TRACO 2019 – K-RAS and Epidemiology
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TRACO 2019 – K-RAS and Epidemiology


THE FIRST SPEAKER IS JI LUO AND GOT HIS UNDERGRADUATE DEGREE AT THE UNIVERSITY OF CAMBRIDGE, ENGLAND AND CAME TO THE U.S. AND WAS AT HARVARD AND DID A POST-DOCTORAL FELLOWSHIP AT HARVARD AND WE WERE SMART ENOUGH TO HIRE HIM AT NCI. HE’LL TALK ABOUT THE K-RAS ONCOGENE. THANK YOU FOR THE NICE INTRODUCTION. I’LL TELL YOU ABOUT THE K-RAS ONCOGENE WHICH IS WHAT MY LAB IS FOCUSSED ON. I’LL SHOW SOME DATA FROM A RECENT PAPER TOWARDS THE SECOND HALF OF THE TALK AND TALKING ABOUT THE PROMINENT ONCOGENE. MY LAB IS FOCUS ON THE SAME MECHANISM OF K-RAS GENESIS AND RECOGNIZING BETTER STRATEGIES AGAINST THE TUMORS. AS THE THREE MEMBERS OF THE RAS FAMILY, K-RAS, N-RAS AND THEY ACCOUNT FOR 10% OF ALL CANCERS. IN PARTICULAR, PANCREATIC AND AND COLON CANCER AND THE LARGE AMOUNT ARE IN THE K-RAS WHICH IS WHAT MY LAB’S RESEARCH IS FOCUSSED ON. CLINICALLY RAS MUTATION IS A MAJOR CHALLENGE. THERE’S OVER 200,000 PATIENTS THAT WOULD HAVE A RAS MUTANT TUMORS BEING DIAGNOSED EVERY YEAR AND CURRENTLY WE HAVE NO EFFECTIVE TARGETED THERAPIES NOR MATH AUTHORITY PATIENTS. THIS IS A SIGNIFCANT CLINICAL PROBLEM AND THINK PART OF THE REASON WE DON’T HAVE EFFECTIVE TARGETED THERAPY IS WE DON’T HAVE A FULL UNDERSTANDING OF THE MECHANISM OF THE K-RAS AND THINK A DEEPER UNDERSTANDING HOW IT DRIVES ONCO-GENESIS TUMOR PROGRESSION AND DISSEMINATION COULD LEAD TO THE DEVELOPMENT OF FOUR EFFECTIVE THERAPIES IN THE FUTURE. SO THIS IS A BRIEF OUTLINE OF WHAT I’M GOING TO TALK ABOUT. I ALWAYS LIKE TO START WITH A HISTORIC PERSPECTIVE OF HOW THE RAS GENE WAS ORIGINALLY DISCOVERED. SCIENTISTS AT THE NCI AND THE CURRENT AND ACTING DIRECTOR HAD PLAYED AN INTEGRAL ROLE IN THE DISCOVERY OF THE ONCOGENE. AND WE LOOKED AT MUTANT RATS AND THE CURRENT THERAPIES WE HAVE FOR SIGNALLING AND THEN I’LL INTRODUCED THE CONCEPT OF AN ADDITIONAL TARGETED CANCER CELLS IN THE CONTEXT OF K-RAS MUTATION AND THEN I’LL TALK ABOUT OUR RECENT WORKS ON IDENTIFYING OPTIMAL DRUG TARGET COMBINATIONS IN THIS CONTEXT. SO THE RAS CRONKA GENE WAS — ONCOGENE WAS DISCOVERED AS DRIVING TUMOR FORMATION IN RATS AND MICE AND THIS PAPER IDENTIFIED MYSTERIOUS VIRUSES THAT CAN INDUCE TUMOR INJECTIONS WHENNIN JECTED INTO MICE AND RATS AND IT WAS KNOWN THEY WERE STUDIES AND HOW THEY DRIVE TUMOR FORMATION IN ANIMAL MODELS WAS UNCLEAR. THEN FAST FORWARD A DECADE LATER OR SO AND A NUMBER OF GROUPS INCLUDING A GROUP AT NIH FOUND THAT IN FACT THESE VIRUSES ENCODE PROTEINS. THEY KNOW IT COMBINES AND CAN GET PHOSPHORYLATED AND JUST THE PRESENTATION OF THIS PARTICULAR VIRAL PROTEINS APPEARS TO BE ASSOCIATED WITH THE TRANSFORMING ACTIVITY OF THE VIRUS OR MOLECULAR CLONING. IT HASN’T BEEN EASY. SO IT WAS INITIALLY CHARACTERIZED AS A PROTEIN SPECIES ENCODING THE ENVIRONMENT GENOME. THEN A FEW YEARS LATER THROUGH TRANSFORMATION STUDIES USING VIRAL AND HUMAN DNA A NUMBER OF PAPERS PRETTY MUCH AT THE SAME TIME REALIZED TWO THINGS. ONE THING IS THERE ARE SPECIFIC ELEMENTS IN DNA FROM HUMAN CANCER CELLS THAT CAN TRANSFORM A NORMAL CELL AND TURN IT USING THE FORMATION AND THE HUMAN CANCER CELLS THERE’S ELEMENTS THAT ARE HOMOLOGOUS TO THE VIRAL SEQUENCES. SO THE DNA THAT THE TUMOR VIRUSES ARE USING TO DRIVE TRANSFORMATION IS RELATED TO THE DNA IN HUMAN CANCER CELLS. THEN, JUST A YEAR LATER AGAIN MORE LABS WERE RACING TOWARDS THE DISCOVERY REALIZED IN FACT THE TRANSFORMING GENE ELEMENT IN THE HUMAN CANCER CELL REPRESENTS A MUTATIVE FORM OF THE GENE THAT ENCODE THE RAS PROTEIN AND THIS IS AN IMPORTANT RAS PROTEIN AND IN FACT THESE ARE ONCOGENIC MUTATIONS IN NORMAL GENES THAT HAVE TURNS A CELL CANCEROUS. AND THEN QUICKLY, A FEW YEARS LATER THROUGH TOUR DE FORCE EXPERIMENTS AND IT DEMONSTRATED THE PROTEIN IS ITSELF TRANSFORMING. IF YOU MICROINJECT MUTANT RAS PROTEINS INTO A CELL IS SUFFICIENT TO DRIVE TRANSFORMATION. IT WAS DIRECT EVIDENCE THE HUMAN GENE CAN BE MUTATED INTO AN ONCOGENIC FORM FOR A PROTEIN THAT DRIVES THE CHANGES IN THE PHENOTYPE OF THE CELL. AND THING A FEW YEARS LATER THERE WERE ADDITIONAL BIOCHEMICAL CHARACTERIZATION FROM THE VARIOUS LABS SHOWING INDEED THE HUMAN RAS PROTEIN APPEARS TO BE A PROTEIN THAT DRIVES THE HYDROLYSIS OF GDP TO GPD AND THE MOLECULAR MUTATION IN RAS PROTEIN APPEARS TO BE AN DEFI DEFICIENCY AND THE McCORMICK LAB AND OTHER LABS HAVE SHOWN THERE’S INDEED GDP ACTIVATING PROTEINS THAT SIMULATES THE HYDROLYSIS OF GDP BY RAS PROTEIN AND THE CIRCUIT IS BROKEN WITH THE MUTANT RAS. SO ALL THESE PIECES OF EVIDENCE SUGGEST A MECHANISM WHERE A PROTEIN WHERE IT CAN NORMALLY BE TURNED ON AND OFF THROUGH GDP CYCLES THROUGH A MUTATION IS NOW BROKEN AND STARTS PERHAPS IN THE ACTIVE STATE AND THIS IS HOW IT’S DRIVING ONCO-GENESIS. FROM THE SERIAL STUDIES WE LEARNED A LOT HOW THE RAS GENE FUNCTIONS AND THE MOLECULAR BIOLOGY OF THE RAS PROTEIN’S FUNCTION. AS I MENTIONED THERE’S THREE IN THE HUMAN GENOME THAT ENCODE THREE HIGHLY HOMOLOGOUS H, N AND K-RAS. AND THROUGH SPLICING, K-RAS CAN ENCODE TWO DIFFERENT PROTEINS, K-RAS 4A AND 4B THAT DIFFER IN THE STRUCTURES. AND THE VAST MAJORITY OF THE RAS PROTEIN IS HIGHLY HOMOLOGOUS AND CONSISTS OF A GTP BINDING DOMAIN. THERE ARE TWO STRETCHES OF SEQUENCE. SEQUENCE 1 AND 2 THEY USE TO TALK TO THE DOWNSTREAM EFFECTERS IN THE SIGNALLING NETWORK AND THE PROTEINS ARE MORE DIVERGENT AND IT CAN IN FACT LEAD TO A DIFFERENCE IN THEIR LOCALIZATION MECHANISM AND SUBTLE DIFFERENCES IN THEIR FUNCTION. SO JUST TO SUMMARIZE THE STUDIES OVER THE YEARS, RAS PROTEINS ARE SMALL GTPs AND THEY FUNCTION HAY SWITCH TO TRANSFUSE SIGNALS FROM EXTRA CELLULAR TO INSIDE THE CELL. AND TYPICALLY THEY’RE ACTIVATED BY KINASES BUT CAN BE MUTATE OTHER PROTEINS. UPON RECEPTOR ACTIVATION THROUGH THE EXCHANGE FACTORS THE GTP WHICH IS INACTIVE IS THEN CONVERTED TO A GTP BOUND FIRM THROUGH THE UNLOADING OF GDP AND LOADING OF GTP AND BINDING THROUGH GTP ALLOWS THE SWITCH ONE AND SWITCH TWO DOMAIN TO BIND TO A NUMBER OF DOWN STREAM SIGNALLING FACTORS I’LL COME TO IN A BIT AND CAN STIMULATE CELL ACCELERATION AND GROWTH. AND NORMALLY, SO-CALLED GAP PROTEINS, GTP ACTIVATING PROTEINS SIMULATE HYDROLYSIS ON RATS AND THIS ALLOWS RATS TO BE TURNED OFF. THIS IS AN ON-OFF SWITCH THAT RESPONDS TO THE ACTIVATION OF RECEPTORS THAT TELLS THE CELLS WHAT TO DO. AND TO PERFORM THE FUNCTIONS RAT PROTEINS FIRST NEED TO BE LOCALIZED TO THE PLASMA MEMBRANE WHERE THE RAS PROTEINS ARE PROLITICLY PROCESSED AND THE RAS BECOMES A MEMBRANE ASSOCIATED PROTEIN THROUGH THIS PROCESS ASSOCIATED TO THE MEMBRANE. IN THE CASE OF H-RAS AND K-RAS THERE’S TWO LIPID GROUPS ADDED. WHERE AS IN THE K-RAS 4B FORM THE PROCESS IS NOT UTILIZED BUT HAS A STRETCH OF POLYSINE IS ASSOCIATE WITH THE PROTEIN. AND A LARGE BODY OF LITERATURE ESTABLISHED IT CAN TALK TO DOWNSTREAM SIGNALLING PATHWAY THE CLASSIC KINASE PATHWAY WHICH DRIVES CELL PROLIVATION, ENTRY — PROLIFERATION AND TRANSCRIPTIONAL RESPONSE AND THE REGULATION OF CELL GROWN AND CELL METABOLISM AND OTHERS THAT REGULATE CYTOSKELETAL CHANGES AND TRANSCRIPTION. AND THE SIGNALLING PROCESSES TOGETHER FORM A SIGNALLING NETWORK THAT DRIVE THE VARIOUS PHENOTYPE OUTCOME NAME CELL PROLFERATION AND CELL GROWTH AND SURVIVAL. YOU CAN SOMETHING IF YOU MUTATE THE PROTEIN TO LEAVE IT IN THE UN STATE FROM THE ACTIVATION THE RAS SIGNALLING NETWORK IS NOW STUCK IN THE ON STATE AND THIS DRIVES MANY OF THE HALLMARKS OF CANCER SUCH AS CELL PROLIFERATION AND CELL SURVIVAL. BECAUSE RAS SUCH A SIGNALLING NEXUS, AS I MENTIONED, 10% OF ALL HUMAN CANCERS HAVE MUTATIONS IN ONE OF THE THREE RAS GENES PARTICULARLY K-RAS. IN ADDITION TO PANCREATIC AND COLORECTAL AND LUNG CARCINOMA, OTHERS ARE HIGH PERCENTAGES OF MUTATION IN THE RAS FAMILY. AND WHEN