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>> ON BEHALF OF THE NIH
DIRECTOR, IT'S MY PLEASURE TO
INTRODUCE TODAY'S NIH DIRECT
DIRECTOR'S SEMINAR SPEAKER,
CRAIG THOMPSON.
DR. THOMPSON IS PRESIDENT AND
CHIEF EXECUTIVE OFFICER OF
MEMORIAL SLONE CANCER CENTER
WHERE HE HAS BEEN FOR THE LAST
COUPLE OF YEARS.
HIS BACKGROUND INCLUDES
BACHELOR'S DEGREE FROM DARTMOUTH
COLLEGE, MD FROM DARTMOUTH AND
UNIVERSITY OF PENNSYLVANIA.
HE DID A RESIDENCE NEMEDICINE AT
THE BRIGHAM'S HOSPITAL AND
UNIVERSITY HOSPITAL IN BOSTON.
AND A HEMATOLOGY ONCOLOGY
FELLOWSHIP AT FRED HUTCHINSON
CANCER RESEARCH UNIVERSITY IN
WASHINGTON.
ONE THING YOU WILL SEE IN HIS
BIO, HE MOVED AROUND QUITE A
LOT, WHICH IS INTERESTING HE DID
A RESIDENCE NEMEDICINE AT THE
BRIGHAM HOSPITAL AND THE
UNIVERSITY HOSPITAL IN BOSTON
AND HEMATOLOGY ONCOLOGY
FELLOWSHIP AT FRED HUTCHINSON
CANCER RESEARCH UNIVERSITY
NEWASHINGTON.
ONE THEME YOU'LL SEE IN
DR. THOMPSON'S BIO, HE MOVED
AROUND QUITE A LOT.
WHICH IS INTERESTING.
IT'S BEEN VERY PRODUCTIVE FOR
HIM.
AFTER FRED HUTCH EXPERIENCE, HE
CAME TO THIS AREA AND ACTUALLY
WORKED FOR SEVERAL YEARS AT THE
NATIONAL NAVAL MEDICAL CENTER AS
A PHYSICIAN AND SCIENTIST.
AND AFTER THAT EXPERIENCE, HE
WENT TO THE UNIVERSITY OF
MICHIGAN WHERE HE BECAME AN
ASSISTANT PROFESSOR, MOVED UP
THROUGH THE RANKS AND BECAME AN
HHMI INVESTIGATOR AND ALSO HAD A
JOINT APPOINTMENT AT THE
UNIVERSITY OF CHICAGO WHERE HE
WAS DIRECTOR OF THE GENAPP
CENTER FOR LUPUS AND IMMUNOLOGY
RESEARCH.
IT TURNS OUT WHEN DR. THOMPSON
WAS AT THE UNIVERSITY MICHIGAN,
HE SHARED A FLOOR WITH TWO OF
OUR NIH DIGNITARIES, GARY NABEL
AND FRANCIS COLLINS.
THEY ARE ALL ASSISTANT
PROFESSORS TOGETHER AND YOU CAN
IMAGINE THE OTHER GROUP THAT WAS
THERE, WHAT A POWERFUL
INTELLECTUAL FORCE THEY MUST
HAVE BEEN AT THE UNIVERSITY.
IN 1999, HE CAME TO THE
UNIVERSITY OF PENNSYLVANIA WHERE
HE BECAME PROFESSOR OF MEDICINE
AND INITIALLY SCIENTIFIC
DIRECTOR OF THE LEONARD AND
MADELINE ABRAMSON FAMILY CANCER
RESEARCH INSTITUTE, CHAIRMAN OF
THE DEPARTMENT OF CANCER AND
ULTIMATELY DIRECTOR OF THE
ABRAMSON CANCER CENTER AT THE
UNIVERSITY OF PENNSYLVANIA.
AS I MENTIONED, A COUPLE OF
YEARS AGO, HE MOVED TO MEMORIAL
SLOAN-KETTERING WHERE HE LEADS
AN INCREDIBLE PROGRAM OF CANCER
RESEARCH AND TREATMENT.
SO, I THINK ALL OF THESE
POSITIONS REFLECT THE ENORMOUS
ABILITY TO GALVANIZE EXCITING
NEW DISCOVERIES IN CANCER
RESEARCH.
DR. THOMPSON HAS CONTRIBUTED
THREE MAJOR AREAS, THE FIRST,
WHICH IS THE WORK HE STARTED AT
THE NAVY CENTER HERE AND ALSO AT
THE UNIVERSITY OF MICHIGAN, WAS
TO EXPLORE THE ROLE OF ONCOGENES
IN HEMAPOIETIC CANCER AND ALSO
IN LYMPHOID DEVELOPMENT.
MANY CONTRIBUTIONS THERE.
AND THEN HE WORKED ON MECHANISMS
OF APOPTOSIS, AND THEIR ROLE IN
CANCER AND YOU ARE PROBABLY
FAMILIAR WITH A LOT OF HIS
CONTRIBUTIONS THERE.
OVER ABOUT THE LAST DECADE, HE
REALLY PIONEERED A NEW
UNDERSTANDING OF THE WAY CELL
METABOLISM INTERACTS WITH ISSUES
RELATED TO CELL GROWTH AND THE
DEVELOPMENT OF CANCER.
AND SOME OF THE WORK THAT HE HAS
DONE WILL BE DISCUSSED TODAY.
IN ADDITION TO HIS MANY
SIGNIFICANT POSITIONS AS A
SCIENTIST, HIS WORK HAS BEEN
RECOGNIZED BY ELECTION TO THE
NATIONAL ACADEMY OF SCIENCES,
INSTITUTE OF MEDICINE, AMERICAN
ACADEMY OF ARTS AND SCIENCES,
AMONG OHERS.
ANDE D IA W AR
D WOT TOU TM L. HES ASSOCIATE EDITOR, FOR
THOSE WHO ARE INTERESTED, OF
"CELL," "IMMUNITY" AND "CANCER
CELL."
HE IS A BOARD MEMBER FOR MANY
SIGNIFICANT ORGANIZATIONS AND A
MEMBER OF THE ALASKA PRIZE JURY.
SO WE REALLY HAVE TO BE NICE TO
CRAIG.
IN ADDITION, HE STARTED IN HIS
CAREER THREE BIOTECH COMPANIES.
BUT HIS MOST IMPORTANT
CONTRIBUTION IS THAT FOR MANY
YEARS, HE WAS CHAIRMAN OF THE
BOARD OF SCIENTIFIC COUNCILLORS
OF THE NCI BASIC SCIENCE
DIVISION.
MANY EVER YOU WHO ARE CANCER
RESEARCHERS GOT TO KNOW HIM IN
THAT CAPACITY.
I THINK WE SHOULD WELCOME CRAIG
MPSON, WHOSE TALK TODAY IS
ENTITLED, IDH MUTATIONS, AN
COMETABOLITE DEREGULATION OF
EPIGENETIC REMODELING.
[ APPLAUSE ]
>> THANK YOU.
IT'S A PRIVILEGE BBA HE HAE GE ISALANSEANA
MA O FEN ITHNIH
DAYS IN SCIENCE.
I SAID THIS BEFORE BUT I'M
ALWAYS EMBARRASSED WHEN WE GIVE
THAT KIND OF INTRODUCTION
BECAUSE AS MY MOTHER TELLS ME
WHEN SHE OCCASIONALLIES AND
LISTENS IN AN AUDIENCE, IT
SOUNDS LIKE YOU CAN'T HOLD A
JOB.
WHAT I AM GOING TO TALK STUDY TO
GIVE AN OVERVIEW SINCE I THINK
IT'S APPROPRIATE ON THESE
WEDNESDY TEOOCOERCE
T SDES STCSO ND P MABISONI. IVYOAN IDEA OF HOW WE GOT
IEY IN THE TITLE AS AN
ONCOMETABOLITE.
WE WILL COVER THAT AT THE END.
I WANTED FOR THE STUDENTS TO GET
AN UNDERSTANDING THAT NO ONE,
THESE DAYS, OTHER THAN KICKING
AD SCREAMING, GETS DRGEBA
TOHEIE WALGO
GH BCHISY S AN
UNDRGDUE MABISIN THLASTOR GNGORRD
PPLTH HAVE DONETH
K LLALABT DAN-
B,UNT A HE. A MB OPODO LD
VEHE O LORORS
ISIE OCAER METAL B SE T N
RK'MOI TTA AUTAS BE AOLBOTI WH SSANARARNDUREMOPET
LIAESNDHAISOT ITTICH A EO ISD
IOS. WEAD LG RMOLBTI
THUKANJO TBRG W PPACS MABICTUESANA W ARAG WH U,
ARD COANCAE- HAACTILSOONGNT
CEF NC MABISTO SO TEENANTH SEIFHE A A TRAUT
NTBD SE T BIC SCNCI'GOG TK OU
AY
TH'SHENTDUIOTO HPELEHOIDHI
I SAID, WE WERE ALL, EVERYONE
IN THIS ROOM, IT'S INTERESTING.
WE SPANNED A SIGNIFICANT PERIOD
OF TIME IN SCIENCE, BUT EVERY
ONE OF US SHARES A COMMON
BACKGROUND AND THAT WE TOOK
EXACTLY THESA BCHISY OUE D Y TK
LLEIMES IN HIGH SCHOOL
AND COLLEGE AND THEN IN GRADUATE
SCHOOL, YOU TOOK THE SAME COURSE
OVER AGAIN MULTIPLE TIMES
BECAUSE THERE HASN'T BEEN A NEW
METABOLIC PATHWAY INTRODUCED IN AIOEMTRTEBO
NC19. A OARIN TY DEON NDHE IWAON AER0
P,EFE ATHEREOU
IROCY EPASN E M,T TE A AOW T TPU O T IS ATDIUSIN AEL SIU
L SVI. E ARD AOADNC
Y TNKG OUORNIAL RI PIO OTI PELFOXENCES N RER
OU LTA B TT
GH IFFIE. THAT WHENGXM
PEOPLE STUDIED
HIGHLY-PROLIFERATIVE TISSUE, AND
THE BEST RECENT EXAMPLE IS IF WE
STUDY THE BIOLOGY OF EF CELLS OR
IPF CELLS.
THEY DON'T ADOPT THIS
METABOLISM.
WHAT THEY DO IS SCAV ANG THE
GLUCOSE AND EVEN IN THE PRESENCE
OF MOLECULAR OXYGEN, THROW THE
VAST MAJORITY OF THE CARBON THAT
IS THEY TAKE UP AWAY AS LACTATE.
