

1720
00:59:21,400 --> 00:59:23,520
>>THANK YOU, DR. KHINCHA.

1721
00:59:23,520 --> 00:59:24,400
DR. HWANG, THIS TAKES US UP TO

1722
00:59:24,400 --> 00:59:24,960
THE HOUR.

1723
00:59:24,960 --> 00:59:26,360
AGAIN, I WANT TO THANK YOU

1724
00:59:26,360 --> 00:59:28,960
PERSONALLY FOR EXCEPTIONAL

1725
00:59:28,960 --> 00:59:35,080
TALKS, WITH THE CLARITY OF SOME

1726
00:59:35,080 --> 00:59:36,760
VERY ROBUST SCIENCE AND

1727
00:59:36,760 --> 00:59:37,800
POTENTIALLY A VERY BRIGHT FUTURE

1728
00:59:37,800 --> 00:59:38,440
FOR THIS POPULATION.

1729
00:59:38,440 --> 00:59:39,520
SO THANK YOU VERY MUCH, AND TO

1730
00:59:39,520 --> 00:59:40,960
THE NIH COMMUNITY, THANK YOU FOR

1731
00:59:40,960 --> 00:59:42,560
JOINING US, AND WE WILL SEE

1732
00:59:42,560 --> 00:59:43,240
EVERYONE NEXT WEEK.

1733
00:59:43,240 --> 00:59:44,320
THANK YOU AGAIN.

1734
00:59:44,320 --> 00:59:44,960
HAVE A GOOD DAY.

1735
00:59:44,960 --> 00:59:45,840
>>ALL RIGHT, THANK YOU.

1736
00:59:45,840 --> 00:59:56,080
>>THANK YOU.