YOU LOOK AT WHAT RESIDUES OF RAS PROTEINS ARE MUTATE THE PATH IS STRIKING. THE LION’S SHARE OF RAS MUTATION OCCUR ON THREE AMINO ACID RESIDUES, G12, G13 AND Q61. THESE ARE THE CLASSIC HAD THE SPOT MUTATIONS THAT LEAD TO THE CHANGE IN THE FUNCTION. AND THE REASON YOU HAVE MUTATIONS THAT ARE CONCENTRATED ON THESE THREE RESIDUES IS APPARENT ONCE YOU UNDERSTAND AT THE MOLECULAR AND STRUCTURE LEVEL HOW IT ACTS. WE’RE SHOWING THE RAS BINDING POCKET AND THE GAP PROTEIN INSERTS AN FINGER INTO THE POCKET AND THIS IS CRITICAL IN STIMULATING THE GTP HYDROLYSIS OF RAS 1,000 FOLD AND THIS IS SIGNALLING IN A VERY TIGHT FASHION TO ALLOW IT TO RESPOND TO ACTIVATION OF RECEPTORS AND QUICKLY TURN OFF WHEN THE STIMULUS IS GONE. AND IF YOU LOOK AT ONE OF THE TYPICAL MUTATION WHERE YOU REPLACE THE GLYCINE WITH AN AMINO ACID, THIS GTP BINDING POCKET IS OCCLUDED AND THIS PREVENTS THE GAP PROTEINS FROM INSERTING ITSELF INTO THIS POCKET TO STIMULATE GDP HYDROLYSIS AND SHIFTS THE STATE TO PREDOMINANTLY A GTP BOUND STATE AND NOW THE PROTEINS ARE CONSTITUTIVELY ON AND IT SIGNALS THE PATHWAYS IRRESPECTIVE OF WHETHER THE UPSTREAMS RECEPTORS ARE STILL ACTIVE AND LEADS TO SIGNALLING AND TRANSFORMATION. IN FACT, RAS MUTATION CAN EITHER BE INITIATION FACTOR SUCH AS IN THE CASE OF LUNG AND PANCREATIC AND/OR CARCINOMA WHERE WE OBSERVE K-RAS MUTATION AT RELATIVELY EARLY STAGES OF THE CANCER OR NAIN THE PROGRESSION WHERE YOU MUTATE APC BEFORE YOU MUTATE RATS AND THIS LEADS TO ACTIVATION OF THE STEM CELL SIGNALLING AND K-RAS NOW PROMOTES THE PROGRESSION FROM THE CARCINOMA. NEVERTHELESS, YOU CAN SEE K-RAS IS INTEGRALLY INVOLVED IN THE INITIATION AND PROGRESSION OF THESE VARIOUS FORMS OF TUMORS. AND THE REASON, AS A MENTIONED, THE RAS IS SUCH A GOOD ONCOGENE AND IT LIKES TO BE — [OFF MIC]>>THAT’S A GOOD QUESTION. I THINK PART OF THE REASON, IT’S NOT CLEAR WHY YOU HAVE THIS SELECTI SELECTIVITY FOR THESE AND RAS MUTATION IS ALMOST NEVER SEEN IN BREAST OR PROSTATE CANCER OR THESE TYPES OF CARCINOMAS. IT GOES TO WHETHER RAS IS ADVANTAGED FOR TUMORS IN THAT PARTICULAR ORGAN IN ITS NATIVE ENVIRONMENT. THERE ARE RAS MUTATION FOR OTHER TYPES OF TUMORS BUT PRESUMABLY THESE TYPES OF ORGANS LIKE TO HAVE RAS SIGNALLING AS PART OF THEIR PHYSIOLOGICAL RENEWAL PROCESS. AND BECAUSE RAS IS INVOLVED IN THE SIGNALLING PATHWAYS, ONCE IT’S MUTATED YOU CAN GET NEOCLASS TICK TRANSFORMATION. — — PLASTIC TRANSFORMATION. THEY CAN LOAD IN THE MEMBRANE AND ANY DIVISION THAT PUTS THEM OUT OF IT LEADS TO CELL DEATH AND WHEN YOU HAVE A MUTANT K-RAS NOW CELLS CAN PROLIFERATE IRRESPECTIVE OF THEIR PROCESS TO THE BASE MEMBRANE AND THIS GIVES RISE TO A NEOPLASTIC TRANSFORMATION. WHAT’S IMPORTANT IN TERMS OF THERAPEUTIC STUDIES DEMONSTRATED IN IN VIVO AND IN VITRO AND CANCER CELLS IN K-RAS BY AND LARGE ARE STILL DEPENDENT ON THE ONCOGENE FOR THEIR TRANSFORMING GENOTYPE. IF YOU PHARMACOLOGICALLY SILENCE THE ONCOGENE YOU CAN REVERT THIS PHENOTYPE IN MANY CASE AND LEAD TO THE RESTORATION OF THE EPITHELIAL MODEL. IN FACT, THIS IS THE CLASSIC PHENOMENON OF THE ONCOGENE PATIENT. IT’S IMPORTANT BECAUSE IT STATES MANY TUMORS, EVEN LATE-STAGE TUMORS ARE STILL CONTINUOUSLY DEPENDENT ON THE FUNCTION OF A MAJOR DRIVER SUCH AS THE K-RAS ONCOGENE FOR THEIR PHENOTYPE AND IT’S THE BASIS OF WHY ONCOGENIC SIGNALLING HAS THERAPEUTIC UTILITY. THERE’S MANY STRATEGIES WE COULD THINK ABOUT THAT ONCOGENIC RAS SIGNALLING CAN BE USED AND WE CAN HAVE INTERACTION WITH THE RECEPTOR AND WITH THE PATHWAY. WE CAN DEVELOP INHIBITERS THAT CAN INHIBIT THE DOWNSTREAM SIGNALLING PATHWAYS OF RAS PROTEINS. YOU CAN ALSO GO AFTER INDIRECT TARGET. MANY WE HAVE AS TARGETS. SOME EXAMPLES INCLUDE METABOLIC PROCESSES OR AUTOPHAGY PATHWAY I’LL TALK ABOUT TOWARDS THE END THAT ARE IN RESPONSE TO ONCOGENIC RAS MUTATION TO SUPPORT THE MALIGNANT PHENOTYPE OF THESE CELLS. SO THERE’S A NUMBER OF ENTRY POINTS ONE COULD THINK OF TO TARGET THE RAS SIGNALLING PATHWAY AND ITS ASSOCIATED CHANGES. BUT SO FAR THIS HAS PROVEN TO BE QUITE DIFFICULT AND THE REASON IS MULTITUDE BUT I’LL GIVE YOU A FEW EXAMPLES AS TO >>WE STILL DON’T HAVE EFFECTIVE TARGETED THERAPIES FOR THE K-RAS GENE. ONE OF THE EARLY ERATTEMPT AT THE LOCALIZATION IS TO DEVELOP INHIBITERS THAT TARGET THE ENZYMES INVOLVED IN THE PROCESSING OF RAS PROTEINS AND THE PROCESS. THE MOST FAMOUS EXAMPLE THAT LOOK AT THE TERMINIS OF RAS. AND FOR REASONS I DON’T HAVE TIME TO GO INTO, WHAT HAPPENS WITH THE RAS PROTEIN, PARTICULARLY K-RAS FOR B PROTEIN, WHEN YOU BLOCK THIS IT CAN UNDERGO A TRANSERASE AND TRANSFORM TO A DIFFERENT LOCATION. THERE’S WAY TO BLOCK THIS AS THE ALTERNATIVE PROCESS. I THINK THE BIGGER PROBLEM IS RAS IS ONE OF OVER 100 SMALL GDPs AS THEY LOOK USE THE PATHWAY FOR THE MEMBRANE. YOU CAN IMAGINE DISRUPTING THE ENZYME’S ACTIVITY OR THE CORRECT LOCALIZATION AND TARGETING OF MANY OTHER SMALL GPAs YOU WOULD HAVE AN EFFECT ON THE CELL FUNCTION. THIS APPROACH LACKS SPECIFIC SELECTIVITY FOR RAS FAMILY PROTEINS AND LIMIT THE INHIBITERS. SO FAR THEY HAVEN’T DISEM — DEMONSTRATE BENEFIT BUT THERE’S INHIBITERS IN CLINICAL STUDIES RIGHT NOW. THE NEXT THING THAT WE CAN TRY IS DIRECTLY INTERFERE WITH THE FUNCTION OF THE RAS ONCOPROTEIN AND WE KNOW HOW TO BLOCK SOME BUT IT TURNS OUT IT’S DIFFICULT TO DEVELOP DIRECT INHIBITERS THAT COMPETE WITH GTP BINDING WHICH IS WHAT WE TYPICALLY DO FOR THE BINDING KINASE. THUS FAR THERE HASN’T BEEN A GOOD GTP INHIBITOR DESPITE THE PHARMACOLOGIC EFFORT TO EFFECTIVELY TURN OFF THE FUNCTION OF THE MUTANT K-RAS. AND YOU CAN IMAGINE WE CAN DEVELOP DRUGS TO DISRUPT INTERACTION BETWEEN MUTANT RAS PROTEINS AND THE EFFECTER FINDINGS SUCH AS THE BINDING BETWEEN K-RAS AND RAF BIND BUT IT’S HARD TO DEVELOP A SMALL MOLECULE TO DISRUPT SUCH EXTENSIVE PROTEIN TRACTIONS. THE REASON THE WORK HAVE POINTED TO PROMISING APPROACHES THAT COULD DISRUPT THE INTERACTION. AND A SUCCESSFUL EXAMPLE IS TO LOOK AT THE C RAS MUTATION AND TAKE A SMALL MOLECULE AND DISRUPT THIS HOMO — HOMO STASIS AND THIS — HOMEOSTASIS AND IT COULD SHIFT EQ LIB RUM TOWARDS — EQUILIBRIUM TOWARDS RAF FORMATION AND YOU CAN SEE IN ANIMAL MODELS IT CAN REALLY INHIBIT AND SHRINK THE GROWTH OF TUMORS WHICH HARBOR THE MUTATIONS IN K-RAS BUT NOT OTHER FORMS OF MUTATIONS LIKE IN THE WILD TYPE TUMORS. AND ANGEN HAS AN EXPERIMENT THAT IS WORKING ITS WAY THROUGH PHASE ONE CLINICAL TRIAL AND DEMONSTRATED IMPRESSIVE ACTIVITY IN CANCER PATIENTS WITH THE K-RAS B MUTATION. IT’S THE FIRST K-RAS SPECIFIC INHIBITOR THAT HAVE DEMONSTRATED PROMISING ACTIVITY IN HUMAN CLINICAL TRIALS. THE PROBLEM HOWEVER, IS THE DRUGS ONLY WORK WITH K-RAS G12C MUTATION AND THAT DO OCCUR IN 40% OF LOUNGE CANCERS BUT IS RELATIVELY RARE IN PANCREATIC AND COLORECTAL CANCERS SO FOR THE MAJORITY OF OTHER K-RAS PATIENTS WE STILL HAVE NO WAY TO INHIBIT THE ACTIVITY OF THE K-RAS PROTEIN. THE ACTIVITY OF THE ONCOPROTEIN THE IDEA IS CAN WE BLOCK THE SIGNALLING PATHWAYS BECAUSE WE KNOW HOW TO INHIBIT PROTEIN KINASES. THERE’S ACADEMIC LABS THAT DEVELOPED INHIBITERS THAT TARGETED KINASE IN THE SIGNALLING PATHWAY IN THE PATHWAYS TO TRY TO BLOCK THE ONCOGENIC PATHWAYS DOWN STREAM AND GENETICALLY AS WELL AS PHAR A AKO — FARM PHARMA COLOGICALLY THEY SHOWED IF YOU GET RID OF ALL THE GENES IN THE CELL IT CANNOT PROLIFERATE. YOU CAN PUT THOSE MUTATIONS IN VARIOUS RAS SIGNALLING PATHWAY COMPONENTS AND THE ONLY PATHWAY COMPONENT THAT CAN RESTORE CELL PROLIFERATION ARE ACTIVE MUTATIONS IN THE KINASE. HOWEVER, IT TURNS OUT THAT INHIBITERS TARGETING THIS PATHWAY ALSO HAVE THEIR OWN PROBLEM. RAF KINASES WORK WELL IN MELANOMA BUT IN RAF MUTANT CELLS THEY CAN PARADOXICALLY BIND TO AND ACTIVATE WILD TYPE PROTEINS TO STIMULATE THE INHIBITION OF THE PATHWAY IN A CONCENTRATION IT HAS BEEN ACHIEVED AND THERE’S INHIBITERS THAT