THAT WAS ACTUALLY FIRST NOTICED
IN TUMOR CELLS IN THE 1920s BY
THE PIONEERING BIOCHEMIST WHO
CONTRIBUTED TO MUCH OF THIS
INFORMATION.
SO THE PREFERENTIAL USE OF
GLUCOSE METABOLISM THROUGH
GLYCOLYSIS HAS BEEN TERMED, THE
WARBERG EFFECT OR AEROBIC
GLYCOLYSIS WHEN IT OCCURS IN THE
PRESENCE OF MOLECULAR OXYGEN.
FOR OVER 80 YEARS, SCIENTISTS,
EVERY DECADE, TRIED TO FIGURE
OUT WHY IT IS THAT TUMOR CELLS N PROLIFERATING NORMAL CELLS,
ACTUALY OPTH ABNORMAL
METABOLISM.
MY INTEREST IN THISIDOTTE
M Y TESTN TALI. T MEROWH ME L
OU
O STUDIES TO UNDERSTAND THE
LYMPHOCYTE PROLIFERATION, WE
CAME TO PROHIBIT THAT EVERY ONE
OF US GOES THROUGH HUGE GLOBAL
EXPANSIONS OF LYMPHOCYTES AS WE
ENCOUNTER NEW BACTERIA AND
VIRUSES IN OUR ENVIRONMENT AND
HAVE TO FIGHT THEM OFF BY A
SPECIFIC IMMUNE RESPONSE.
AND THAT BY THIS POINT IN OUR
LIFETIME, HU HUNDREDS OF THOSE
ENCOUNTERS WITH FOREIGN
PATHOGENS AND IF YOU KEPT ALL
THE LYMPHOCYTES YOU CREATED TO
PROTECT YOU DURING THOSE
EPISODIC EVENTS OF INFECTION,
YOU WOULD NEED A WHEEL BOROUGH
TO CARRY THE EXTRA CELLS ALONG
WITH YOU TO MAINTAIN
HOMEOSTASIS.
SO, OTHER INVESTIGATORS THINKING
ABOUT THAT PROBLEM IN EVERY
LINEAGE OF THE BODY CAME UP WITH
THE IDEA THERE MEMBER MECHANISM
TH DET CELLS FROM THE BODY
AND THE SIMPLEST MEANM UL
ANRGIZ FM OF CELL
EH ATECE OWAS P
Y WH E NEC ISVE ITHWO
OPSI
FE YEARS AGO TO TRY TO
EXPLAIN HOW IT S KP AC OUALD HETH 60
TRILLION CELLS AND HOW YOU KEEP
TRACK OF 60 TRILLION CELLS WHEN
ANY ONE OF THEM COULD DIE IN THE
NEXT 15 MINUTES, BECAME THE
PUZZLE OF THE 1990s FOR THE
PEOPLE INTERESTED IN THE FIELD
OF CELL DEATH.
THERE WAS SIMPLIFIED BY MARK IN
THE MID 1990s WITH THE
STATEMENT THAT HE WAS PRETTY
SURE THAT ORGANISMAL HOME STAYS
SIS MAINTAINED BECAUSE EVERY
CELL IN YOUR BODY WAKES UP
THINKING ABOUT SUICIDE AND HAS
TO BE TALKED OUT TESTIFY BY
NEAREST NEIGHBORS TO MAINTAIN
HOMEOSTASIS.
THE MODEL SAID THAT SINGLE CELLS
TAKEN FROM OUR BODY PLACED IN
ISOLATION WITHOUT THE NORMAL
NEAREST NEIGHBOR SIGNIFICANT
FALSE ACTUALLY INITIATEOV A
DEFINED PERIOD OF TIME THIS A
APOPTOTIC CASCADE THAT SILENTLY
IMINATES THEM FROM THE BODY,
SO-CALLED DEATH BY NEGLECT.
AND THE ARGUMENT BECAME THAT YOU
NEEDED SPECIFIC INSTRUCTION
SIGNALS TO MAINTAIN THE
VIABILITY OF THAT CELL OVER THE
NEXT FEW YEARS.
THOSE WERE IR KWNS URVASIALANAS'MGOG SHOW YOU IN A MITE
THLA 10sWO
POD E MMAL THE IGFIANT UNLESSNALS IS THAT
INSTRUCTED CELLS TO TAKE UP
GLUCOSE TO MAINTAIN ATP
PRODUCTION IN HOMEOSTASIS.
SECONDARILY, WE ALSO NOTE TO
MAINTAIN ORGANELLE HOME STAYSIS
AND MAINTAIN THE PROLIFERATIVE
ADVANCES, YOU NEED ADDITIONAL
SIGNALS AND THOSE HARNESS NOT
NUTRIENTS BUT NUTRIENT
TRANSCRIPTION IN TRANSLATION
NECESSARY FOR A CELL TO ENTER
AND PROGRESS TO THE CELL CYCLE.
AND IF THIS MODEL IS CORRECT, IT
SUGGESTS, AS I WILL SHOW YOU
AGAIN IN A MINUTE, THERE ARE TWO
FUNDAMENTAL BARRIERS TO THE
REGULATION OF CELL SURVIVAL AND
ULTIMATELY CELL AUTONOMOUS
PROLIFERATION.
THE CELL NEEDS TO ACQUIRE THE
INFORMATION DODE PROLIFERATE AND
NEEDS THE NUTRIENTS TO ENACT THE
SURVIVAL DURING THAT
PROLIFERATION RESPONSE.
SO, STARTING WITH THAT
HYPOTHESES, JEFF IN THE
LABORATORY IN 1999, HE IS NOW
DOWN TO DUKE CARRYING OUT THIS
K H LOROR, STARTED
TO LOOK AT INDIVIDUAL CELL TYPES
BY DEATH AND TO CHARACTERIZE
WHAT HAPPENS.
SO THE SIMPLE EXPERIMENT YOU IS
TAKE YOUR FAVORITE CELL TYPE OUT
OF THE BODY AND MAKE A SINGLE
CELL SUSPENSION AND THEN ASK
WHAT HAPPENS TO THE CELL DURING
THE NEXT TWO DAYS BEFORE IT
COMMITS TO APOPTOSIS.
WHAT HE FOUND IN EVERY CELL TYPE
HE WAS ABLE TO EXAM, IN THE
ABSENCE OF SERUM DERIVED GROWTH
FACTORS IN THE FIRST 12 HOURS,
EVERY CELL PROCESSES NUTRIENT
ANORRSECSA TTA
NRITSROTHE
RLLARNVONNTFF
E LLUFRSNDELER
M T LOSE ERE THEY
E GRED
CL ENTAS E LL THT CLOCK IS DEPENDENT ON THE
CELL TYPE AND THE NUMBER OF
INTERMEDIATE METABOLITES THE
CELL HAS AVAILABLE TO IT
INTRACELLULARLY, BUT ULTIMATELY
THAT CELL OVER THE NEXT 24 HOURS
HAS A DECING OERGIC ROINTH A ATSUACEORNEE ATS TIVATES 3
THMICHDRL MBNEO
ACTIVATE THE DEA-IUCG RORTS T P APTICFLYACTOAC
D ROH ISROSSAUS ISLUONF ET
OCNDAL MEMBRANE IN THE
INITIATION OF THIS ORDERLY FORM
OF CELL DEATH KNOWN AS
APOPTOSIS.
SO, WE PROPOSE, AS I JUST
SUGGESTED, THAT THE KEY FACTOR
THAT REGULATES THE SURVIVAL IS
ACTUALLY HEOSOFHEBITY TOICUPUTE A
ININ BIOENER JETTI. UTHE W AOPNGIE
D ATS,OUE T IN
MUATED BY HEROH CTS N URNVONNTNYONR.YOCATA AORINL
OLY D AT BIOLOGY JUST
SIMPLY ALLOWS YOU AT THE LEVEL
YOU CAN DETECT THEM TO SEE THE
DECLINE IN NUTRIENT
TRANSPORTERS.
THEY ARE STILL THERE IN ADEQUATE
QUANTIIE
WTRD ARES THAT
QUESTION BY CREATING A MOUSE
COMPLETELY DEFICIENT OF
BACK-TO-BACK TO BACK.
SO IT COULDN'T INITIATE
APOPTOTIC CELL DEATH AND THEN
ASKED, IN CELL NEANINHE WHE GASMWH HPE
L RVALHETHCE
ILEXRICENEEC LSS
OF EXTRACELLULAR SIGNALING BUT
NO LONGER CAN INDUCE APOPTOSIS?
WHAT WE DISCOVERED WAS THAT CELL
NOW TOWERS A MORE ANCIENT
SURVIVAL PATHWAY THAT WAS
PRIOLYELDERID
NG CL KAOT IPLTS NACLUR ATU MP A AVGEWHE E LLSEESRSAR OIT
ENELERTH VIC'S CEN TTHLYSE F
- EPDE DRATI OTH
IDTORODEUBRAS R HEITHR TMATA
INCREASED
BIOENERGETIC DEMAND NOT MATCH
WITH INCREASED NUTRIENT SUPPLY
CREATES A CASCADE THAT READS OUT
IN THE BCL2 FAMILY.
AND ARGUES THAT IF YOU WERE
GOING TO HAVE AN INITIATING
LESION OF CANCER, IF WE
UNDERSTAND IT'S A SERIES OF
GENETIC LESIONS THIS IS NOT A
VERY EFFECTIVE LESION TO
INITIATE CANCER IN.
THAT'S WHY SO MANY MOUSE MODELS
THAT INITIATE WITH THESE KINDS
OF ONCOGENIC LESIONS TAKE MONTHS
BEFORE YOU SEE A TUMOR PLAY OUT.
IN CONTRAST, WE ARGUED IF THERE
WAS SUCH A THING AS FUEL
SIGNALING, AND YOU HAD A
MUTATIO ITHREPTORS OR THE
SIGNALING THAT DIRECTED THAT
PROCESS, THIS WOULD PROMOTE CELL
SURVIVAL BECAUSE THE CELL WOULD
TAKE UP IN RESPONSE TO THIS
INCREASED RESPONSE OR SUSTAINED
SIGNAL TRANSDUCTION THAT IS
ONCOGENIC, INCREASE GLUCOSE
UPTAKE OVER DEMAND AND NEED.
FUEL INCREASE ATP PRODUCTION AND
MAKE TRANSCRIPTION AND
TRANSLATION MORE EFFECTIVE.