TRY TO CIRCUMVENT THIS PROPERTY AND I WON’T GET INTO BUT INHIBITED RAF KINASE THUS FAR HAVE NOT REALLY BEEN EFFECTIVE IN BLOCKING THE SIGNALLING IN K-RAS AND THE INHIBITERS THAT TARGETED THIS TYPE OF KINASE WHICH IS APPROVED FOR RAF MEL KNOW NA HAVE NOT — M MELANOMA HAVE NOT VIEWED IT IN GOOD RESULTS AND THERE’S A FEEDBACK LOOP TO LIMIT HE THE ACTIVITY IT CAN HAVE AND ONCE YOU BLOCK THE KINASE YOU DISABLE THE NEGATIVE FEEDBACK AND LEADS TO INCREASED SIGNALLING TO THE PATHWAY AND DIMINISH EFFICACY. AND THIS IS ONE OF THE MOST RECENT OF PHASE 3 CLINICAL TRIAL. IN COMBINATION WITH CHEMOTHERAPY IN LUNG CANCER PATIENTS. THE ORANGE LINE IS THE CHEMOTHERAPY ALONE AND THE BLUE LINE YOU CAN SEE THE CROSS-THERAPY. THERE’S NO SURVIVAL BENEFITS FOR THE PATIENTS ON COMBINATION THERAPY AND THIS IS DISHEARTENING BUT IT GOES TO SAY THAT THIS PERHAPS IS NOT THE IDEAL COMBINATION DESPITE IT BE THE STANDARD OF CARE AND WE NEED TO THINK ABOUT WHAT ARE THE RATIONAL COMBINATION THERAPIES WE CAN USE. I WON’T GO INTO DETAIL TO MECHANISM BUT A PART OF WHY WE THINK THE COMBINATION WOULDN’T WORK IS THE TWO DRUGS BLOCK CELLS AT TWO DIFFERENT STAGES OF THE CELL CYCLE SO YOU DON’T NECESSARILY EXPECT SYNERGY AND OTHERS IN CLINICAL TRIALS CAN BLOCK CELL SIGNALLING OR PROLIFERATION PATHWAYS AND THE QUESTION IS CAN YOU DISCRIMINATE THE K-RAS TUMOR CELLS FROM THE PROGENITOR CELLS. IT’S THE KEY BEFORE WE THINK ABOUT COMBINATION OF THERAPIES THAT YOU DON’T WANT A COMBINATION THERAPY TO BE JUST TOXIC PER SE. YOU WANT IT TO BE TOXIC IN A SELECTION FASHION IN A SENSE THAT THE COMBINATION SHOULD BE MORE TOXIC IN CANCER CELLS WHEREAS IT’S SHOULDN’T BE COMPOUNDING IN NORMAL CELLS. SO YOU DON’T WANT TO NARROW THE WINDOW BUT INSTEAD YOU WANT IT TO WIDEN THE WINDOW AND SHIFT THE RESPONSE CURVE OF CANCER CELLS FARTHER TO THE LEFT THAN THAT OF THE NORMAL CELLS. SO CONCEPTUALLY FOR GOOD COMBINATION THERAPIES TO WORK, THEY HAVE TO CONFER SOME GENOTYPE SPECIFIC SYNERGY. THEY NEED TO WIDEN THE THERAPY WINDOW AND HOPEFULLY, IF THEY HAVE MECHANISMS OF ACTION, THEY CAN ALSO DELAY THE ONSET OF DRUG INDUCED RESISTANCE. AND THIS LEADS TO SEARCH FOR ADDITIONAL TARGETS. THIS IS A SPACE WHERE MY LAB HAS PLAYED AN ACTIVE ROLE. IN ADDITION TO DIRECTLY TARGETING THE ONCOGENE AND SIGNALLING PATHWAY YOU CAN EXPOSE OTHER FORMS OF VULNERABILITIES IN CANCER CELLS AND TO DO SO WE UTILIZE A CLASSIC CONCEPT SUCH AS THE IDEA IS BECAUSE OF GENETIC BUFFERING CANCER CELLS, USUALLY THERE SHOULD EXIST GENES WHOSE LOSS OF FUNCTION IS WELL TOLERATED IN A NORMAL SETTING. IF YOU USE THE FUNCTION OF GENE B BUT THE ACTIVITY CAN BE BUFFERED BY THE FUNCTION OF GENE A THE LARGE WILL BE LARGELY OKAY BECAUSE GENE A CAN TAKE OVER GENE B. HOWEVER, WHEN IT’S MUE TATATED
AND YOU PERTURB THE BUFFERING POWER OF THE CELL IT’S NO LONGER TOLERATED. THIS IDEA HAS BEEN AROUND FOR DECADES. BUT WHEN YOU HAVE A TUMOR MUTATION YOU CHANGE THE FITNESS OF THE CELLS THROUGH VARIOUS FORMS OF ONCOGENIC STRESS NOW HAVE YOU THE OPPORTUNITY TO DISABLE THE PATHWAY AND THE INCOMPATIBILITY WITH THE MUTATION AND CANCER CELL. MORE AND MORE CELLS ARE WILD TYPES FOR THE GENES NOT MUTATED THAN THE DISRUPTION OF THE FUNCTION OF THE SECOND GENE LARGELY TOLERATED. SO AS A MENTIONED, TUMOR CELLS THAT HARBOR MUTATIONS IN THE RAF GENES, PARTICULARLY K-RAS ARE CONTINUOUS CONTINUOUSLY DEPENDENT BECAUSE IT NEEDS CONSTANT SIGNALLING TO MAINTAIN THIS ABNORMAL CELL PROLIFERATION TUMOR RESPONSE. AND WHAT WE’VE COME TO APPRECIATE IN THE LAST DECADE OR SO, THE COST OF THE MALIGNANT LIFESTYLE IS TUMOR CELLS ALSO EXPERIENCE A WIDE VARIETY OF STRESS SUCH AS DNA DAMAGE, GENOMIC INSTABILITY, OXYGEN SPECIES AND SO FORTH AND THE TUMOR CELLS ARE ALSO DEPENDENT ON THE CONTINUOUS FUNCTION OF VARIOUS CELLULAR STRESS RESPONSE PATHWAYS. AND WE CALL THIS TO INDICATE THE PATHWAYS THOUGH THEY ARE THEMSELVES NOT MUTATING CANCER CELLS HAVE BECOME MORE ESSENTIAL DUE TO THIS UNIQUE ASPECT OF ONCOGENIC STRESS AND THEY CAN BE EXPLOITED AND TUMOR CELLS AND YOU THINK OF TUMOR CELLS ARE THE CLASSIC EXPLOITING OF ONCOGENIC STRESS BECAUSE THE DAMAGE WAS EXPRESSED COMPARED TO CANCER CELL. THE WORK FROM MY LAB AND OTHER LABS ARE HAVING A NUMBER OF SYNTHETIC LETHAL INTERACTIONS CHARACTERIZED IN THE CONTEXT OF CANCER SELLS WITH K-RAS MUTATION — CELLS WITH K-RAS MUTATION THAT EXPLOIT THE GENE EM — GENOMIC INSTABILITY AND SENESCENCE WHICH CAN CONTRIBUTE TO THE SELECTIVE TARGETING OF K-RAS MUTANT CELLS IN ADDITION TO TARGETING K-RAS ONCOGENIC SIGNALLING PATHS. AND ONE THING I WISH TO POINT OUT IS THERE’S NOT A UNIVERSAL GOLDEN BULLET IN THE CONTEXT OF SELECTIVELY KILLING K-RAS CELLS AND IT OCCURS IN THE TISSUE AND GENETIC CONTEXT MANNER AND WE BELIEVE THE BEST WAY TO EXPLOIT THEM TOGETHER WITH INHIBITERS THAT TARGET THE SIGNALLING PATHWAYS. AND THEN TOWARDS THIS END, WE HAVE INITIATED A PROJECT TO REALLY LOOK AT THE CONTRIBUTION OF THE K-RAS CELLS TO IDENTIFY THE MOST TARGETED DRUG COMBINATION AND INSTEAD OF USING INHIBITORS WITH OTHER INHIBITORS WE WANTED TO EXPLORE THE TARGET SPACE TO TRY TO FIND THE MOST PROMISING TARGET BEFORE WE DEVELOP INHIBITERS OR TRY TO PUT DRUGS TOGETHER TO TEST IN ANIMALS AND HOPEFULLY GET MUTATION. THE SCIENTIFIC QUESTION WE ARE ASKING IS WHAT ARE THE CRITICAL ONCO EFFECTERS, SIGNALLING PATHWAYS TO DISTINGUISH THE PHYSIOLOGICAL ACTIVITY OF K-RAS AND HOW IT COMMUNICATES IN THE NETWORK. YOU HAVE TO KNOW WHICH NODE ARE THE MOST CRITICAL TO TARGET AND WHAT ALLEVIATED ONCOGENIC STRESS AND THROUGH THIS KNOWLEDGE CAN WE IDENTIFY THE TARGET COMBINATION THAT DOES SHOW PROPERTIES OF GENOTYPES OF ACTIVITY AND HOPEFULLY MECHANISMS OF ACTION. TO DO THIS WE TOGETHER IN COLLABORATION WITH McCORMICK’S LAB DEVELOPED A TECHNOLOGY LOGICAL TRIP USING RNII AND CRISPR TO TARGET MULTIPLE GENES IN THE SAME CELL TO ASK THE QUESTION IF WE COINHIBIT THE FUNCTION OF CELLAR GENES WHICH CAN LEAD TO THE CELL. THIS SHOWS WE CAN KNOCK DOWN THE ACTIVITY OF SEVEN GENES SIMULTANEOUSLY AND ASK THIS FUNCTIONAL QUESTION. SO IN USING THE PLATFORM, A RESEARCH FELLOW IN MY LAB HAS BASICALLY LOOKED AT ALL THE RAS SIGNALLING PATHWAYS AND A NUMBER OF STRESS RESPONSE PHAGE PATHWAYS FOR THE ONCOGENIC STATE AND THE REASON WE HAVE THIS APPROACH IN THE HUMAN GENOME EACH OF THE SIGNALLING REPRESENTS WHAT IS FUNCTIONALLY REDUNDANT IN THEIR ACTIVITY. IF YOU KNOCK DOWN THE ACTIVITY IN THE GENE WHICH WAS DONE TRADITIONALLY YOU CAN UNMASK THIS BECAUSE THE OTHER GENE OPERATES AND YOU HAVE TO KNOCK DOWN SOME COMBINATION OR ALL OF THESE DIFFERENT FORMS OF RAS KINASE TO SEE THAT. SO WE LOOKED AT THE NODES SHOWN HERE AND ALSO LOOKED AT NODE PAIRS IN ORDER TO IDENTIFY THE BEST COMBINATION. THERE’S ALMOST 400 TOGETHER WITH 47 SO THIS CONSTITUTES 47 GENES AND 26 STRESS RESPONSE GENES. AND THEN WHAT HE DID WAS HE BASICALLY ASKED THE QUESTION, IN K-RAS MUTANT COLORECTAL AND CANCER CELL LINE AND WILD TYPE CANCER CELL LINE AND UNTRANSFORMED CELL LINES, HOW DOES THE KNOCK-DOWN OF EITHER INDIVIDUAL GENE NODES OR PAIRS OF GENE NODES CAN SELECTIVELY KILL K-RAS CELLS. IN OTHER WORDS, CAN IT EFFECTIVELY ELIMINATE K-RAS GENES AND FROM THERE CAN WE SHOW THE COMBINATIONS HAVE REDUCED OR NO TOXICITY IN EITHER K-RAS WILD TYPE CANCER CELLS OR UNTRANSFORMED NORMAL CELLS AND CAN WE PARSE DOWN THE SIGNALLING NODES DOWN TO THEIR GENE COMPONENTS IN TERMS OF NOMINATING THE MINIMUM NUMBER OF TARGETS FOR PHARMACO LOGICAL EFFORTS. SO THE OVERALL GOAL IS TO TARGET THE COMBINATION FOR THE SELECTIST AND TOXICITY OF K-RAS ONCOGENE ELIMINATION. IF YOU HIT IT ON ITS HEAD IT’S POTENT BUT SINCE WE CAN’T DO THAT WHAT ARE THE NEXT BEST OPTIONS? THIS IS A HEAT MAP OF KNOCKING DOWN VARIOUS COMPONENTS IN THE RAS SIGNALLING PATHWAY ACROSS K-RAS AND WILD TYPE CELLS AND HAVE A NUMBER OF MATRIX TO LOOK AT THE SCORE BETWEEN K-RAS MUTANT AND WILD TYPE CELLS AND THE PARTICULAR COMBINATION FROM THE CORRELATION OF THE G NODES BEHAVIOR ARE POSITIVE IN THE K-RAS KNOCK DOWN. THE SCATTERED MAP SHOWS THE SIGNALLING NODES CLOSEST TO THE CONTROL IS THE RAF KINASE. IN OTHER WORDS, IT REPRESENTS WHAT IS MOST THE ONCOGENIC SIGNALLING AND OTHER RAS CONTRIBUTES. BUT WHAT IS ALSO STRIKING, IF YOU LOOK AT DIFFERENT KRAERNS CELL LINES THEY HAVE DEPENDENCY ON THE SIGNALLING PATHWAYS AND WE KNOW CANCER IS A HETEROGENUS DISEASE AND THIS EXPLAINS WHY IT INHIBITS PATHWAYS AND HASN’T SHOWN A LOT OF ACTIVITY IN PATIENTS. NEXT WE LOOKED AT VARIOUS COMBINATIONS OF RAF SIGNALLING NODES FOR THEIR ABILITY TO RECAPITULATE. IN OTHER WORDS, THEY CAN KILL CELLS BUT NOT SPARE WILD TYPE CELLS. THE CLUSTER THAT BEST CAPTURES THIS IS VARIOUS TYPES OF RAF KINASE AND THE SIGNALLING NODE IS THE MOST CRITICAL IN THE RAS SIGNALLING AND BY LAYERING A SECOND TARGET GROUP ON TOP OF IT YOU CAN PROVE THE CAPTURE AND IT’S SHOWN HERE IN THE SCATTERED SCATTEREDER — SCATTERED MAP CAN GETS IT CLOSER TO THE CORRELATION OF K-RAS. IT SHOWS UP IN A NUMBER OF CANCER CELL AND THE SCATTERING EXHIBITS DIFFERENT DEGREES OF UTILIZATION OF THE ONCOGENIC SIGNALLING. AGAIN, WE SEE THIS HETEROGENEOUS PATTERN OF PATHWAY DEPENDENCY DIFFERENT CANCER CELL LINES AND SENSITIVITY TO PAIR WISE COMBINATION OF G NODES KNOCKED DOWN AND DRIVEN BY THE DEPENDENCY IN THE PARTICULAR CELL LINE. AND HE THEN PARSED DOWN THE THREE MOST PROMISING SIGNALLING NODES AND THIS IS THE AUTOPHAGY PATHWAY TO IDENTIFY THE MINIMUM NUMBER OF GENES HE COULD KNOCK DOWN AND TO CUT A LONG STORY SHORT HE FOUND BY COMPARING THE SENSITIVITY OF MUTANT K-RAS VERSUS K-RAS WILD TYPE CANCER CRESS VERSUS NORMAL CELLS, THE COMBINATION OF RAF KINASE AND THE AUTOPHAGY PATHWAY APPEARS TO BE THE MOST IDEAL COMBINATION AND PHARMACOLOGICALLY YOU CAN SEE THE CANCER CELL LINE AND THE PANCREATIC CELL LINE KNOCKING DOWN RAF 1 OR ACT7 CAN GO TO THE INHIBITOR FOR THE PATHWAY AND SOMETIMES REDUCE IT. PHENOTYPICALLY WHEN YOU TARGET RAF 1 OR ACG7 YOU CAN EITHER INCREASE OR INDUCE APOPTOSIS AND IN WILD TYPE CELLS THIS COMBINATION DOESN’T REALLY HAVE THIS EFFECT. THESE THE GREEN CELLS. SO THIS SATISFIES OUR CRITERIA OF HAVING A GENOTYPE SPECIFIC COMBINATION THAT SHOWS K-RAS MUTANT SPECIFIC STIMULATION. IN V SUMMARY WE FOUND BY INTERROGATING THE RAF SIGNALLING PATHWAY AND STRESS RESPONSE PATHWAY THE RAF KINASE AND AUTOPHAGY PATHWAY IDENTIFIED REPRESENTS A STRONG COMBINATION THE ATG7 AS WELL AND WE HAVE ONE TARGET THAT COMES DIRECTLY FROM ONCOGENIC K-RAS SIGNALLING AND THEN A STRESS RESPONSE THAT WOULD ALLEVIATE ONCOGENIC STRESS AS A RESULT OF THE PATHWAY. AND THE MODEL WE’RE WORKING WITH IN THE AUTOPHAGY PATHWAY IS DISPENSABLE AND PHYSIOLOGICAL RAS SIGNALS CAN TOLERATE UP TO TWO COMPONENTS OF THE B RAF AND C RAF AND IN THE CONTEXT OF THE CELLS THE SIGNALLING GOES THROUGH THE RAF KINASE AND WHEN YOU TAKE OUT THE C AND B RAF KINASES YOU IMPAIR THE RAF AND YOU ELIMINATE THE AGT7 AND YOU EXACERBATE ONCOGENIC STRESS. SO TWO OTHER LABS, THEY DISCOVERED INDEPENDENT APPROACHES AND THESE WERE PUSH ESTABLISHED WITHIN A MONTH OR TWO OF EACH OTHER. WAT THESE LABS ARE PRETTY MUCH THE SAME AS WHAT WE HAVE SHOWN BUT THE COMBINED TARGETING OF THE KINASE PATHWAY WITH K-RAS AS WELL AS THE AUTOPHAGY PATHWAY CAN SHOW A STRONG SYNERGY IN K-RAS MUTANT CELLS WHERE MOST OF OUR WORK WAS AN APPROACH IN CANCER CELL LINES AND TWO STUDIES WENT TO ANIMAL MODELS AND ONE PATIENT WHERE IT SHOWED THE COMBINATION. THIS YELLOW LINE SAY COMBINATION OF THE KINASE INHIBITOR WITH AN INHIBITOR FOR WHAT WAS ORIGINALLY USED TO DISRUPT MA MAMALIA AND IT HIT INHIBITED TUMOR GROWTH OF THE PANCREATIC CANCER CELL LINE AND THEY TOOK THE APPROACH AND TREATED IT AND THIS IS A TERMINAL STAGE PANCREATIC CANCER STAGE AND YOU LOOK WHERE THE PATIENT HAS PRETTY MUCH EXHAUSTED ALL AVAILABLE STANDARD OF CARE THERAPY AND AS WELL AS EXPERIMENTAL THERAPIES AND WITH NO RESPONSE BUT ONCE THEY PUT THE PATIENT ON THE COMBINATION KO — TARGETING THE PATHWAYS THERE WAS A RESPONSE FOR THE DURATION THE PATIENT WAS FOLLOWED. THE STUDIES HAVE LED TO A PHASE 1 TRIAL NOW TO FORMALLY TEST THIS PATHWAY TO LIMIT THE AUTOPHAGY AND OTHER PATHWAYS AND GOING FORWARD WITH OTHER FORMS OF TUMORS. IN CONCLUSION, I TALKED ABOUT THE VARIOUS TECHNOLOGIES AND CHALLENGES IN MUTANT K-RAS AND THE SIGNALLING PATHWAY IN ORDER TO TREAT APPROXIMATELY 10% OF THE TUMORS THAT HAVE MUTATIONS IN THE RAS MUTANTS. I THINK GOING FORWARD CLEARLY TO ELIMINATE THE CANCER CELLS, THERE HAS TO BE A COMBINATION THAT IS IN SOME FORM OF K-RAS INHIBITOR AND ONCOGENIC SIGNALLING PATHWAY AS WELL AS PART OF THE STRESS RESPONSE. I DON’T HAVE TIME TO GO INTO THIS BUT THE THERAPY SPEARHEADED BY DR. ROSENBERG AND DR. YANG WOULD HAVE AN IMPORTANT ROLE IN THE COMBINATION SETTING. AND TOGETHER THE IDEA IS THAT TO FIND THE OPTIMAL COMBINATION EXHIBITED AND THE GREATEST THERAPY OF WINDOW OF CELLS FOR THE BODY IN ORDER TO EFFECTIVELY SHRINK THE TUMOR AND HOPEFULLY WITHSTAND THE ONSET OF DRUG RESISTANCE THROUGH THE THERAPY. WIH THIS I’D LIKE TO CLOSE BY THANKING VARIOUS CURRENT AND FORMER MEMBERS OF MY LAB AND THE STUDY WAS DONE BY MY RESEARCH FELLOW AND THE HELP FROM MANY COLLABORATORS THAT MADE OUR WORK POSSIBLE. THANK YOU FOR YOUR ATTENTION.>>I DID WORK ON THE SARC KINASE. I BELIEVE THIS IS WITH WHAT HAS TO DO WITH THE OCCURRENCE. MY BASIC QUESTION IS I KNOW THERE’S A VIRAL FORM. DOES IT APPLY TO RAS AS WELL?>>THE K-RAS AND H-RAS FORM WAS ZO DISCOVERED AND IT HAS ORIGINS IN THE HUMAN GENOME. IT’S PRETTY MUCH THE SAME ANALOGOUS STORY TO AND THERE ARE SARC INHIBITERS TESTED IN TUMORS WHERE THERE’S SARC ACTIVITY AND RAS COMES THROUGH.>>THIS ACCOUNTS FOR 90% OF MUTATIONS. MOST DISABLE THE HYDROLYSIS ACTIVITY TO RAS’ EXTENT MAKING A SLOW TURNOVER ENZYME STUCK IN THE ACTIVE STAGE FOR MOST THE TIME AND UNCOUPLED RAS STIMULATED MICROGENIC SIGNALS BY RECEPTOR TYPES >>WHY DID YOU TAKE THE GENETIC BASED APPROACH RATHER THAN USING OWNER INHIBITERS?>>IF YOU LOOK AT THE SPACE OF AVAILABLE INHIBITERS, THEY ARE VERY UNEVENLY DISTRIBUTED CROSS ALL TARGETS. AND FOR MANY POTENTIAL TARGETS INCLUDING RAS ITSELF, THERE ARE NO — AND THE SECOND COMPLEXITY IS THAT THEY TEND TO HAVE TARGET EFFECT ARE HARD TO ANTICIPATE. IT LOOKS LIKE ATP AND THEY BIND TO THE POCKET BUT THEY HAVE OTHER WITH A SIMILAR TARGET. YOU CAN EXPLORE THE TARGET SPACE IN AN UNBIASSED FASHION TO DOWN REGULATE OR KNOCK OUT A GENE TO SEE IF IT’S A TARGET AND WE CAN SHOW THE GENETIC PROHIBITION INTO THE CELL IS UNTARGETED DUE TO THE PART OF THE GENE AND THERE’S OTHER GENES THAT ARE SRNA OR OTHER AND THIS IS NOT ALWAYS AVAILABLE TO CONCLUSIVELY SHOW THE INHIBITOR IS GETTING YOUR INTEND TARGET. IT’S AN ISSUE WITH INHIBITOR STUDIES WHERE IT’S UNCLEAR WHEN HAVE YOU SIMPLE ACCESS TO THE CELL DEATH WHETHER IT’S HITTING THE PRIMARY TARGET OR ANOTHER TARGET.>>THANK YOU. I WANTED TO KNOW YOU ALLUDED TO THE MUTATION ON THE STRUCTURE. HAS ANYONE TRIED TO DESIGN INHIBITERS AGAINST THAT STRUCTURE?>>THAT’S A GOOD QUESTION. THAT’S A TENSE INTENSELY ACTIVE AREA FOR OVER TWO DECADES. THE PROBLEM WITH RAS IS SOME SCIENTISTS IN THE FIELD WOULD REFER TO IT AS A TEFLON PROTEIN. IT’S A RELATIVELY SMOOTH SURFACE. IT DOESN’T HAVE A LOT OF POCKETS FOR SMALL MOLECULES. THE ONLY WITH YOU DEEP POCKET IS THE GTP BINDING POSSIBILITY POCK — POCKET BUT IT’S SO SMALL THERE’S STILL ONGOING EFFORTS TO TRY TO GET DRUGS TO STICK TO VARIOUS SMALL POCKET ON THE RAS PROTEIN AND USE CLEVER APPROACHES THROUGH FRAGMENT DISCOVERY TO LINK THEM UP TO HAVE SUFFICIENT AFFINITY FOR RATS. AND WE’VE LOOKED FOR A COMBINATION OF TARGET AND DRUGS TO LOOK AT THE DROWN STREAM OF RAS BUT THE SINGULAR FOCUS IS TO USE THE CLEM — CHEMISTRY AND BIOLOGICAL APPROACHES. OUR NEXT SPEAKER IS NEIL CAPORASO AND DID HIS RESIDENCY AND THEN CAME TO NIH AS AN ONOLOGY FELLOW AND THEN BECAME A BIOTECHNOLOGY FELLOW IN THE EPIDEMIOLOGY BRANCH. BECAME CHIEF OF THE PHARMACOGENETIC SESSION OF THE GENETIC EPIDEMIOLOGY BRANCH AND WILL TALK TO US ABOUT EPIDEMIOLOGY. WHAT A SURPRISE.