THE CELL WOULD BE ABLE TO DEAL
WITH THAT BUT ULTIMATELY WOULD
CREATE BY OVEREATING THE EXTRA
REACTIVE OXYGEN SPECIES AS THE
ELECTRON TRANSPORT CHAIN IS NOW
EXCEEDED ITS CAPACITY FOR ATP
PRODUCTION AND THAT WOULD
PROMOTE AS THE CELL OVEREATS,
THE EXTRA CARBON TO BE SECRETED
AS LACTATE.
THE INCREASED ATP RATIO WILL
MAINTAIN BIOENER JETTICS AND
CELL SURVIVAL AND RESIST TONES
APOPTOSIS AND THE REACTIVE
OXYGEN SPECIES WILL TAKE THIS
NOW CELL AUTONOMOUS FOR SURVIVAL
DISPEL BEGIN TO MUTAGENICE IT.
AND SO, THIS IS INTERESTING
OUE INTORYO ITTEA MO TS T KD
SI Y SULINIA WH. ANSOASE RETAINTOTHK OUTH, D K,RETHE Y GNIP ADIS
HACOROPRARY E GLOS WWE RIND O
COEAESN DOINOLE, THE S E LLHACTIZ
GN TNSCTN THY AT
IDXALYHA DEL TTA UMO
UCEAHENE F
EMLV. NDN STCTTH TPA
OSEXA UCE AYORHE RE OTHBO.
AT T ISLG GNIN
ADM,USE,ATLIR, ACVAON RECEPTOR TYROSINE TA UMO GCO TN U
KINASE BY LIGAND CALLED INSULIN.
THAT ACTIVATION OF THE PROTEIN
KINASE DOMAIN LOADS TO
RECRUITMENT TO CREATE PIP3 AND
RECRUITS THE MEMBRANE IN SEREIN
3 KINASES.
AND IN INSULIN RESPONSIVE
TISSUES, THAT IS SUFFICIENT FOR
AKT AND ACTIVATED FORM TO DETECT
THE CELL TO PLACE GLUCOSE
TRANSPORTERS ON THE CELL
SURFACE.
ON THE LAST DESCRIBED
BIOCHEMISTRY OF REGULATION OF
BIOENERGETICS.
AKT PREFERRED SUBSTRATE THIS
PATHWAY IS FPK TWO WHICH
PRODUCES THE REGULATOR AND
ACTIVATION OF PFK1S THAT PATHWAY
IN INSTRUCTS THE CELL IN
RESPONSE TO THE SUSSTATEMENT AND
MAGNITUDE OF SIGNAL TRANSDUCTION
TO TAKE UP GLUCOSE IN EXACTLY
THE PRECISE PROPORTIONS.
SO THE CELL IS NOT MAKING THE
DECISION.
SIGNAL TRANSDUCTION IS MAKING
THE DECISION.
WE WENT ON TO TAKE A VARIETY OF
NONINSULIN RESPONSIVE TISSUES
AND SHOW IF WE TRANSFORM THEM
WITH AKT, IT DIRECTED ALL THESE
PROCESSES IN EVERY TISSUE WE
COULD FIND AND WE FOUND THAT IN
EVERY TISSUE WHERE THERE ARE
SURVIVAL RECEPTORS IDENTIFIED,
THAT THEY DIRECTED THIS PROCESS
BECAUSE THEY MIMICKED THE
INSULIN RECEPTOR EXCEPT THEY
WERE LINEAGE RECEPTOR KINASE
THAT IS RESPONDED TO
TRANSCRIPTION FACTORS TO
INITIATE THE SIGNALING PARADIGM.
AT THE SAME TIME AT THE NIH,
THEY CAME TO OUR RESCUE IN THE
TCGA BECAUSE AS NEW SEQUENCING
WAS DONE, IT WAS DISCOVERED THE
MOST COMMON ACTIVATING MUTATION
IN HUMAN CANCERS AFTER RAS IS
ACTIVE MUTATIONS OF THE
CATALYTIC SUBUNIT OF THE KINASE
AND WHEN YOU PUT THAT IN TUMORS,
IN HUMAN BEINGS, IN THE CELL
LINES, THEY DIRECT EXACTLY THIS
PROCESS.
AND THE SECOND MOST COMMONLY
LOST TUMOR SUPPRESSOR GENE IN NETI RULITOFHIRS IS THE
HW, ICISHE PHPHASTH AIVESHI
HW. O,N SEE,T PES ATINAC TS A PATHWAY.
THE DIFFERENCE IS IT'S NOT INLITH ITHLIND
S NEE ECICURVA
FACTORS.
THESE ARE HEMATOPOIETIC STEM
CELLS THAT ARE GROWN IN THE
PRESENCE OF IL THREE AND THEY
WILL GROW NICELY AND UNDERGO
GROWTH WHEN WE PACKAGE THEM IN
CULTURE.
IF WE NUT A TRANSGENE EXPRESSED
IN LOW LEVELS IN THE ABSENCE OF
INDUCTION, WE SEE A DIRECTORY
SPONSE TO THE INTRODUCTION OF
AKT OR ITS INDUCTION.
INCREASED IN GLYCOLYSIS.
THERE IS NO CHANGE IN THE GROWTH
RATE THROUGH THE IL3 SIGNAL
TRANSDUCTION.
AT THE HIGHEST LEVEL, THEY
REPRODUCE THE SUPPRESSOR OXYGEN
CONSUMPTION EXACTLY WHAT WARBERG
DESCRIBED.
THIS IS A MEANINGFUL REDUCTION
OF OXYGEN CONSUMPTION BY THE
HIGH RATE OF GLYCOLYSIS IS
SATISFYING THE CELL.
THERE IS A PROBLEM HERE.
IF THE CELL TAKES UP THIS MUCH
GLUCOSE, IN ACCESS OF NEEDS, IT
HAS SOME PLACE TO PUT IT.
THESE ARE NOT PROFESSIONAL
STORAGE TISSUES.
THESE ARE HEMATOPOIETIC
PROGENITOR CELLS.
SO TO MAINTAIN CARBON
HOMEOSTASIS BECAUSE THE CELLS
CAN'T PUT THE CARBON INTO THEIR
GROWTH CURVE, THEY HAVE TO GET
RID OF THE EXTRA CARBON AND THEY
HAVE TO SECRETE IT FROM THE
CELL.
THERE IS AN EXACT CORRESPONDENCE
OF THE EXTRA CARBON TAKEN UP BY
GLYCOLYSIS BEING COMMITTED TO
SECRETION BY LACTAID.
AND THAT'S WHAT THE CLINICIANS
HERE IN THIS HOSPITAL HAVE BEEN
USING TO DIAGNOSIS CANCER FOR
THE LAST DECADE.
IN FACT, PEOPLE RECOGNIZING
WARBERG INDEPENDENTLY DISCOVERED
YOU COULD USE POSITRON EMISSION
TOMOGRAPHY TO IMAGE THE HIGH
AVIDITY OF TUMORS FOR GLUCOSE
THAT OCCURS IN NATURALLY
OCCURRING HUMAN TUMORS.
TAKE A POSITRON 18402 AND INJECT
INTO THE FOREARM OF A PATIENT
AND ASK BY SCANNING THE PATIENT
OVER 15 MINUTE INTERVALS, WHERE
DOES THAT GLUCOSE GET TAKEN UP
IN THE SOMEBODY IT'S REASSURING
OF WHAT WE ALL LEARNED, THE
FIRST TISSUE THAT LIGHTS UP ARE
ALL THE HEMISPHERES OF THE
BRAIN.
THE LIVER IS THE NEXT MOST
RECOGNIZED IN TERMS OF GLUCOSE
UP TAKE AND THEN THIS ORGAN IS
THE HEART.
BUT IN EVERY POINT OF THIS
PATIENT WHICH IS INDOLENT
THYROID CARCINOMA THE IMAGE THAT
TAKES UP THE MOST GLUCOSE IS
THIS ADD NO PAP LARRY CARCINOMA
OF THE THYROID AND WHEN THIS
TUMOR WAS SEQUENCED THIS TUMOR
HAD AN ACTIVATING MUTATION OF
THE TSH RECEPTOR, THE LINEAGE
RECEPTIVE KINASE RECEPTOR THAT
INITIATE THE SIGNAL TRANSDUCTION
PATHWAY THAT MAKES THE CELL SCAV
ANG ALL THE GLUCOSE IN THE
ENVIRONMENT.
THIS CELL HAS NO PROLIFERATIVE
RATE BECAUSE IT'S A CANCER THAT
HAS GROWN OVER A SEN- - SO MUCH
TESTIFY HEN YEAR PERIOD.
IT'S NOT HYPOXIC BECAUSE THE
GLUCOSE ITSELF GOT THROUGH THE
VASCULAR SYSTEM TO THE TISSUE
FIRST.
SO, THESE ARE THE NATURAL
OCCURRING TUMORS THAT HAVE
ACTIVATING MUTATIONS THAT
ACTUALLY DIRECT CELLS TO TAKE UP
EXTRA NEWT REPRESENTS AND
THEREFORE, A PUSHES IS THAT PUT
IN MREUTEN IN THE CELL
EDANPU T CL BNG RESTT APTEIAN
HETHCES ALL TH
ILNGLOS EAGIN NSHT AND ALLOWS US TO
HYPOTHESIS THE FOLLOWING THINGS
T SUGGESTS THAT MANY ONCOGENES,
THIS IS RIGHT THAT CELLS LACK
THE CELL AUTONOMOUS UPTAKE OF
NUTRIENTS AND MANY ONCOGENES WE
HAD PRIESTLY NOT UNDETA
LLMITIMILHA T
LLO GUTEELLA
ABIS IN MULTICELLULAR
ORGANISMS AND THE ANTIAPOPTOTIC
GENES AND THE TUMOR SUPPRESSORS
MIGHT BE NEGATIVE REGULATORS OF
THAT PATHWAY SO CELLS WOULD
MATCH THEIR ENERGETIC RESOURCES
TO THE DEMANDS BEING PUT ON THEM
BY CELL PROLIFERATION.
AND SO, AT THE TIME WE
HYPOTHESIZED THAT, IT SEEMED
LIKE A CRAZY IDEA BECAUSE BOB
WEINBERG JUST FINISHED THE TESTS
OF BEAUTIFUL BOOK, I URGE YOU TO
READ, IN WHICH HE COMPILED ALL
THE KNOWN MOLECULES INVOLVED IN
EXPERIMENTAL CARCINOGENESIS AND
THIS BEAUTIFUL SIGNALING DIAGRAM
TO THE CELL SURFACE WITH
RECEPTORS ANDHERACRTI. T E MEIM D KLON
WAS RETIRING FROM THE UNIVERSITY OFNGNDHE HHAPRUC
R ERONOFS, THAT EVER
SEEN A METABOLIC CHART ON OUR
CELL WALL, HE IS THE GUY THAT
PRODUCED IT.