>>IT USUALLY TAKES A FEW MINUTES TO FIGURE OUT HOW THE SLIDES WORK.>>OKAY, I HAVE THREE GROUPS. I’LL SPEND TIME ON THE CONTROVERSY AND THE FACTS YOU CAN GOOGLE. I’LL TELL YOU WHEN WE GET TO A LINE OF FACTS AND WE’LL GO THROUGH THOSE PRETTY QUICK. THE CONCEPTS I’LL TALK ABOUT A LITTLE BIT. SO I’M AN INTERNIST/ONCOLOGIST. I HAVE SOME BACKGROUND IN EPIDEMIOLOGY AND ENVIRONMENTAL SCIENCE AND METEOROLOGY SO I HAVE A CHECKERED HISTORY TO GET HERE. SO WHAT IS EPIDEMIOLOGY? THE FUNDAMENTAL THING IS IT’S POPULATION SCIENCE. AND YOU’RE TALKING ABOUT POPULATION AND WE KIND OF TAKE A LOT OF WHAT WE KNOW FOR GRANTED ABOUT WHAT CANCER RISK FACTORS ARE AND WHAT THEY’RE NOT. A LOT OF OUR GENERAL KNOWLEDGE COMES FROM SOCIETY AND JUST SOME DECADES AGO, CIGARETTES WERE CONSIDERED NOT REALLY HARMFUL AND TRUSTED FIGURES IN THE CULTURE WERE USED TO PROPER TRAY THE IDEA — PORTRAY THE IDEA THAT THEY WEREN’T BAD AND IF THEY WERE BAD, CERTAINLY SOME KINDS WEREN’T AS BAD AS OTHERS SO SO THERE’S LOTS OF THINGS IN THE ENVIRONMENT THAT MAY BE ALMOST AS BAD BUT HAVEN’T REALLY BEEN THE TARGET OF STUDY. BUT I BELIEVE AS WE GET AROUND TO STUDYING SOME OF THESE AREAS WE MAY FIND THAT ACTUALLY THEY ARE QUITE HARMFUL SO SUGAR IS ONE EXAMPLE. AND THERE’S OTHERS. SO EPIDEMIOLOGISTS ARE CONCERNED WITH HUMAN POPULATIONS AND IT’S AN OBSERVATIONAL SCIENCE AND YOU CONTRAST THAT WITH AN EXPERIMENTAL SCIENCE. YOU DON’T GET TO PICK WHO IS EXPOSED AND WHO IS UNEXPOSED SO YOU HAVE TO OBSERVE. PEOPLE MAKE CHOICES ABOUT WHAT THEY DO AND SO THERE’S A LOWELL SET OF RULES AND LAWS FOR HOW WE DRAW INFERENCES IN EPIDEMIOLOGY. THE DIVISION THAT FOCUSES ON EPIDEMIOLOGY IS CANCER, EPIDEMIOLOGY AND GENETICS AND THERE ARE NINE BRANCHES AND I’M IN THE OCCUPATION AND ENVIRONMENTAL EPIDEMIOLOGY BRANCH. IT’S AN INTRAMURAL BRANCH. AS THE ABOUT 15% OF MCI AND 85% IS THE EXTRAMURAL ACTIVITIES BRANCH. THE OTHERS ARE METABOLIC WITH NUTRITION AND HORMONES. A GROUP OF FOLKS FOCUSSING ON INFECTION AND STATISTICS AND RADIATION. I WON’T GO INTO DETAIL BUT DCE G HAS BEEN RESPONSIBLE FOR A LOT OF PUBLIC HEALTH ADVANCES FOCUSSING ON AREA DIVERSE SUCH AS DRINKING WATER AND WORKPLACE SAFETY, MOST STUDIES OF FARMING AND PESTICIDES, CANCER STUDIES AND MALIG NAN SAYS AND STUDIES — MALIGNANCIES AND STUDIES OF OBESITY AND HPV AND CERVICAL CANCER. SO THE GOALS ARE TO IDENTIFY A GENETIC AND ENVIRONMENTAL CAUSES OF CANCER IN THE ENVIRONMENT AND THE USUAL BLAH, BLAH, BLAH, IMPACT HIGH QUALITY RESEARCH. THERE’S A LOT OF COLLABORATION. WE HAVE STUDIES IN CHINA ALL OVER EUROPE, PRETTY MUCH EVERY COUNTRY. YOU CAN FIND A LOT ON THE WEB IF YOU SEARCH FOR US. THERE’S RISK ASSESSMENT TOOLS ON THE WEB YOU CAN FIND. SO MORE ABOUT OBSERVATIONAL VERSUS EXPERIMENTAL STUDIES. WE’RE ETHICALLY PROHIBITED FROM DOING STUDIES ON PEOPLE THAT ASSIGN EXPOSURE. WE CAN’T RANDOMIZE PEOPLE TO BE SMOKERS AND THAT WAS A DESIGN WEAKNESS THAT WAS A FLAW THAT TOBACCO COMPANIES USED SO QUEN THE FIRST CASE CONTROL STUDIES EMERGED IN THE LATE ’40s AND 1950s, TOBACCO COMPANIES ATTACKED THEM SAYING WOW, THEY’RE REALLY NOT METHOD LOGICALLY SOUND. A LOT OF THE SCIENCE OF EPIDEMIOLOGY EVOLVED TO ADDRESS THESE KINDS OF CONCERNS. THIS IS AN IMPORTANT SLIDE AND YOU’LL HEAR THIS CRITIQUE A LOT SO I’LL SPEND A MINUTE HERE ABOUT THE KINDS OF STUDIES WE SHOULD DO TO PROVE THINGS IN EPIDEMIOLOGY SO PEOPLE WILL SAY WHAT WE NEED IS A RANDOMIZED CLINICAL TRIAL. AND IN FACT YOU CAN IMAGINE THIS IS A PYRAMID. WHERE DO IDEAS COME FROM ABOUT WHAT CAUSES CANCER AND DISEASE? IN FACT THEY COME FROM ANECDOTES ABOUT INDIVIDUAL PATIENTS AND OBSERVATIONS OF ASTUTE CLINICIANS AND THEN STUDIES ARE DONE IN SMALL UNREPRESENTATIVE SAMPLES AND THEN WE DO CROSS-SECTIONAL STUDIES AND THEN WE DO CASE CONTROL STUDIES AND THEN WE DO COHORT STUDIES AND FINALLY, FOR THE VERY BEST HYPOTHESIS, WE TAKE THEM TO RANDOMIZED CLINICAL TRIALS. WHY DO WE DO THEM IN THIS ORDER? IT’S A MATTER OF COST. IT COSTS NOTHING TO DO THESE KINDS OF STUDIES AND YOU CAN GO TO OTHER DATABASES AND FOR RELATIVELY MINOR COSTS, $1,000 YOU CAN ASSEMBLE A DATABASE AND DO A STUDY. DOING A CASE CONTROLLED STUDY CAN COST TENS OF THOUSANDS OF DOLLARS. I’VE DONE A CASE CONTROLLED STUDY THAT COST $5 MILLION SO IT CAN COST A LOT OF. COHORT STUDIES ALMOST ALWAYS COST MILLIONS AND RANDOMIZED CLINICAL TRIALS CAN COST HUNDREDS OF THOUSANDS TO CLOSE TO A BILLION DOLLARS. SO PLCL PROBABLY COST $300 MILLION. PEOPLE SAY YOU SHOULD HAVE CLINICAL TRIALS AND GREAT IF YOU HAVE MONEY AND HAVE TO ALLOCATE THE MONEY WISELY. YOU HAVE TO IDENTIFY THE CAUSES AND QUANTIFY RISKS AN EPIDEMIOLOGISTS TYPICALLY WANT TO DO GOOD FOR PUBLIC HEALTH. THERE’S BOTH GOALS THERE. WE WANT TO IDENTIFY SYNDROMES, TRENDS, EPIDEMICS. A MORE RECENT GOAL AS WE BECOME MORE BIOLOGIC IS TO IDENTIFY MECHANISMS AND OF COURSE PREVENTION. WHY PREVENTION? IT HEADS OFF THESE AT AN EARLY STAGE. IT’S EFFECTIVE AND CHIEF — CHEAP, YOU ELIMINATE DISEASE AT THE SOURCE. IT REQUIRES EDUCATION AND COMMUNICATION. THERE’S PROBLEMS WITH PREVENTION. THE BIG PROBLEM IS THAT IT REQUIRES A LOT OF TIME TO DEMONSTRATE ITS EFFECTIVENESS. IT’S LESS DRAMATIC THAN TREATMENT. IT DOESN’T PLAY AS WELL TO FUNDING AGENCIES AND CONGRESS. IT’S MUCH MORE FEFEFFECTIVE TO
HAVE CURED PATIENTS THAT ARE GRATEFUL AND SAY I’M CURED. THIS IS WONDERFUL. IT’S NOT AS POLITICALLY IMPACTFUL. AND TOBACCO COMPANY AND SOFT DRINK COMPANIES ARE ALL POWERFULLY OPPOSED TO EFFORTS TO DO PREVENTION AND ALSO YOU DON’T GET A NOBEL PRIZE FOR DOING PREVENTION. AND SCIENTISTS THAT FIRST IDENTIFIED SMOKING AS A RISK FACTOR PROBABLY SAVED A BILLION LIVES. AND MAYBE THERE’S A BILLION MORE THAT WILL BE SAVED. DID THEY GET A NOBEL PRIZE? NO. THEY GOT VILIFIED AT THE TIME. THEY ALSO WORRY ABOUT BIAS. YOU CAN LOOK THESE UP. I WON’T GET INTO THEM BUT A KEY AND ARE YOU WORRIED THAT THE SUBJECTS YOU STUDIED ARE NOT REPRESENTATIVE OF YOUR TARGET POPULATIONS AND THERE ARE YOUR RESULTS ARE NOT GENERALIZABLE TO THE POPULATION. THE LARGE CASE CONTROL STUDIED I TOLD YOU ABOUT WAS A STUDY OF LUNG CANCER AND WHEN WE PROPOSED THE STUDY THEY SAID GREAT, IF YOU WANT TO SPEND $5 MILLION TO GET A CASE CONTROLLED STUDY WE WANT A HIGH PARTICIPATION RATE SO YOUR SUBJECTS ARE REPRESENTATIVE AND SO WE DID A SERIES OF PILOTS. THE FIRST PILOT WE DID WE CALLED UP PEOPLE WE SAID HOW WOULD YOU LIKE TO BE IN A STUDY AND WE’LL GIVE YOU A QUESTIONNAIRE AND TAKE SOME BLOOD. 30% OF PEOPLE SAID THEY’D DO IT. WE THEN SAID, OKAY, WE SENT THEM AN INVITATION LETTER AND FOLLOWED UP WITH A PHONE CALL AND SAID WE’D STUDY PEOPLE AT HOME OR IN THE HOSPITAL. WE PUT IN ADDS. WE GAVE THEM CASH. WE SENT THE LETTER FROM THEIR POSITION. WE GOT IT UP TO 49%. NOT GOOD ENOUGH. STILL COULDN’T DO THE STUDY. THEN, WE GOT EXTREMELY CHARMING INTERVIEWERS OF THE OPPOSITE SEX. WE GOT THE PHYSICIAN TO CALL AND GAVE THEM GAS COUPONS WHICH WERE VALUABLE AND THIS GOT US OVER 70%. EPIDEMIOLOGISTS HAVE CONTROLS. WE’LL STUDY EVERYONE IN THE LAB. THOSE WILL BE THE CONTROLS. THAT’S NOT GOOD. YOU WANT CONTROLS THAT ARE COMPARABLE IN TERMS OF THEIR RISK FACTORS, ETHNICITY, EDUCATION, AGE, ACCESS TO CARE AND SOCIOECONOMIC STATUS. THE IDEAL CONTROL IS A POPULATION CONTROL. SOMEONE SELECTED AT RANDOM FROM THE POPULATION WHICH WHICH YOUR CASES ARISE. THESE ARE EXPENSIVE. THEY ALLOW YOU TO DO THINGS LIKE CALCULATE ABSOLUTE RISK WHICH IS REALLY A GOOD THING TO CALCULATE INSTEAD OF RELATIVE RISK. I HAD A NEW SET OF SLIDES WHERE I SHOWED CONTRAST BETWEEN RELATIVE RISK AND IT’S GETTING INCREASINGLY HARD TO GET POPULATION CONTROLS. THE GOLD STANDARD FOR DOING THIS IS RANDOM DIGIT DIALLING, RDD. IN TODAY’S ENVIRONMENT WE CAN CALL UP PEOPLE AT RANDOM. AND IN OUR LARGE POPULATION OF COHORT THE RESPONSE RATE TENDS TO BE 3% TO 5%. AND IT’S A REPRESENTATIVE SAMPLE. AND THAT’S JUST THE WAY IT IS TODAY. OKAY. IF YOU GET A CONSULTANT AND AN EPIDEMIOTHERE IS EPIDEMIOLOGICAL COMPONENT AND DID YOU DO HYPOTHESIS AND DID YOU DO CALCULATIONS AND VAL DATE YOUR BIOMARKERS. THE MOST COMMON QUESTION WE GET IS OH, I HAVE A GRANDMOTHER WHO SMOKED HER WHOLE LIVE. SHE NEVER DID EXERCISE. SHE ATE BACON AND DONUTS AND LIVED TO 90. WHY IS THAT? OF COURSE THE ANSWER IS IT’S A PROBLEMISTIC. IT’S NOT DETERMINISTIC. THERE ARE OUTLIERS. IT’S MATHEMATICALLY INEVITABLE THERE’S OUTLIERS. WE MAKE CANCER MAPS AND THIS IS ONE THAT WAS MADE ABOUT 15 YEARS AGO. AND YOU CAN MAKE THEM USING SURVEILLANCE EPIDEMIOLOGY AND END RESULTS IT INVOLVED 26% OF THE U.S. POPULATION, 11 STATES. THERE’S A LOT OF RESOURCES FOR IT ONLINE. I’LL LET YOU FIND THEM. THE REASON I MADE THIS GRAPH IS TO LOOK AT CANCER RATES IN RELATION TO TIME ZONES AND BECAUSE WE HAVE A HYPOTHESIS YOUR PHYSICIAN AND TIME ZONE IS RELATED TO CERTAIN HORMONE RELATED CANCERS BECAUSE OF CIRCADIAN DISRUPTION. WE’RE LOOKING FOR A TREND WHICH IS A LITTLE BIT HARD TO SEE. ANYWAY, WE USED DATA WHICH IS A CONSORTIUM OF CANCER REGISTRIES AND IT’S FOUR TIMES LARGER THAN SEER SO THERE’S GREAT RESOURCES. SO JUST TO SHOW YOU AND ANOTHER THERE’S EMERGING AREA VERY EXCITING IN THE LAST FEW YEARS USING GEOGRAPHIC INFORMATION SYSTEMS USING SATELLITE DATA TO GET COOL INFORMATION ABOUT ENVIRONMENTAL FACTORS FROM SATELLITES. LOOKING AT CANCER INCIDENT AND TIME AND YOU SEE SOMETHING HAS CANCER INCIDENTS HAS GONE UP WITH MEN. DOES ANYONE KNOW WHAT CAUSED THE BUMP IN THE ’90s. HERE’S WHITE MEN AND AFRICAN AMERICAN MEN AND WOMEN ARE FLAT. THE ANSWER IS IT WAS PROSTATE CANCER. AND IT WAS DUE TO THE FACT THAT PSA SCREENING WAS INTRODUCED AND THERE WERE EARLY STAGES OF PROSTATE CANCER WERE DIAGNOSED. IT’S SURVEILLANCE BIAS. HERE’S AN INTERESTING FINDING THE INCIDENTS RATE AND THE MORTALITY RATE AND PEDIATRIC CANCER ARE QUITE DIFFERENT. AND WHAT DOES THAT INDICATE? IT SHOWS YOU THAT TREATMENT IS EFFECTIVE. OUR TREATMENTS FOR PEDIATRIC CANCER, MANY KINDS OF PEDIATRIC CANCER DO A DECENT JOB. A FEATURE THAT EPIDEMIOLOGISTS ARE CONCERNED WITH IS CAUSATION. AND ARE THERE A LOT OF WAYS THAT EPIDEMIOLOGISTS ADDRESS CAUSATION. I’LL TELL YOU ABOUT THIS CRITERIA. AN EXCITING AREA IS MEDIATION ANALYSIS. AND GENETICS TO DETERMINE CAUSALITY AND BIOMARKERS. THIS PARTICULAR BOOK THE BOOK OF WHY I RECOMMEND TO ANYONE THAT IS INTERESTING IN — INTERESTED IN THIS AREA. IT DESCRIBES SOME OF THE MATHEMATICS OF MEDIATION ANALYSIS AND IT’S AN EXCITING AND COOL APPROACH. FOR INSTANCE, IN CLIMATE YOU WANT TO KNOW TO WHAT EXTENT IS STRENGTH OF HURRICANES RELATED TO CLIMATE CHANGE AND USE MODEL BASED APPROACHES TO DRAW IN FERENCE ABOUT THAT — IN FERENCE ABOUT THAT. WE CAN PROVE A CAUSE IN EPIDEMIOLOGY BY CARBISTICS AND — CHARACTERISTICS AND WE TEND TO ASSOCIATE A CAUSE IF IT’S CONSISTENT AND PRESENT IN A NUMBER OF DIFFERENT STUDIES AND IF THERE’S A DOSE RESPONSE. MORE OF A CAUSE IF THERE’S MORE OUTCOME. IF THE CAUSE OCCURS FIRST TEMPORALLY OR CAUSES BEFORE OUTCOMES AND IF THE BIOLOGY MAKES SENSE IF THERE’S MECHANISTIC STORY BEHIND IT. AND YOU LOOK AT THE ASSOCIATION OF CANCER AND RED MEAT CONSUMPTION ODDS RATIO OF 1.2. IT’S OBVIOUS. LOW RISKS TEND TO BE CALLED INTO QUESTION. FIRST, THE RISK IS NOT CRITICALLY SIGNIFICANT AND I DIDN’T GO INTO IT BUT RELATIVE RISKS, LOW RELATIVE RISKS ARE ASSOCIATED WITH VERY NON-SIGNIFICANT ABSOLUTE RISKS. SO AN ODDS RATIO OF 1.2 IS AN EXTREMELY NOT SIGNIFICANT ABSOLUTE RISK. RESIDUAL CONFOUNDING TENDS TO DISTORT LOW ODDS RATIOS. SO WHAT COULD DISTORT RED MEAT? ANYTHING ASSOCIATED WITH IT LIKE SMOKING AND OTHER SHARED RISKS. THERE’S A LONG LIST OF THEM HERE. MEDIATORS TEND TO DRINK MORE ALCOHOL AND EXERCISE LESS. THEY’RE MORE OFTEN SEDENTARY AND LESS EDUCATED AND CONDITION ASSUME MORE PROCESSED FOODS AND SUGAR AND FAT. AND I SHOWED THE PREVIOUS SLIDE LAST YEAR. THERE WERE PAPERS IN THE AANNALS OF INTERNAL MEDICINE SAYING THERE’S LITTLE EVIDENCE FOR ADVERSE CANCER AND CARDIOVASCULAR OUTCOME WITH RED MEAT SO IT’S GOOD TO HAVE SOME SKEPTICISM ABOUT THESE KINDS OF FINDINGS. IN GENERAL IT’S GOOD TO HAVE A LOT OF SKEPTICISM ABOUT ISOLATE DIETARY FINDINGS. WHEN YOU READ ABOUT YOGURT I’D BE CAUTIOUS ABOUT THAT KIND OF STUDIES. HERE’S AN EXAMPLE OF THE LUNG CANCER TO SHOW A TRUE ASSOCIATION. HERE’S THREE DIFFERENT COHORT STUDIES AND NOTICE THE CONSISTENCY AND THE DOSE RESPONSE. THIS IS THE ODDS RATIO AND CIGARETTE SMOKE PER DAY AND A BEAUTIFUL CONSISTENCY BETWEEN THE THREE COHORT STUDIES AND RISK OF LUNG CANCER. WOMEN BEGAN SMOKING LATER THAN MEN IT WAS SOCIALLY ACCEPTABLE. AND THE RATE AS MALE SMOKING INCREASED, MALE LUNG CANCER INCREASED AND AS FEMALE SMOKING INCREASED, FEMALE CANCER RATES ROSE. THIS IS A FAMOUS STUDY IN THE NEW ENGLAND JOURNAL WHERE THEY ATTACH ATTACHED EAGLES TO SMOKING MACHINES AND SHOWED THE HISTOLOGIC CHANGES AND IN HUMANS GOING TO EARLY CARCINOMA TO LUNG CANCER. THIS WAS GOOD MECHANISTIC EFFORTS IMPLICATING TOBACCO SMOKE IN LUNG CANCER DEVELOPMENT. FINALLY, A NICE STUDY IN THREE DIFFERENT COHORTS WHERE THEY HAD PEOPLE QUITTING SMOKING AND SHOWED AS THE YEARS PASSED QUITTING SMOKING THE RATE OF LUNG CANCER DROPPED CONSISTENTLY. IT’S HIGHLY COMPELLING EVIDENCE ALSO. WHAT KINDS OF THINGS HAVE EPIDEMIOLOGIST ACCOMPLISHED? I CAN TOUCH ON A FEW EXAMPLE. GENERAL AND SPECIFIC CAUSES OF CANCER. ADVOCATES OF PUBLIC HEALTH. WE TALKED ABOUT TOBACCO. I’LL MENTION A LITTLE BIT ABOUT SECONDARY TOBACCO SMOKE BECAUSE IT’S SOMETHING THAT EFFECTS ALL OF OUR LIVES. AND THERE’S BEEN INVOLVEMENT IN DIFFERENT AREAS HAVE SILICON BREAST IMPLANT TO CHERNOBYL. THERE’S A WHOLE UNIT THAT FOLLOWS CHERNOBYL AND A LOT OF THESE OTHER AREAS. AND THERE’S A THOUGHT MOST CANCER IS DUE TO THE ENVIRONMENT AND THAT’S BECAUSE OF THE DRAMATIC INCREASES IN CANCER RATES OVER TIME AND GEOGRAPHY ARE ONLY COMPATIBLE WITH INTRINSIC ENVIRONMENTAL CAUSES. THIS IS A SLIDE THAT SUMMARIZES SOME OF THE DATA. THIS SHOWS THE COUNTRY THE RATES HAVE THE HIGHEST AND THE RATES ARE THE LOWEST. THE DIFFERENCE NOT 1.2 OR 1.7. THE DIFFERENCES ARE A HUNDREDFOLD IN SOME CASES. SOME CANCERS THE DIFFERENCE NOT SO GREAT BUT THERE’S STILL QUITE SUBSTANTIAL. MELANOMA, LUNG AND THOSE ESTABLISHED AS CARCINOGENS AND SOME OTHERS ARE LESS. CANCER MAPS. HERE’S AN EXAMPLE OF A COPPER SMELTER THAT CAUSED A LUNG CANCER HOT SPOT IN A PARTICULAR AREA IN MONTANA. IT WAS REMOVED AND THE HOT SPOT WENT AWAY. IN CHINA WE HAVE A STUDY HERE AND FOCUS ON INDOOR OVENS AND THEY WERE NOT VENTED. SO THE POLLUTION INDOORS WAS SPECTACULARLY HIGH AND WHEN THEY INTRODUCED INDOOR VENTING THESE RATES IMPROVED TREMENDOUSLY. AND OF COURSE STUDIES HAVE BEEN DONE SHOWING YOU COULD HAVE SUBSTANTIAL REDUCTION IN CANCERS BY IDENTIFYING AND ELIMINATING CERTAIN CANCER RISK FACTORS PARTICULARLY FOR EXAMPLE HPV IS A GREAT EXAMPLE. THE TWO BIGGEST RISK FACTORS, SMOKE AND ALCOHOL COULD MAKE SUBSTANTIAL IMPACTS. IT’S TOUGHER TO DEAL WITH FAMILY HISTORY. A WORD ABOUT TOBACCO BECAUSE IT’S STILL THE NUMBER ONE PREVENTIBLE CAUSE OF MORBIDITY AND MORTALITY AND RESPONSIBLE FOR 1-5 OVERALL DEATHS. THE NUMBER OF DEATHS WORLDWIDE CONTINUE TO INCREASE WHICH IS HARD TO BELIEVE BUT IT’S TRUE. IT’S RELATED TO CANCERS THAT ARE DIFFICULT TO TREAT. THE TOBACCO-RELATED DISEASE COSTS OVER $10 MILLIBILLION A