THIS IS THE 23rd OF THOSE
CHARTS HE PRODUCED AND IN IN HIS
RETIREMENT PARTY, HE SAID THANK
GOD WE'LL NEVER NEED PRODUCE
ANOTHER ONE BECAUSE WE KNOW
EVERYTHING WE EVER NEED TO KNOW
ABOUT METABOLISM.
AS WE WERE HYPOTHESIZING IN
2007, THERE WASOSA NG
NEN ISHA TT S
ISHA VE RS
D ATEED U
OSBL
CAE ES AE E O ST REICITHUGSIALTRSDTI A T.
OCMIRYO AIT
HEENT ON TO TRANA
ATREHEDVTAS
ERTI GCO A
TEIAY HE NUTRIENTS TO
LLTH WT EAGIN UCASANR LLFATN
WE FSTNTTH
OCS , Y ITH
ROC YCYS ISU A SPIA OR SELECTED EVENT IN
TUMORS?
RECOGNIZED FROM THE 1920s,
IT'S RECURRENTLY DONE AND IMAGE
EVERY DAY.
77 HUMAN TUMORS HAVE THAT ANESBY P SN.THFIT INWEISVED,
TT ENOUNGE
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IS -- THAT MITOCHONDRIAL IS NOT
ACCESSIBLE TO THE CELL FOR
SYNTHETIC REACTIONS.
N
IN CELLS.
I'M JUST GOING TO SHOW YOU TWO
IDEAS ABOUT THIS THAT'S ALL BEEN
PUBLISHED.
IT'S ALREADY BEEN WELL
ESTABLISHED AT THE POINT WE
STARTED OUR WORK THAT DECLINING
BIO, BECAUSE INCREASE IN THE NED
AND NADH RATIO WAS CRITICAL FOR
THE ACTIVATION OF HISTONE
DEACETYLASES, CRRT1.
A PATTERN EVER ORGANIZATION THAT
MAKES IT LESS ç INDUCIVE FOR GENE
EXPRESSION, PARTICULARLY IN THE
FORM OF GENE ELONGATION.
WHAT WE REALIZED IN THE DYNAMIC
REGULATION OF'(>jó) /I'1wo#myÑ zYÑI/ózB#ÑiU7ç]IÑ
SIGNAL.
THIS IS LOW ENERGY SIGNAL AND
LOW FLUX OF THE FLUCOLYSIS
PRODUCE THIS IS CONDITION.
HIGH FLUX WILL PRODUCE THIS
CONDITION AND WE FOUND A 10-FOLD
DYNAMIC RANGE INsaF] THE CYTOPLAC ñ
BASED /
GLYCOLYSIS.
WE TESTED AND FOUND THESE WERE
HIGHLY SENSITIVE IN THAT DYNAMIC
RANGE OF ASEATAL COLAYS AND
TO THE OPPOSITE REACTION AND
WILL DRIVE CHROMATIN INTO A
PLACE WHERE GENE EXPRESSION IS
ENHANCED THROUGHOUT CHROMATIN
NETWORK.
THIS HAS A ROBUST SOURCE OF
ENERGY AND CAN ENGAGE IN MORE
PRODUCTION OF INITIATED
TRANSCRIPTS.
SO, I'M NOT GOING THROUGH THIS
EXPERIMENT.
WE DYNAMICALLYíOX9ñwM w[gÑ[3;c&5 Y >5Yú
THESE ARE RESTING FIBROBLASTS
THAT ARE SIMULATED WITH A
COCKTAIL AND WE HAVE DONE THAT
OVER FOUR DAYS IN THE CONDITIONS
OF A PHYSIOLOGIC LEVEL OF
GLUCOSE OR DIABETIC LEVEL.
WHAT YOU CAN SEE HERE IS THE
GLOBAL ACETYLATION OF HISTONE H3
AND H4, THE GREATER SUBSTRATES
OF ACETYLATION REACTIONS IN THE
HISTONES IS REASONABLE IN THE
RESTING CELLS BUT IT UNDERGOES A
DRAMATIC INDUCTION WITH MIGHT
JEN STIMULATION AND THAT IS
THOUGHT TO BEC PROFOUNDLY
RETARTED IF WE DO RNAI AGAINST
CITRATE.
AND THAT IS MOST DRAMATIC WHEN
HAVE YOU BOTH A HIGH
YOU3u 2I
NEGATIVE SENSE BY THE FAMILY OFm;YJÑ
GENES WHEN YOU'RE COMPROMISED
AND THE POSITIVE SENSE BY FLUX
THROUGH THE PATHWAY.
SO THAT IS A VERY BEAUTIFUL
ARGUMENT IN WHICH THE GENERALIZE
STATE OF THE ABILITY TO ENGAGE
IN TRANSCRIPTION VERSUS
<
CONTROLLED BY THE LEVEL OF
HISTONE ASTETALATION IN A
VARIETY OF MARKS THAT HAVE BEEN
WORKED I
ON THIS SIDE WILL BE DISCOVERED
THAT CYTOKINES DEDICATED TO THE
SIGNALING PATHWAY, IN FORMS THE
TRANSCRIPTION OF THE ESSENTIAL
FIBERS OF THE SO-CALLED MEMBERS
FOUND THAT REGULATES UPFAKE AND
DIRECTED BY MYC AS A
TRANSCRIPTION FACTOR WHICH PUTS
IN A CASCADE OF GENES THAT
CONTROLS THE UPTAKE AND
METABOLISM OF GLUTAMINE MUCH THE
WAY THIS SIGNALING PATHWAY
CONTROLS THE UP TAKE AND
METABOLISM OF GLUCOSE.
AND THE UPTAKE OF GLUTAMINE
PROVIDES A NICE SOURCE OF
BIOSYNTHESIS AND A CARBON SOURCE
TO ALLOW GLUCOSE TO BE
REDIRECTED INTO BIOSYNTHESIS AND
IT ALLOWS A SUBSTRATE TO BE
CONVERTED IF THE METABOLIZED IN
ACCESS TO PRODUCE NADPH TO FUEL
THE SYNTHESIS OF NUCLEOTIDES AND
LIPIDS.
THAT SEEMED TO COMPLETE ALL THE
MAJOR BUILDING BLOCKS WE NEED
FOR CELL GROWTH AND CONSISTENT
WITH THAT, BURNS MADE A MOUSE
THAT IMMUNOLOGIC LINEAGE, THE
B-CELL LINEAGE, HAS THE ACT
VISION BY ENHANCER OF AKT AND
MYC, AND INSTEAD OF NOW TAKING
MONTHS, THESE TWO INDIVIDUAL
MICE, THIS MYC B-CELL MOUSE WILL
PRODUCE TUMORS AROUND SIX MONTHS
OF AGE.
AKT MOUSE ABOUT NINE MONTHS OF
AGE, IF HE BRED THOSE TWO
TOGETHER, AS ANTON PRODUCED, HE
FOUND THESE TWO GENES
COMPLIMENTED EACH OTHER, HE
FOUND THE FIRST B-CELLS MADE IN
THE MOUSE DAY 18 OF EMBRYO
GENESIS AND EVERY ANIMAL DIES OF
ITS TUMOR AT BIRTH THREE DAYS
LATER.
BECAUSE THE MINUTE THE CELL
COMMITS TO THE B-CELL LINEAGE,
THESE TWO PATHWAYS ARE FULLY ON
AND THE CELL CYCLE TIME OF 5
HOURS.
IT DOESN'T MATTER T DIVIDES.
IT DIVIDES WHERE IT IS NO MATTER
WHAT ELSE IT IS DOING.
SO WHAT WAS INTERESTING ABOUT
THAT IS WE THOUGHT THAT THE MYC
PATHWAY WOULD TELL BUS NITROGEN
METABOLISM AND THEN WE DID THIS
EXPERIMENT WHICH GOT US TOTALLY
CONFUSED.
IN TISSUE CULTURE CELLS -- FOR
THE STUDENTS AND POSTDOCS, THE
REASON WE KNEW GLUTAMINE WOULD
BE IMPORTANT IS THE DIRTY LITTLE
SECRET OF CELL CULTURE THAT WE
ADD 10 FOLD MORE ACCESS
GLUTAMINE TO EVERY TISSUE
CULTURE IN THE WORLD SINCE WE
ARE IMMUNOLOGY LAB, WE DOUBLE
THAT BECAUSE WE DON'T TRUST
ANYBODY ELSE.
ALL THE IMINOLOGISTS DO THAT.
SO WE ARE NOT UNIQUE.
AND SO WE THOUGHT THAT GLUTAMINE
WOULD BE SPECIAL.
SO WE DEMONSTRATED THAT TO TAKE
MARTIN LUTHER KING TRANSFORMED
CELLS NATURALLY OCCURRING TUMORS
OR MAKE MYC TRANSFORMED CELLS
AND WE FOUND THEY WERE ADDICTED
TO GLUTAMINE.
IF WE LEFT THE GLUCOSE AT 11
MILL I MOLOR AND TOOK ALL THE
OTHER NUTRIENTS EVERY CELL DIED
WITHIN 3-4 DAYS IN THE TISSUE
CULLURE.
-- CULTURE.
A SURPRISE CAME WHEN WE TRIED TO
ASK, WHAT WOULD RESCUE THIS
DEATH?
WE FOUND THE ONLY THINGINOSIS
RESCUE THE CELL DEATH WAS THE
CARBON BACKBONE OF GLUTAMINE.
WE DIDN'T NEED ANY OF THE
NITROGEN TO SURVIVE THE REST.
WE DID NEED SOME OF IT TO
INITIATE FULL PROLIFERATION BUT
NO CELL DIED IF WE JUST ADDED
THIS.
AND THAT WAS A PUZZEL AND MADE
US WANT TO DIG DEEPER.
NOW, WHAT WE LEARNED FROM THOSE
STUDIES IS THAT IN FACT, FOR
ROBUST GROWTH, TO BE ABLE TO
FUEL THE CITRATE BIOSYNTHESIS I
TALKED ABOUT, AS CITRATE IS
EXPORTED, YOU DON'T ONLY EXPORT
THE CARBON EQUIVALENT THAT COME
FROM PIE RATE I TALKED ABOUT,
IT'S CONVERTED TO ASEAT ELKO
LACE, IT'S CONDENSED WITH AS
TIGHT PRODUCE CITRATE.