YEAR. AND SO THERE’S STILL A LOT OF WORK TO DO WITH TOBACCO. WE’RE DOING IT SINCE THE SURGEON GENERAL’S REPORT IN OVER HALF A CENTURY AGO. RATES OF SMOKING HAVE GONE DOWN. IT’S NOT THE CASE IN THE DEVELOPED WORLD. HUNDREDS OF MILLIONS OF DEATHS NEEDING TO OCCUR. WE CAN BE THANKFUL THOUGH STUDIES IN ENVIRONMENTAL TOBACCO SMOKE SHOWED CONSISTENT RISK. THIS WAS PUSHED BY SPECIAL INTEREST GROUPS. AND IT’S FUNDED AND PUSHED STUDIES AND THOSE STUDIES SHOWED THAT SPOUSES OF SMOKERS WERE AT HIGHER RISK AND THAT IN TURN EVENTUALLY LED TO CONSENSUS ENVIRONMENTAL TOBACCO SMOKE IS A CARCINOGEN AND ANALYSES ALL AGE AGEED — AGREED AND LED TO CLEAN AIR LEGISLATION AND WHY WE ALL CAN GO TO THEATERS AND REST RAJTS AND OTHER PLACES — RESTAURANTS AND OTHER PLACES AND NOT HAVE TO BREATHE OTHER PEOPLE’S SMOKE. WE’VE DONE STUDIES ON LIGHT AND INTERMITTENT SMOKING AND THIS IS AN AREA RISING PARTICULARLY IN SELECTED ETHNIC GROUPS. AND IN NATIONAL SURVEYS SUBSTANTIAL NUMBERS OF PEOPLE INTERMITTENTLY SMOKE. THIS IS A SCARY THING AND THE QUESTION IS IS IT ASSOCIATED WITH DANGER. WHEN YOU JUST SMOKE ON WEEKENDS OR WHEN YOU GO TO A BAR IT’S OKAY. NO. NOT THE CASE. ALL MORTALITY INCREASES SUBSTANTIALLY AS YOU SMOKE. EVEN INTERMITTENTLY. THERE’S RADIATION, CHERNOBYL, INFECTIONS TO SAY THESE ARE ALL AREAS OF VERY ACTIVE STUDY. OCCUPATIONAL CARCINOGENS. FIELDING STUDIES OF OCCUPATIONAL AND ENVIRONMENTAL CARCINOGENS IS A VERY DIFFICULT THING BECAUSE THERE’S OPPOSITION. SO MANUFACTURING GROUPS ATTACK YOU AND YOU GET BROUGHT BEFORE CONGRESS AND YOU HAVE TO TESTIFY AND THEY USE THE FREEDOM OF INFORMATION ACT TO DEMAND ALL YOUR DATA AND HIRE INDUSTRY SHELLS TO ANALYZE YOUR DATA AND FIND EVERY FLAW. IT’S A RATHER DIFFICULT THING. BUT WE DO IT. AND THERE’S WAYS TO STUDY OCCUPATIONAL CARCINOGENS AND PESTICIDES AND STUDIES AGAINST THE CONTINUAL WAVE OF OUTSIDE OPPOSITION. SO WHAT CAN GO WRONG? SO HERE’S THE OPINION AND PERSPECTIVE OF HAVING BEEN IN THE AREA 30 YEARS. I WANTED TO GIVE YOU FLAVOR OF THE THINGS THAT GO WRONG. THE PROBLEM WITH EXPOSURES AS I TOLD YOU — AND I’LL TRY TO FINISH IN 20 MINUTES TO LEAVE ROM FOR QUESTIONS. FOR MANY CANCERS WE HAVE NO CLUE WHAT ARE THE EX TRENSIC AND VARIETIAL CAUSE. BRAIN, SARCOMAS, PEDIATRIC AND LUNG AND NON-SMOKERS, UP TO A QUARTER OF LUNG CANCER IS IN NON-SMOKERS. SOME ARE ASBESTOS AND RADON AND HEAVY METALS BUT A SUBSTANTIAL NUMBER WE HAVE NO CLUE WHAT’S GOING ON. ALL THAT VARIATION I SHOWED YOU WE CAN EXPLAIN HALF OF IT. THE REST IS VERY UNKNOWN. EARLY LIFE EXPOSURES ARE A BIG GAP. WE DON’T KNOW WHAT REALLY IS GOING ON. WE KNOW THAT THERE ARE VULNERABILITIES AT CERTAIN TYPES OF LIFE. FOR EXAMPLE, SMOKING FOR YOUNG WOMEN AT [INDISCERNIBLE] IS LIKELY A RISK FACTOR BUT NOT LATER UPON MANY EXPOSURES ARE DIFFICULT TO ASSESS AND SO PEOPLE HAVE STARTED TO ASK ABOUT SLEEP BUT THEY DON’T ASK ABOUT CRONO TYPE. WHETHER YOUR TENDENCY IS TO BE AN EARLY OR LATE RISER. THEY DON’T ASK MANY ABOUT QUALITY OF SLEEP WHICH IS SUPER IMPORTANT. SO IT’S WELL ESTABLISHED THAT SLEEPING LESS THAN SIX HOURS OR MORE THAN 10 HOURS IS BAD. THAT’S PROBABLY BECAUSE THIS OTHER SLEEP PATHOLOGY GOING ON THERE. THINGS LIKE SNORING OR SLEEP APNEA. AND SO YOU NEED TO ASK ABOUT THOSE KINDS OF THINGS. ACTIVITY LEVELS IT’S REALLY DIFFICULT TO ASK ABOUT ACTIVITY AND MORE DIFFICULT TO ASK ABOUT INACTIVITY WHICH IS A SEPARATE AND INDEPENDENT FACTOR. DIET IS NOTORIOUSLY DIFFICULT. NO ONE ASKED ABOUT CIRCADIAN DISRUPTION. LIGHT IS IMPORTANT. THERE’S NEW AND DIVERSE THINGS IN THE ENVIRONMENT AND CLIMATE CHANGE HAS BEEN IGNORED AS AN AREA TOO HOT TO STUDY. HERE’S AN EXAMPLE OF MALIGNANCY THE MOST COMMON IN THE WESTERN WORLD. WE HAVE NO IDEA WHAT THE ENVIRONMENTAL CAUSE IS. FAMILY HISTORY AND AGE. THAT’S IT. OKAY. I’D LIKE TO SAY A WORD ABOUT GENETICS. GENES ASSOCIATED WITH ALL THE COMMON CANCERS CONFER SOME RISK. WE’VE KNOWN THIS SINCE — WELL, WE’VE KNOWN IT A FEW DECADE BASED ON EPIDEMIOLOGIC AND GWA STUDIES BUT KNOW LITTLE HOW GENE AND ENVIRONMENT WORK TOGETHER. YOU’LL HEAR A LOT ABOUT GENE ENVIRONMENT STUDIES BUT THEY TEND TO BE UNDERPOWERED AND THERE’S LIKE TWO OR THREE GENE VARIETY INTERACTIONS THAT ARE WELL ESTABLISHED AND THE REST ARE NOT BEEN STUDIED WITH SUFFICIENT POWER TO ESTABLISH ANYTHING. THAT SAID, ALL CANCER SEEMS TO BE ASSOCIATED WITH SOME GENETIC ALTERATIONS. WHEN WE TALK ABOUT GENETICS, YOU HAVE TO BE CAREFUL. WE TALK ABOUT GERM LINE AND SOMATIC AND I’M TALKING ABOUT SOMATIC WHEN I SAY ALL CANCER. FAMILY STUDIES ARE USED TO STUDY RARE MUTATIONS THAT DICTATE CERTAIN CANCERS. POPULATION CANCERS LOOK AT THE COMMON GENETICS AT RAGES. — ALTERATIONS AND CANDIDATE VERSUS AGNOSTIC. AND DIAGNOSTIC IS WHAT WE LOOK FOR. AND LOOKING AT FAMILIES. WE HAVE FAMILIES WHERE WE HAVE WHERE CERTAIN LEUKEMIAS SUBROGATE. AND A LOT OF MAMMALIAN GENES HAVE BEEN CLONED OUT OF SUCH. AND THIS IS AN OLDER SLIDE WHEN WE HAD 240 DISEASE AND NOW THERE’S OVER 1,000. FOR A SURPRISING NUMBER OF THESE WE REALLY DON’T KNOW. WE DON’T KNOW WHAT THE UNDERLYING GENE IS. SO I SAID WE DID A LARGE CASE CONTROL WITH 2,000 CASES AND 2,000 CONTROLS OVER 10 YEARS AGO. WHY DID WE DO IT? LUNG CANCER STILL NUMBER ONE IN TERMS OF MORTALITY. WE KNOW TOBACCO THE’ BIG RISK FACTOR AND WE SAID, LOOK, BOTH TREATMENT AND SCREENING DON’T WORK. WE NEED TO UNDERSTAND THE GENETICS BETTER. WE NEED TO UNDERSTAND HOW GENES AND ENVIRONMENT WORK TOGETHER. WE NEED TO UNDERSTAND MORE ABOUT THE RISK FACTORS. OUR STUDY WAS AFTER BEHAVIORAL FACTORS. WE WANTED TO GET BIOLOGIC INFORMATION AND COLLECT TISSUE IN OPERATING ROOMS. WE SHOWED, FIRST, YES, FAMILY HISTORY IS A RISK FACTOR. HAVE YOU A RELATIVE WITH LUNG CANCER YOU HAVE TO TAKE INTO ACCOUNT OTHER RISK FACTORS AND THE ODDS RATIOS IS GENETIC. TRADITIONAL EPIDEMIOLOGY LOOKS AT AN EXPOSURE AND DISEASE AND USE STATISTICS TO INFER RELATIONSHIP AND WE WANTED EPIDEMIOLOGY WHERE YOU LOOK AT GENES AND DIFFERENT FACTORS ON THE CAUSAL PATHWAY. AND WE LOOK AT THE BEHAVIORS RELATED TO THE EXPOSURES. FOR INSTANCE, IF YOU HAVE A TENDENCY FOR ADDICTION, HOW DOES THAT ALTER YOUR SMOKING AND OKAY, HAVE YOU LUNG CANCER BUT HOW DOES THAT EFFECT YOUR SURVIVAL. HOW DO THE GENES AFFECT WHETHER YOU LIVE OR DIE OR RESPOND TO THE TREATMENT? THOSE ARE THINGS. AND WE GOT TISSUE. WE INCLUDED DETAILED DIETARY ASSOCIATIONS INCLUDING ALL SORTS OF QUESTIONNAIRES TO ASSESS STRESS, ANXIETY, ADDICTION, HDHD. WHETHER THEY FELT LIKE THEY WANTED TO QUIT WHETHER THEY WERE ABLE TO QUIT AND OF COURSE TREATMENT SURVIVAL PROGNOSIS. DON’T HAVE TIME TO GO INTO THE ACCOMPLISHMENTS OF MOLECULAR EPIDEMIOLOGY IN GENERAL. THE STUDY HAS PUBLISHED OVER HUNDREDS OF PAPERS IN DIFFERENT AREAS. ONE THING THE STUDY DOES AND ALL THE STUDIES DO NOW IS WE FORMED A CONSORTIUM. SO OUR LUNG CANCER STUDY BASICALLY WE CONTRIBUTE TO THREE DIFFERENT LUNG CON SORE THAT — CONSORTIA. OF 2,000 LUNG CANCER CASES WE HAVE 150 NON-SMOKERS SO WE PULL OUT ALL THE NON-SMOKERS TO INVESTIGATE WHAT’S GOING ON WITH NON-SMOKERS. WE ALSO CONTRIBUTE TO QUESTIONNAIRE CONSORTIA SO IF ANYONE IS FUNDING A NEW STUDY, THEY CAN BENEFIT FROM THE EXPERIENCE OF EVERYBODY ELSE AND PULL IN THE BEST QUESTIONNAIRES TO CHARACTERIZE EXPOSURES. SO THOSE ARE SOME CHALLENGES. WHAT ELSE CAN GO WRONG? IN SCIENCE, PARADIGM CHANGE IS HARD. THERE WAS THE STRUCTURE OF SCIENTIFIC REVOLUTIONS WAS WRITTEN AND HE SAID IN A NUTSHELL THINGS DON’T CHANGE BASICALLY THE OLD SCIENTIST HAVE TO DIE OFF. THAT’S THE ONLY WAY ANYTHING CHANGES AND I THINK THAT’S A BIT OF AN EXAGGERATION. WE ACTUALLY CHANGE A LOT. YOU CAN MAKE THE ARGUMENT THAT PEOPLE BECOME ENTRENCHED WITH WHAT THEY BELIEVE AND IT’S HARD TO CHANGE THEM. SO HERE’S AN EXAMPLE. HERE ARE OBESITY RATES FROM 1992 TO 2015. AND THIS IS A STAGGERING CHANGE. NO STATE HAS OVER 20% OBESITY AND TODAY NO STATE HAS UNDER 20%. IT’S HARD TO BELIEVE. IF YOU