AND WHEN IT IS EXPORTED AND USED
FOR SYNTHESIS AND VARIOUS
SYNTHETIC REACTIONS DOWNSTREAM
OF THIS, YOU NEED A SOURCE OF
SOMETHING TO PRODUCE EXTRA MALL
AID TO THEN REENTER THE TCH
CYCLE AS A SUBSTRATE, SOMETHING
TO REPLENISH TO PRODUCE THE
ACETATE.
WE DISCOVERED THAT AN
EFFECTIVELY GROWING CANCER CELLS
TRANSFORMED, ALL THE SUBSTRATE
THAT MAINTAINED THE TCA CYCLE
ENTERS THIS DERIVED FROM -- FROM
GLUTAMINE.
SO THE RESCUE OF CELL SURVIVAL
WAS THE ABILITY OF THIS TO
BUILDUP A FULL CELL THAT
MAINTAINED THE INTEGRITY OF THE
TCA CYCLE.
THAT WAS A SUFFICIENT
EXPLANATION.
IN MYC TRANSFORMED CELLS, WE
FIND THAT THIS ALPHA GLUTE RATE
POOL, EQUALIB RIM WITH GLUTAMATE
TO EXCHANGE NITROGEN IS ABOUT A
HALF TO ONE MILL I MOLAR.
THAT'S UNIQUE.
WE NEVER SEE THESE LEVELS
COMBINED BUILD UP TO THOSE
LEVELS EXCEPT WHEN THE CELLS ARE
INSTRUCTED FROM THE ENVIRONMENT.
SO WE ASKED, WHAT IS SPECIAL
ABOUT HAVING THIS LEVEL OF THIS
AND THAT WILL BE RELEVANT TO THE
LAST 15 MINUTES OF MY TALK.
ONE THING THAT CAME OUT OF THAT,
PUBLISHED BY SIX GROUPS IN THE
LAST SIX MONTHS NOW, IS THAT
GLUTAMATE METABOLISM IS SPECIAL
WHEN THE CELLS WANT TO SURVIVE
HYPOXIA.
WHEN YOU WANT TO SURVIVE HYPOXIA
AND YOU WANT TO GENERATE A TP, I
THINK AS EVERYONE KNOWS, YOU
ENGAGE IN METABOLISM THAT I
SHOWED YOU IN THE FIRST SLIDE.
THAT MEANS NO SUBSTRATE TO
SUPPLY THE TCA CYCLE AND A
CARBON TO DO SYNTHETIC REACTIONS
TO BUILD GROWTH.
YET WHEN YOU CUT YOURSELF AND
YOU HAVE A WOUND, AND YOU NEED
TO GROW THE VASCATURE BACK OR
RECOVER THE INTEGRITY OF THAT
TISSUE, IN THE ABSENCE OF
MOLECULAR OXYGEN, YOU NEED SOME
WAY TO BUILD THE LIPIDS AND THE
NONESSENTIAL AMINO ACIDS UNDER
THOSE CONDITIONS OF HYPOXIA.
SO, WITH THAT KIND OF REASONING,
SIX LABORATORIES LITERALLY
SIMULTANEOUSLY ASKED, I WONDER
IF THE SIGNAL TRANSDUCTION
THROUGH GLUTAMINE COULD DO THAT.
AND WHAT WE AND TWO OTHER
LABORATORIES DESCRIBED EARLIER
IN THIS YEAR, WAS THAT IN FACT,
GLUTAMINE METABOLISM DOWNSTREAM
OF MYC COULD INFORM CELL GROWTH
UNDER HYPOXIA, GLUCOSE
METABOLISM PROVIDE ATP BUT
GLUTAMINE BY PROVIDING THIS
LARGE POOL OF ALPHA GLUTE 8 IN
THE TCA CYCLE SO YOU CAN'T MOVE
METABOLISM IN THIS DIRECTION,
THAT WOULD REQUIRE ELECT TRON
RECEPTOR AND OXYGEN TO DO
ELECTRON TRANSPORT T CAN NOW
WORK IN REVERSE AS THE TCA CYCLE
IS REPROGRAMMED.
DECARBOXYLATED.
THIS IS REDUCTIVE CAR BOXALATION
INTO CITRATE, WHICH IS CONVERTED
TO CITRATE AND EXPORTED TO
PROVIDE THE SAME SYNTHETIC FUEL
FOR ACETYLATION REACTIONS AND
LIPID BIOSYNTHESIS.
AND I CELL CAN GROW USING
GLUTAMINE AS A SUBSTRATE TO
PROTECT THE MITOCHONDRIA UNDER
HYPOXIA BY PRY VENTING REDOX
STRESS IN THE MITOCHONDRIA AND
PROVIDE SYNTHETIC FUEL FOR
GLUCOSE.
SO THIS POOL OF ALPHA GLUTEERATE
IN RESPONSE TO GLUTAMINE,
PROVIDES A SPECIAL ADAPTIVE
ABILITY TO CELLS THAT HAD
LESIONS THAT SCAV ANG GLUTAMINE
FROM THE ENVIRONMENT.
AND THAT IS EXTENDED NOW BY
SEVERAL LABS THIS HAD THE
COMPONENTS OF TRANSPORTERS THAT
CAPTURED GLUTAMINE, EITHER DNA
OR GBH AND ALT, ENTERED INTO A
PARTIAL CYCLE, WE FOUND THE
NADPH PRODUCED BY MALLIC ENZYMES
PRODUCING NADPH PROVIDING THE
ELECTRON FOR THE REACTIONS
REQUIRED FOR NUCLEOTIDE
BIOSYNTHESIS AND LIPID
BIOSYNTHESIS AND YOU COULD THROW
AWAY EXTRA CARBON THE CELL
DIDN'T NEED BY USING LDHA, A MYC
TARGET IN THE CYTOSOL.
WHAT WAS EXCITING ABOUT THIS FOR
US AND SHOWS HOW NERDY WE ARE,
IS THAT WHEN WE ADD UP CELL
GROWTH AS A PROBLEM, THE
LIMITING SUBSTRATE FOR US IS THE
LACK OF ANY KNOWN WAY TO PRODUCE
ENOUGH NEDPH TO ACTUALLY FUEL
CELL GROWTH.
YOU CAN NOT DO LIPID SINT SIS
AND CANNOT DO NUCLEOTIDE
SYNTHESIS WITHOUT A ROBUST POOL.
IF YOU GO AND ASK YOUR TEST
BOOK, NONE OF YOU KNOW ANY
SYNTHETIC PATHWAY TO PRODUCE
NADPH EXCEPT FOR A FEW WHO
REMEMBERED YOUR BIOCHEMISTRY
WELL ENOUGH BECAUSE THE GOT THE
HONORS.
THAT ENZYME IS G6PD WHICH IS THE
PENTOSE FOR OXIDATIVE ARM.
AND WE KNEW EARLY ON IN THESE
STUDIES THAT WASN'T THE POSSIBLE
ANSWER FOR NADPH DOES FOR GROWTH
BECAUSE THERE ARE 3 MILLION MEN
WALKING AROUND THE MEDITERRANEAN
THAT HAVE NONE OF THIS.
THEY GOT THROUGH EMBRYO GENESIS
WITHOUT THIS AND THEY HAVE BEEN
WELL STUDIED AND ALL OF THE
MEDITERRANEANS THEY HAVE
IDENTICAL RATES OF CANCER IN AGE
MATCHED CONTROLS.
SO G6PD IS NOT THE SUBSTRATE
THAT PRODUCES NADPH FOR GROWTH.
THERE WERE ONLY TWO REMAINING
CANDIDATES AND WE WERE EXCITED
ABOUT MALLIC ENZYME BECAUSE IT
CAN PRODUCE -- IN THIS PATHWAY
AND NADPH, PATRICK SHOWED THAT
MICK INDUCED MALLIC ENZYME COULD
PRODUCE NADPH BUT WHEN WE DID,
THAT WE DISCOVERED WE HAVE ONE
THING ABOUT THIS MODEL WRONG.
MALLIC ENZYME PRODUCED BY MYC IS
ACTUALLY IN THE -- MIGHT
QUANDARYIAL LOCALIZATION
SEQUENCE.
SO EVEN THOUGH IT WAS TRUE, THAT
MYC INDUCED NADPH PRODUCTION IT
WAS IN THE WRONG PLACE BECAUSE
YOU PRODUCE NADH AND NADPH IN
EITHER THE SITE SOLOR
MITOCHONDRIA AND THEY ARE
INDEPENDENT POOLS THAT DON'T
EXCHANGE.
NOW WE HAD A PROBLEM BECAUSE
ALTHOUGH THEY ARE WELL DESCRIBED
WAYS TO CONVERT NADH TO THE
MITOCHONDRIA AND BACK THERE WERE
NO KNOWN WAYS TO TRANSPORT NADPH
ACROSS THE MEMBRANE.
AND SO PATRICK WARD IN THE
LABORATORY A COUPLE EVER YEARS
AGO RECOGNIZED THERE WERE TWO
OTHER ADDITIONAL ENZYMES RELATED
TO THE TCI CYCLE ENZYME
HYDROGENASE I JUST TALKED ABOUT
THAT CONTROLS.
THEY ARE CALLED IDH1 AND 2.
AND THEY ARE NADPH DEPENDENT
ENZYMES AND THEY ARE RESPONSIBLE
FOR THE REDUCTIVE CAR BOXALATION
I JUST TALKED ABOUT.
IT'S ALSO RESPONSIBLE AT LEAST
IN THE DATA WE HAVE BEEN ABLE TO
DERIVE SO FAR, TO BE ABLE IN
THIS REDISTRICTIVE CAR
BOXALATION, EXPORT INTO THE
CYTOSOL AND THEN REVERSE
METABOLISM THROUGH ITS HOMOLOGUE
IDH1 IN THE CYTOSOL TO
REGENERATE TO TRANSFER ONE NADH
EQUIVALENT TO THE MITOCHONDRIA
TO THE SITE SOL.
SO PATRICK BUILDUP A
CONSIDERABLE AMOUNT OF DATA THAT
A MYC TRANSFORMED CELL, THE WAY
THEY DEAL WITH THEIR PROBLEM IS
TO PRODUCE IN THE MITOCHONDRIA
AND EXPORT THROUGH THIS
SHUTTLING PATHWAY.
IT IS -- IN SUPPORT OF THAT
ARGUMENT, HE WAS ABLE TO SHOW IF
YOU ELIMINATE EITHER IDH1 OR 2
BY RNAI, FROM TUMOR CELLS, THEY
DON'T DIE BUT THEY LOSE THEIR
ABILITY TO PROLIFERATE IN TISSUE
CULTURE COMPARED TO THE
UNMANIPULATED CELLS.
SO WE WERE INCREDIBLY EXCITED TO
SAY THIS IS A REALLY COOL THING.
THIS SAY NEW PATHWAY OF
METABOLISM IN WHICH WE EQUALIZE
ELECTRON AWAY FROM THE
COMPARTMENT WHERE THEY ARE USED
TO FUEL OXIDATIVE
PHOSPHORYLATION.
WE TRANSFER THEM BACK TO THE
MITOCHONDRIA TO FUEL IN
SYNTHETIC REACTIONS WHEN THE
FOLLOWING DISCOVERY WAS MADE BY
BURT VOGELSTEIN AND HIS
COLLEAGUES AT HOPKINS.
IT'S BEEN EXTENDED BY MANY
GROUPS.
THIS SLIDE IS NOT UP-TO-DATE.
BURT WAS ABLE TO DISCOVER IN
SECONDIARY GLIOBLASTOMAS THE
LESION OF ISOCITRATE
DEHYDROGENASE.
SHALLY EVERY GLIOBLASTOMA THAT
ARISES IN A BED OF INDOLENT
GLIOMA.
INITIATE WITH A LESION IN EITHER
THE CYTOSOL, A FORM OF IDH1 OR
THE MITOCHONDRIAL FORM.
IT'S OVERNIGHTY% OF ALL
GLIOMAS -- 90% -- HAVE MUTATIONS
AND THEY APPEAR TO BE THE
INITIATOR GENE.
SUBSEQUENTLY IT'S BEEN SHOW THAT
60% OF SARCOMAS HAVE THIS AS A
INITIATING LESION.
30% OF ADULT AMLs AND A LARGE
PERCENTAGE, OVER HALF OF
CARCINOMAS HAVE IDH1 OR IDH
MUTATIONS.
THAT DIDN'T FIT OUR DATA.
BECAUSE WHEN BURT CHARACTERIZED
THEM, THESE ENZYMES HAD LOST
THEIR ABILITY TO CONVERT
ISOCITRATE.
AND I HAD JUST ARGUED THAT THAT
ABILITY WAS REQUIRED FOR THE
SHADOWING OF NADPH EQUIVALENT TO
PROVIDE THE ENERGY SUBSTRATES
FOR CELL GROWTH.
BUT, THERE WAS SOME HOPE FOR
WHAT WE WERE THINKING AND WHAT
THEY WERE THINKING BECAUSE WHAT
THEY HAD NOTICE SAID THAT ALL
MUTATIONS WERE MISS SETS AND
THAT ALL THE MISS SET MUTATIONS
OCCURRED IN A SINGLE ARGININE
IDH1 AND IT'S IDENTICAL ARGININE
IN THE REACTION CENTER ON IGH2.
AND IN EVERY CASE, ONE IDH1
ALLELE OR ONE IDH2 ALLELE IS
ALWAYS MAINTAINED WILDTYPE.
SO THERE IS ALSO WILDTYPE
ACTIVITIES IN THE OTHER
HOMOLOGUE.
AND SO, WE JUST LOOKED AT THAT
REACTION FOR US TO PLAIN WHAT
THEY WERE FINDING BY RECURRENT
NATURALLY REOCCURRING HUMAN
MUTATIONS IN 4 MAJOR
MALIGNANCIES.
AND THAT IS, THIS IS THE
REACTION BY THESE AMINO RAGS
UNITED STATES THAT LINE THE
SUBSTRATE BINDING SIGHT OF
ISOSIT STRAIGHT AND HOW IT IS
COORDINATED BY A BOND WITH THE
ENZYME IN THE IDH TUMOR.
WHAT YOU CAN SEE IS THIS BLUE
CARBON, WHICH WAS LABELED HERE,
BECAUSE IT'S THE CO2 THAT LEADS.
ITS ABILITY TO BE BOUND INTO THE
SITE IS COORDINATED BY THE
ARGININE 132 AND IDH1 AND
ARGININE 172 AND IDH2 AND THESE
WERE THE MUTATIONS AND THE ONLY
MUTATION THAT IS BURT'S LAB WAS
ABLE TO FIND IN GLIOMAS.
THAT MAKES SEN IF YOU CAN'T
COORDINATE THE THING THAT YOU'RE
GOING TO BREAK OFF OF THIS
MOLECULE, YOU CAN'T BIND
ISOCITRATE VERY EFFECTIVELY.
BUT IT'S INTERESTING BECAUSE THE
PRODUCT OF THE REACTION, THE
NORMAL FOREREACTION SHOULD BIND
WITH THE WILDTYPE AFFINITY
BECAUSE IT DOESN'T HAVE THIS.
SO ARMED WITH THAT INFORMATION,
JOSH ROBIN WITS TRANSFORMED
NORMAL CELLS WITH AN IDH1 MUTANT
AND ASKED IS THERE ANY MEW
METABOLITES PRODUCED?
AND WHAT HE DISCOVERED IS THE
NEW METABOLITE BASED ON THE
METABOLOMICS ANALYSIS AND READS
IN THE FOLLOWING LIGHT.
IT MAKES PERFECT SENSE.
THE METABOLITE IS HYDROXY GLUTE
EXPIRATE IT WORKS BECAUSE IT CAN
BIND TO THE REACTION POCKET WITH
WILDTYPE AFFINITY BECAUSE IT IS
NOT DEPENDENT ON ARGININE FOR
FINDING.
BUT IT IS DEPENDENT ON THE
ARGININE THAT'S BEEN LOSS FOR
THE ABILITY TO ENGAGE REVERSE
CAR BOXALATION.
WITHOUT THE ARGININE TO
COORDINATE THE READDITION OF
CO2, THAT PART OF THE REVERSION
REACTION CAN'T OCCUR BUT CAN
STILL ACCEPT REACTION, ELEC TONS
FROM NADPH EXCEPT THE PRODUCT IS
A HYDROXYLASE OF THE BETA
CARBON.
SO YOU PRODUCE TWO HYDROXY GLUTE
RATES INSTEAD OF ISOSIT A
LITTLE.
NOW WHAT IS GOING ON BY A -- SO
YOU LOOK AT TUMORS THAT HAVE
MUTATIONS IN ID.
AND YOU WHAT FIND IS THAT THOSE
TUMORS WHEN ISOLATED, THIS IS
JUST DATASETS WE DERIVED FROM
AML PATIENTS, WILDTYPE TUMORS
THAT HAVE WILDTYPE IDH THAT ARE
AML, HAVE EITHER NO DETECTIVE
IDH OR THIS IS THE LEVEL OF THE
DETECTION OF THE GC MASS SPEC N
CONTRAST, THESE MUTATIONS ALSO
SEEN IN THE LEUKEMIAS, IDH132
AND IDH2R172.
THIS SAY LOG SCALE.
BUILDUP 10 MILLION MOLAR
INTERSELL LA CONCENTRATIONS.
THAT MAKES IT THE MOST COMMON
METABOLITE INSIDE THE CELL.
WE SCREENED ALL LEUKEMIAS FOR
TWO.
HG FOUND ANOTHER HAD HIGH 2HG
AND THEY HAD A MUTATION IN IDH
TWO.
BUT IN A DIFFERENT 140 AND THAT
SEALED THE DEAL BECAUSE 140 IS
THE OTHER AMINO ACID IN THE
REACTION SITE THAT COORDINATES
THAT CO2.
SO WHAT THAT SAYS, WHAT IS SHOWN
BITE INVESTIGATORS, IS THAT THE
PREFERENTIAL OPERATIVE IN THED
CELL IS A HIT ROW DIMER OF THE
MUTANT ENZYME.
THE WILDTYPE PARTNER CONVERTS
ISOCITRATE IN THE PRESENCE OF
NADP AS AN ELECTRONIC RECEPTOR
AND CO2 WITH NADPH.
THE CONCENTRATION OF NADP.
AND GLUTEERATE AT THIS REACTION
SITE DRIVERS THE PRODUCTION OF
THE REVERSE PRODUCT AT THE
MUTANT.
SO THIS IS A HETERODIME THEY'RE
IS NATURALLY OCCURRING AS A
RESULT OF THIS MUTATION AT THE
ACTIVITY THAT CONVERTS
ISOCITRATE TO HG AND THIS IS A
WAY TO DO THAT.
THE CELL SLOWLY BUT SUREY BUILDS
UP A LETTER THAT CAN BE MEASURED
IN MILLI MOLAR OF 2HG.
SO THAT BECAME INTERESTING
BECAUSE THIS IS ISN'T A GENETIC
LESION BUILDING UP.
IT'S A METABOLITE.
SO THE QUESTION IS, HOW DOES A
METABOLITE INFLUENCE ANYTHING
THAT HAS TO DO WITH CELL
BIOLOGY?
SO WE TOOK ADVANTAGE OF THE FACT
THAT IN LEUKEMIA, WE WERE
SURPRISED TO FIND A MUTATION
THAT HAD A PENETRANTS OF 30% IN
OUR PATIENTS BECAUSE IT MADE NO
SENSE.
WE THOUGHT WE KNEW EVERY
LEUKEMIC MUTATION THAT EXISTED.
AND WE ASKED BECAUSE WE KNEW SO
MUCH ABOUT IT, WERE THERE ANY
GENES THAT WERE ALWAYS MUTATED
OR WERE THERE GENES THAT WERE
FOR MUTATED TO SUGGEST THEY
EITHER DEPENDED ON EACH OTHER
FOR FUNCTIONALITY OR EP STATIC
TO EACH SOME OTHER.
>> THERE WAS ONE GENE THAT WAS
EP STATIC WITH IDH1 AND 2.
WHEN YOU LOOK FOR PATIENTS, THIS
IS JUST A CONNECTION GRAPH OF
PATIENT AND TUMORS WITH MORE
THAN ONE MUTATION.
THESE ARE ALL THE TUMORS IN IDH1
OR 2 MUTATIONS.
THEY COULD HAVE MUTATIONS IN ANY
OTHER KNOWN ONCOGENE THAT CAUSED
LEUKEMIA EXCEPT ONE AND THAT WAS
TET2 AND IN REVERSE, PATIENTS IN
HAD TET TWO MUTATIONS COULD HAVE
BLUEITATIONS IN ANY OTHER KNOWN
ONCOGENES EXCEPT FOR IDH1 OR 2.
HIGHLY STATISTICALLY SIGNIFICANT
AND REPLICATED THROUGH MULTIPLE
DATABASES.
AND THAT GAVE US AT LEAST THE
CLUE FOR WHAT HAS BEEN THE
INITIATION OF THIS SECOND
CONNECTION OF METABOLISM
EPIGENETICS.
THAT WAS THE REALIZATION THAT
TET 2 IS AN EN SOMETIME CAN
INITIATE THE CPG ISLANDS BECAUSE
TET 2 TAKES THE SUBSTRATE AND
STRIPS THE ELEC TONS OUT OF IT,
AND CHANCES OF THE ELECTRON AND
HYDROXIC -- THAT INITIATE
ULTIMATELY THEIR ACTIVELY PASSER
LIVE METHYLATION AND 2 HYDROXY
GLUTE RAISE BECAUSE IT'S A
HOMOLOGUE OF ALPHA -- IT WOULD
BLOCK THIS REACTION.
SO WE WENT TO TO THEFTIAD.
WE ADOPTED AN ASSAY AND
TRANSFECTED TET 2.
YOU CAN SEE THE CELLS HAVE A
FLAG TAG THAT OUR TET 2
TRANSFECTED AND THOSE CELLS
ACQUIRE A HUGE HYDROXYLASE MARKS
IN DNA AS THE EXOGENOUS
PRODUCTION OF TET 2 AND IF YOU
COTRANSFECT IN THE MUTANT IDH1,
YOU COMPLETELY BLOCK THE ABILITY
OF TET 2 TO PRODUCE HIGH DOCKS
LATED DNA.
YOU CAN SEE THAT'S A ONE LOG
EFFECT IF YOU DO IT BY ANALYSIS.
WE WENT ON TO SORT OF SAY THAT,
THIS IS SOMETHING I DON'T HAVE
TIME TO SHOW YOU THE DATA FOR.
WE NOW BELIEVE THAT THAT BURST
THAT COMES ON THE SCREEN OF MYC
THAT PRODUCE THIS IS POOL OF
ALPHA GLUTERAISE IS ABSOLUTELY
ESSENTIAL AS THE COFACTOR THAT
ALLOWS DEMETH LACES OF BOTH DNA
AND HISTONES TO ACTIVATE THE
RETURN OF SILENCE CHROMATIN FROM
AN INACTIVE STITE AN ACTIVE
STATE.
AND ON THAT BASIS, IF YOU CAN'T
REACTIVATE GENES THAT ARE
SILENCED TO ALLOW CELLS TO
ENGAGE IN DIFFERENTIATION
PROGRAM, THERE ARE STUCK IN
THEIR CURRENT OR STEM CELL-LIKE
STATE.
AND 2 HYDROXY GLUTE RAISE BY
ACTING AS AN ANTAGONIST,
PREVENTS THE CELL FROM UTILIZING UTILIZING
THAT BURST OF ENERGY TO INITIATE
THE METHYLATION OF SILENCED CARB
NAS.
SO TO PROVE THAT, WE
DEMONSTRATED THAT WHEN YOU
EITHER TRANSFECT IN MUTANT IDH
OR YOU DELETE TET TWO BY SHRNA,
YOU GET PERSISTENCE IN CELL
CULTURE OF C TET POSITIVE STEM
CELLS AND THEY LOSE THEIR
ABILITIES TOW DIFFERENTIATE AND
THAT FITS THE MODEL.
IT LOST THE ABILITY TO
DIFFERENCY 8 AND THE LOSS OF TET
2 TO THE INITIATE OF THE OPENING
OF CHROMATIN, OR 2HG TO
COMPETITIVELY ALPHA GLUTEERATE
TO BE USED IN THE SUBSTRATE.
BLOCKS CELLULAR DIFFERENTIATION
AND THEREFORE INITIATE THE BLOCK
OF THE DIFFERENTIATION THAT
CONTRIBUTES TO AML PATHOGENESIS.
THE QUESTION IS, WHAT ABOUT
GLIOMAS?
THE SAME TIME WE WERE DOING THIS
WORK, WE ALSO LOOKING AT
GLIOMAS.
WE DIDN'T SEE ANY TET MUTATIONS.
WE REALIZED THAT THERE IS A
DIFFERENT SET OF METHYLATION,
THAT DEPEND ON THIS GLUTERAISE
BURST OF MYC FOR DEMETHYLATION
AND THAT IS THE HISTONE
REPRESSIVE MARKS ON H3K9 AND
H3K27 REQUIRED TO MAINTAIN
SILENCED CHROMATIN ALONG WITH
METHYLATED CPG.
WE WERE ABLE TO DEMONSTRATE OR
OTHERS DEMONSTRATED THE CLASS
EVER ENZYMES THAT DO THOSE
DEMETHYLATION REACTIONS OF THE
REPRESSIVE MARKS ARE THE HISTONE
LYSATES DEMETH LACES AND THEY
DEPEND ON THE SAME ENZYMES
KINETICS BEING CONVERTED AND WE
WERE ABLE TO DEMONSTRATE IF YOU
TAKE THE H3K9 DEMETH LAYS KDM4C,
YOU HAD ALPHA 2HG SHOWN HERE AND
YOU TAKE HISTONES THAT ARE
HEAVILY MODIFIED ON H3K9 AND
NATURALLY OCCURRING.
YOU ADD THEM TO CULTURE AT THE
ENZYME AND THE PRESENCE OF ONE
MILL MOLAR, YOU COMPLETE DEMETH
LAYS THEM.
ADD TWO HG AND COMPLETELY BLOCK
THAT DEMETHYLATION BUT IT'S
COMPETITIVE AS WE DOSE UP ALPHA
T GLUTEERATE, YOU REVERSE THE
ABILITY OF TWO HG TO CONVERT.
IF YOU BUILD THAT INTO
SPONTANEOUS HUMAN GLIOMAS, YOU
FIND H3K9 IS HIGHLY METHYLATED
ASSOCIATED WITH -- THIS IS JUST
THE CHEMISTRY TO DEMONSTRATE
THAT.
HIGH H3 METHYLATION AND THAT IS
HIGHLY STATISTICALLY SIGNIFICANT
IN MUTANT TUMORS AND WHEN WE
TAKE AN ASTROCYTE, PRIMARY CELL
SHRINE INTRODUCE THE MUTANT, WE
SEE HISTONE METHYLATION AND THAT
SUBSEQUENTLY FOLLOWS SEVERAL
GENERATIONS BY DNA
DEMETHYLATION.
IT'S NOT AFFECTING.
IT SEEMS TO BE COOPERATING THE
INABILITY OF DIMETHYLATED
HISTONES AND DNA.
AND BESIDES THAT INDEPENDENTLY
OF OUR WORK, THE GROUP AT UCS
THAT WORKS ON EPIGENETICS WAS
LOOKING AT GLIOMAS AND ASKING
FOR GLIOBLASTOMAS
ACROSS-THE-BOARD, CAN WE DEFINE
SUBGROUP SPACE?
RED IS HEAVILY METHYLATED.
YOU CAN SEE THERE IS A GROUP ON
THIS SIDE THAT IS HEAVILY
METHYLATED BY THEIR ANALYSIS
COMPARED TO ALL OTHER GLIOBAST
OHMS AND WHEN YOU ASK WHY GENE
EXPRESSION PHENOTYPE THOSE ARE
THE PRO NEUROTUMORS EXCLUSIVELY.
THE ONES STUCK AT THE TRUE STEM
CELL STATE OF
GLIOBLASTOMATHEYAREHIGHLY
HYPERME
THYLATEDANDWHENYOUADDTHEEXTRA
GEN
OTYPE,YOUFINDOUGHTTHE SO THIS
COMPLETELY BLOCKS THE ABILITY TO
ACCESS THE GENES BY
DEMETHYLATION.
SO WE ARE STUCK WITH A MODEL,
HISTONE AND DNA METHYLATION
ACQUIRES METHYLATION THROUGH THE
SUBSTRATE TO BE A SUBSTRATE FOR
THE SPECIFIC ENZYME THAT
DEMETHALATES SEATS ACTIVATE
REPRESSED CHROMATIN TO ALLOW
CELLS TO FUNCTION.
WHEN THAT'S BLOCKED BY
GLUTEERATE AS A GLOBAL
INHIBITOR, THE CELL IS STUCK.
SO AT THAT POINT, WE ARE
THINKING THIS IS VERY
INFORMATIVE IN TERMS OF A
BALANCED EPIGENETICS IS REALLY
CREATING THROUGH METABOLISM TO
INSTRUCTION INSTRUCT WHAT PART
AND HOW MUCH OF THE GENOME
SHOULD WE ACCESS BASED ON THE
NUTRIENTS THE HOST IS MAKING
AVAILABLE TO THE CELL TYPE AND
MUTATIONS IN THAT WILL PATHWAY
BY ONCOMETABOLITES AND SIGNAL
TRANSDUCTION GENES OR
METABOLISM.
THAT'S ALL I HAVE TO SAY.
I APOLOGIZE FOR GOING A COUPLE
OF MINUTES OVER BUT I'M HAPPEN
TO TAKE A COUPLE OF QUESTIONS
AND I REALLY APPRECIATE YOUR
ATTENTION.
I WAS GOING TO SHOW YOU, IF YOU
DO THIS, YOU BLOCK NEURAL
DIFFERENTIATION.
I JUST WANT TO SHOW THAT AS I
FINAL POINT.
IF YOU TAKE WHAT HAS BEEN
PUBLISHED, IF YOU TAKE PRIMARY
CELLS, INTRODUCE AN MUTATION AND
ASK NEUROSPHERES TO
DIFFERENTIATE PRIMARY CELLS LUIS
THEIR ABILITY TO DIFFERENTIATE
WHICH IS WHAT THAT MOUSE DOES.
OVER EXPRESSION OF WILDTYPE HAS
NO EFFECT ON THAT AT ALL.
SO THIS SEEMS TO BE A CRITICAL
CONNECTION BETWEEN THE
METABOLISM AND THE ABILITY OF
CELLS TO ENGAGE IN NEW PROGRAMS
BY ACCESS OF NEW DNA THROUGH
METHYLATION.
SO THAT, THANK YOU AND I'M
HAPPEN TO TAKE QUESTIONS.
[ APPLAUSE ]
SOMEBODY HAS TO BE BRAVE TO BE
THE FIRST ONE.
[ OFF MIC ]
>> TALKING ABOUT WAY TO BLOCK
-- [ INDISCERNIBLE ] IT'S
ANOWING -- [ INDISCERNIBLE ]
>> SO, THE SURPRISE IS, WHICH
DOESN'T REALLY ANSWER THE
QUESTION, CAN DOE USE THIS KIND
OF INFORMATION TO DO SOMETHING
WITH STEM CELLS, THAT'S THE
QUESTION.
THE ONLY THING WE CAN DO TO GET
CELLS TO REALLY SHOW US THEIR
TRUE CORE PHENOTYPE IN A STATE
IN WHICH THEY WILL NEVER
DIFFERENTIATE IS IF WE STARVE
THEM FOR THE TWO NUTRIENTS I
JUST TOLD YOU ABOUT.
IF WE STARVE CELLS FOR GLUE
COATS AND GLUTAMINE, IF THEY
DON'T COMMIT SUICIDE, THEY
RESTRICT TO MAINTAINING PURE
PHENOTYPE AND EVEN THOUGH WE
KNOW THEY ARE CAPABLE OF
DIFFERENTIATION, WEEP CAN'T ADD
A GROWTH FACTOR TO MAKE THEM DO
IT.
THE ABSENCE OF METABOLISM, WE
CANNOT FORCE THEMSELVES TO
DIFFERENTIATE.
DOES THE CELL NEEDS TO BE TOLD
THROUGH THE MEDICAL PATHWAYS
IT'S TIMING AND HAVE YOU THE
RESOURCES TO TAKE LEAP OF FAITH
TO BE SOMETHING ELSE AND WE HAVE
NEVER DONE UNDER A LOW ENERGY
CONDITION.
SO THE PROBLEM IS STARVING A
CELL ISN'T A VERY GOOD WAY TO
MAINTAIN OR GET MORE STEM CELLS.
SO IT'S NOT -- IT WAS -- WE
LIKED THE JUDGED BUT IT DIDN'T
WORK --
WE LIKED THE IDEA -- WE DO THINK
THAT WHAT REALLY THIS IS SAYING,
AND I DIDN'T HAVE TIME TO TALK
ABOUT IT, IF YOU LOOK AT ANOTHER
PART WHAT HAVE PETER JUST
PUBLISHED, THERE IS ANOTHER
GROUP OF CELLS STUCK IN THE STEM
CELL STATE.
THEY HAVEN'T BEEN TALKED A LOT
ABOUT.
THEY ARE COMPLETELY
HYPOMETHYLATED AT THE DNA AND
HISTONE.
I THINK THAT REALLY MEANS, AND
WHAT WE ARE TRYING TO PUSH AS AN
IDEA TO THINK ABOUT, IS THAT IF
YOU'RE STUCK WITH ALL OF YOUR
GENES EXCEPT THE CORE GENES THAT
MAINTAIN AND YOU WHAT YOU ARE
STUCK IN A HETEROCHROMATIN
STATE, YOU'RE STUCK IN THE
DIFFERENTIATION YOU HAVE.
IF ON THE OPPOSITE SIDE,
EVERYTHING IS OPEN, STEM CELL
MAINTENANCE GENES SEEM TO
DOMINATE AND THE CELL CAN'T
DIFFERENCE ACE, LIKE EVERYTHING
ELSE THERE IS A COUPLE OF
BARRIERS.
IT'S NOT SURPRISING GIVEN CELL
BIOLOGY.
YOU HAVE TO SILENCE JEANS THAT
MAINTAIN.
BUT AT THE SAME TIME YOU HAVE TO
GAIN ACCESS TO THE GENES THAT
ALLOW YOU TO BE THE NEXT CELL IN
THE LINEAGE.
IT'S THIS DYSREGULATION OF THAT
IF YOU TAKE THAT MODEL, YOU CAN
SEE THAT ALMOST EVERY CANCER
TYPE HAS DYSREGULATION OF ONE
DIRECTION OR ANOTHER.
>> [ INDISCERNIBLE ]
BECAUSE THESE PATHWAYS ARE SO
FUNDAMENTAL, DOES THAT POSE A
PROBLEM FOR ONCOLOGIST FOR
THERAPEUTIC INTERVENTIONS
BECAUSE YOU RISK DISRUPTING
THINGS THAT ARE LOCKED IN THE
CELLS IN THE BODY?
>> THERE IS A LOT OF LONG
ANSWERS TO THAT.
IT'S REALLY IMPORTANT.
CORE METABOLISM IS CORE
METABOLISM.
ALL CELLULAR ORGANISMS, WE HAVE
A CORE METABOLISM.
SO YOU MIGHT KILL THE CANCER
CELL BUT YOU'LL KILL A LOT OF
NORMAL CELLS AT THE SAME TIME
AND MORE TOXICITY.
THE FIRST ANSWER WE HAVE FOR
THAT THAT WE PUBLISHED IN
MULTIPLE FORMS IS IF YOU GO BACK
AND ASK HOW DO TRADITIONAL CHEMO
THERAPEUTICS CURE YOU OR AS
INTERVENTION, ALMOST ALL OF THEM
ARE INTERVENING IN THAT
METABOLIC PATHWAYS.
SO ANTIMETABOLITES,
METHOTREXATE.
WE SHOWED THAT TRADITIONAL
ALKALOIDS AND GLYCOLYTIC
METABOLISM CONSUME ALL THE ***.
WE DO THINK THAT OUR SUCCESS IN
CANCER CHEMOTHERAPY HAS NOT BEEN
REALIZED AS MOSTLY METABOLIC
STRATEGY.
IF TUMOR CELLS ONCE ADDICTED
THROUGH ACTIVATION OF SIGNALING
PATHWAYS COULD REPROGRAM THEIR
METABOLISM TO BE ADDICTED TO
METABOLITES, ARE FUNDAMENTALLY
DIFFERENT THAN NORMAL CELLS THAT
WHEN THEY LUIS GLUCOSE AND DON'T
HAVE A DRIVING MUTATION THROUGH
THE PATHWAY, SAY THERE IS NO
MORE GLUCOSE RIGHT NOW, BUT I
CAN METABOLIZE FATTY ACIDS.
WHEN AKT IS ON, IT SAYS YOU
DON'T GET TO DO THAT.
SO YOUR SURVIVAL STRATEGY
DOESN'T WORK HERE.
WE WENT ON TO DESCRIBE A WHOLE
TUMOR SUPPRESSOR NETWORK NEEDED
FOR REACTIONIVATION OF
OXIDATION.
SO YOU CAN DO, STUPID
EXPERIMENTS WHICH IS WHAT WE DO.
YOU TAKE OUT A SINGLE METABOLITE
AND ASK HOW DOES A TUMOR CELL
ADAPT.
THAT'S HOW WE CATEGORIZE.
HALF OF TUMOR SUPPRESSORS MODEL
OR BEING ABLE TO ACCOMMODATE
GLUTAMINE WITHDRAWAL OR GLUCOSE
WITHDRAWAL.
NORMAL CELLS ACTIVATE THOSE
IMMEDIATELY AND ONCOGENIC
LESIONS PREVENT THE PATHWAYS OR
THE LOSS OF THOSE GENES AS
SENSORS LOSE THAT PATHWAY.
SO I THINK WE'LL BE ABLE TO
EXPLOIT IT.
THAT GETS TO THE FINAL THING AND
MAYBE THIS SHOULD BE THE FINAL
THING.
I THINK THERE IS A FUNDAMENTAL
DIVIDE WE HAVE IN ONCOLOGY.
WE ARE VERY IMPRESSED WE SHOULD
ALL BE, WE DISCOVERED ONCOGENIC
DRIVER MUTATIONS IN MANY HUMAN
GENES AND WE DEVELOPED THE
ABILITY TO DEVELOP INHIBITORS OF
THOSE DRIVER MUTATIONS THAT WILL
TURN THOSE GENES OFF.
BUT THE REAL FEATURE IS, WE HAVE
TREMENDOUS SUCCESS BUT MOST OF
THE TIME TURNING THEM OFF HASN'T
REALLY HELPED THE PATIENTS.
IT HASN'T CURED MANY PEOPLE
BECAUSE CANCER HAS THINGS ON GET
AROUND THE INHIBITION OF DRIVING
ONCOGENES AND IT'S HARD TO
COMPLETELY INHIBIT AN ACTIVATED
ONCOGENE.
IN CONTRAST, ALL THE THERAPIES
THAT CURE PATIENTS HAVE LEFT THE
ONCOGENES IN PLACE.
ALLOW THEM TO FORCE THE CELL
INTO DOING SOMETHING THAT A
NORMAL CELL EQUIVALENT MIGHT NOT
DO UNDER THOSE CONDITIONS AND
MAKE THAT CONDITION HARMFUL FOR
THE CELL.
THE ATTEMPT TO TRY AND DIVIDE
WHEN THERE ARE NO NUCLEOTIDES IS
A REALLY BAD IDEA.
AND SO, THAT IS THE BASE OF MOST
ANTIMETABOLITE THERAPIES.
AND SO, THAT'S THE BASE OF
METHOTREXATE.
SO I THINK WE FORGOTTEN THAT
APPROACH AND WE THINK METABOLISM
WILL REACTIVATE THAT APPROACH.
THE UNDERSTANDING THAT CANCER
PATHWAYS, ALTHOUGH DO ALL THE
OTHER THINGS.
I'M NOT TRYING TO NEGATE THE
IMPORTANCE OF THE SIGNAL
TRANSDUCTION PATHWAYS AND GENES
NECESSARILY TO ORDER YOU THROUGH
THE CELL CYCLE BUT THERE HAS TO
BE FUEL TO DO THAT.
IF YOU ASK A SELL TO GO THROUGH
A CELL DIVISION AND YOU SWEEP
OUT A FUEL FROM IT, IT IS IN A
LOT MORE TROUBLE THAN A CELL
HANGING OUT THERE SAYING I
OCCUPY SPACE AND KEEP ALIVE T
HAS A LOT MORE ADAPTIVE
MECHANISMS.
I THINK THERE ARE GOING TO BE
WAYS TO EXPLOIT BUT NOT BY
ELIMINATING THE ONCOGENES.
BUT LEAVING THIS IN AND CHANGE
METABOLIC CONDITIONS.
THAT'S THE APPROACH WE ARE
EXING.
THANK YOU VERY MUCH FOR YOUR ALL
YOUR TIME AND ATTENTION.
AND THANK YOU.
[ APPLAUSE ]
>> WE HAVE A RECEPTION, WHICH IS
SPONSORED BY THE FAES IN THE
LIBRARY AND AN OPPORTUNITY TO
ASK DR. THOMPSON REALLY BURNING
QUESTIONS YOU HAVE.
THANK YOU.