WANT AN INTERESTING EXERCISE GO TO YOUR PARENTS’ COLLEGE YEAR BOOK AND LOOK THROUGH IT AND LOOK AT THE PICTURES. THEY LOOK LIKE STICK FIGURES. THEY’RE SO THIN. IS THERE SOMETHING WRONG WITH THEM? ARE THEY NOT FEEDING PEOPLE? WHAT WAS THE MATTER? OKAY, SO FOLLOWING OBESITY, DIABETES HAS ACCELERATED. HERE’S DIABETES PREVALENCE IN 2012 AND IT’S CONTINUED TO RISE. 50% OF THE POPULATION IS DIABETES. WHO KNOWS WHAT PERCENTAGE IS DIABETIC OR PRE-DIABETIC. GREATER THAN 15%, PRE-DIABETIC. GREATER THAN 50%. . SIT — IS IT ONLY THE UNITED STATES? NO. VIRTUALLY EVERY COUNTRY IS FOLLOWING THE SIMILAR TREND. I DON’T KNOW OF ANY COUNTRY THAT’S NOT. DO WE CARE? YES, THERE’S 200 CONDITIONS ELATED AND I WAS AT A MEETING AT CLEVELAND CLINIC LAST WEEK WHERE THEY HAD THE FIRST LECTURE IS ALWAYS OKAY, WHY IS THERE AN OBESITY EPIDEMIC. THEY DON’T REALLY KNOW. SO THERE’S ALWAYS A LIST OF CONTRIBUTING FACTORS, CHANGES INDICT, MACRO NUTRIENTS, FAST FOOD, THE ENVIRONMENT, CHANGES IN ACTIVITY, WE’RE LESS ACTIVE, WE’RE LOOKING AT OUR PHONES ALL THE TIME. THE SOIL IS DEPLETED OF KEY NUTRIENTS. WE’RE SUR — CIRCADIAN DISRUPTED. ALL THESE ARE LONG LISTS BUT NONE ARE ACTUALLY WHEN YOU EXAMINE EACH ONE CLOSELY IS A GREAT EXPLANATION. IF YOU LOOK AT HISTORY, ONE CLUE IS THAT WAY BACK AND THIS IS WITH THE DIETARY HEART HYPOTHESIS IN THE ’70s WHEN EISENHOWER GOT HIS HEART ATTACK AND EVERYONE PANICKED. AT THE TIME NO ONE SAID YOU’RE A TWO-PACK A DAY SMOKER. THEY SAID YOU HAVE SAUSAGE FOR BREAKFAST AND YOU NEED TO CUT BACK AND IN ITALY EVERYONE WAS EATING PASTA AND NO ONE WAS FAT AND THEY SAID I THINK WE NEED TO DO LOW FAT. I’M EXAGGERATING. THE McGOVERN COMMISSION PROPOSED LESS FAT AND AS A DIETARY CHANGE AND IF YOU TAKE THE FAT OUT OF FOOD? SUGAR AND CARBOHYDRATES AND YOU DON’T HAVE MEAT AND MILK AND DAIRY AND YOU HAVE TO PUT IN PROCESSED VEGETABLE OILS. YOU HAVE THE FOOD PAIR — PYRAMID FROM THE USDAs. YOU GET REVISIONS FROM THEIR RECOMMENDATIONS THIS WEEK. AND THE AMERICAN HEART ASSOCIATION PUTS THEIR HEART HEALTHY LOGO ON FOODS THAT CONTAIN OATS AND OTHER MARGARINE AND THINGS THAT ARE LOWER CHOLESTEROL BUT LOADED WITH SUGAR. BECAUSE OF THESE DIETARY CHANGES, OVER THE DECADES THE CARB CONSUMPTION HAS GONE UP. CARB CONSUMPTION HAS GONE DOWN. SATURATED FAT HAS GONE DOWN AND PEOPLE CONSUME LESS MILK NOWADAYS BUT THAT DIDN’T DO MUCH GOOD AND THE STANDARD AMERICAN DIET IS IDENTICAL TO OBESOGENIC RAT AND WHEN THE PROTEIN IS LOW AND FAT’S MODERATE, CARBOHYDRATE’S MODERATE. ESSENTIALLY, LIKE A DONUT. AND THE LANCET COMMISSION AND IF YOU READ IT YOU’LL SEE STUDIES AND THEY’RE PROMOTING A PLANT-BASED DIET. AND THE MOST FAMOUS EPIDEMIOLOGIST FROM HARVARD AND HE IS VEGETARIAN. HE’S A GOOD GUY. THERE’S POSITIVE FEATURES TO THIS DIET. I FEEL THERE’S A LOT OF DANGER IN PROMOTING A DIET THAT LACKS SCIENTIFIC BACKGROUND. WE MADE DIETARY CHANGES IN THE UNITED STATES DECADE AGO THAT WERE NOT SCIENCE BASED. BASE ON THE COMMISSION AND THEY SAID WE HAVE TO DO SOMETHING. SO THERE’S A LOT OF DEBATE IN NUTRITIONAL EPIDEMIOLOGY AND THERE’S BEEN CRITICISM EPIDEMIOLOGY AND THE HARVARD EPIDEMIOLOGISTS ARGUED AGAINST HIM. I THINK WE NEED A LOT OF REFORM IN NUTRITIONAL EPIDEMIOLOGY BECAUSE IT’S A CATASTROPHIC SITUATION. THE OBESITY EPIDEMIC AND THE COSTS OF THE OBESITY AND DIABETES EPIDEMIC IS A THIRD OF A TRILLION WORLD WIDE AND AN UNSUSTAINABLE COST. MORE NEEDS TO BE DONE. HERE’S AN EXAMPLE OF THE MEAT STUDIES. MEAT WAS ASSOCIATED WITH COCLON CANCER. BUT WHEN YOU THINK OF HOW MEAT IS CONSUMED, IT’S CONSUMED WITH OTHER FACTORS. THE QUESTION WE USE TO ASSESS MEAT ARE HIGHLY LIMITED AND DON’T CAPTURE ALL THE OTHER STUFF THAT GOES WITH THE MEAT. THERE’S A LOT OF METHODOLOGIC LIMITATIONS HERE. I SAID I’D STOP A FEW MINUTES BEFORE SO I’D RAPIDLY GO TO THE LAST SECTION ON PREVENTION. RANDOMIZED CLINICAL TRIALS AND LOW FAT. I SAID THERE WAS NO SCIENTIFIC BAS BASE S AND I REMEMBER WHEN THERE WAS A POLYP PREVENTION TRIAL AND THERE WAS A STUDY IN THE NEW ENGLAND JOURNAL WHERE THEY SPENT AN ENORMOUS AMOUNT OF MONEY TO RANDOMIZING PEOPLE TO A LOW-FAT DIET WITH DIETICIANS EVERY WEEK AND HAD THE WHOLE GRAINS AND LOW-FAT MARGARINE AND FOR YEARS THEY DID THIS DIET AND THEN CALCULATED THE NUMBER OF POLYPS AND THE CURVE WAS IDENTICAL. THERE WAS NO BENEFIT FROM THE LOW-FAT AND PRETTY MUCH EVERY OTHER STUDY THOUGH ONE STUDY SHOWED A TINY DIFFERENCE FOR ONE CARDIOVASCULAR END POINT. ANYWAY, THE STUDIES WERE NOTHING AND THEY SPENT MILLIONS ON THIS. I’LL SKIP OVER THE REST OF THE OBESITY BUSINESS. MY STUDIES ARE OF INSULIN. I THINK INSULIN’S PROBABLY THE BAD ACTOR. OKAY. WHERE SHOULD EPIDEMIOLOGY GO? WE HAVE TO GO AFTER EXPOSURE AND WE NEED MORE EXPENSIVE DATA. WE NEED TO REDUCE MISCLASSIFICATION AND VALIDATE DATA AND NEED BETTER RISK MODELS. TRADITIONAL RISK FACTORS ARE WHAT WE USUALLY COLLEC SO TECHNOLOGY CAN CAPTURE SLEEP. WE’VE DONE THIS AND HOW TO CAPTURE ACTIVITY AND INACTIVITY WITH ACTIVEGRAPHY AND CIRCADIAN VARIATION AND CAPTURE SOCIAL DATA. YOU CAN CAPTURE PULSOX AND TO DO RISK MODELS YOU NEED TRADITIONAL IP DATA AND GENETICS AND BIOMARKERS AND TECHNOLOGY AND THAT’S HOW YOU’LL GET RISK MODELS THAT WILL WORK. I’LL STOP THERE.>>QUESTIONS.>>THANK YOU FOR YOUR TALK. I WAS WONDERING ABOUT THE NEW WAYS OF SMOKING THE VAPES AND THE E-CIGARETTES. IS THERE ANY STUDIES YOU GUYS HAVE DONE OR ARE DOING FOR THAT?>>I’M SORRY WHICH STUDIES?>>VAPING AND E-CIGARETTES.>>SO TWO STUDIES HAVE BEEN IDENTIFIED FOR BIG STUDIES. ONE IS CANNABIS AND ONE IS VAPING. NCI HAS BEEN A LITTLE BIT RETICENT TO GET INTO BOTH OF THOSE AREAS. WHY IS THAT? THE MAIN REASON IS WE STUDY OR ARE MOST INTERESTED IN CANCER AND CANCER IS A TOUGH END POINT FOR VAPING BECAUSE WHATEVER VAPING IS DOING, CANCER IS NOT THE MOST LIKELY OUTCOME. IT’S LIKELY A LONG-TERM OUTCOME. SO WHAT WE NEED TO DO IS CAPTURE VAPING IN OUR COHORTS BUT OUR COHORTS FOR ECONOMIC REASONS ARE FOCUSSED ON THE AGE GROUPS THAT GET CANCER. WE DON’T HAVE 20-YEAR-OLD COHORT. WHY IS THAT? YOU HAVE TO WAITED FIVE DECADES FOR THEM TO GET CANCER. FOR PEOPLE IT’S LIKE THE COHORTS WOULD LIKE TO BE ALIVE WHEN THEY CAN GET ENOUGH POWER, ACCUMULATE ENOUGH CANCER END POINTS. FOR REASONS LIKE THIS, NCI HAS NOT BEEN THE LEAGUE INSTITUTE TO DO THESE STUDIES. SO IF YOU SEE THIS EPIDEMIC NOW OF INFECTIOUS OR TOXIC DISEASES COMING OUT OF VAPING AND NCI’S NOT LOOKING AT IT BECAUSE IT’S NOT OUR END POINTS. IT’S EXTREMELY IMPORTANT AND CRITICAL AND THE CONTROVERSY IS HEY, IS THE DISEASE THE SHORT TERM DISEASES ARE WE GETTING BENEFIT IN THAT THESE PEOPLE ARE ACTUALLY QUITTING SMOKING OR IS THE VAPING ACTUALLY A STEP AND THESE PEOPLE WILL MOVE ON TO TOBACCO SMOKING DOWN THE ROAD. SO — >>WHAT ABOUT MICROBIOTA CHANGES AND OBESITY?>>CHANGES IN THE MICROBIOME AND OBESITY ARE ONE OF THE MOST CONSISTENT FINDINGS IN ANIMALS. SO YOU DO GET CHANGES IN SPECIES AND SOME RATIOS AND THAT HAS NOT BEEN WELL STUDIED. IN FACT THERE’S BEEN A LOT OF WORK IN OUR GROUP, NOT MY GROUP BUT OTHER GROUPS TO VALIDATE MICROBIOME STUDIES TO DO THEM IN A REPRODUCIBLE AND LARGE-SCALE IN LARGE POPULATIONS. SO WE’VE KIND OF PASSED THROUGH THE LET’S JUST DO A FEW PEOPLE AND SEE WHAT WE SEE STAGE TO LET’S DO THIS IN A WAY THAT IT CAN BE REPRODUABLE IN A LARGE COHORT STUDY AND DO A COHORT OF HUNDREDS OF PEOPLE AND FOLLOW THEM OVER WHICH MICROBIOME CHANGES ARE REALLY ASSOCIATED WITH DISEASE. I THINK THE OBESITY FEATURES ARE VERY IMPORTANT BUT ONE THING YOU’D LIKE TO SEE IS WHEN PEOPLE LOSE WEIGHT DO THEY ACTUALLY CHANGE THEIR MICROBIOME? UNFORTUNATELY, IN COHORTS YOU PROBABLY ARE AWARE THERE ARE NO GREAT INTERVENTIONS THAT MAKE PEOPLE SUSTAIN A WEIGHT LOSS OVER TIME. THE THREE MAJOR INTERVENTIONS ARE SURGERY, WHICH TO SOME EXTENT DOES WORK. MEDICATIONS, PARTIALLY WORK AND LIFESTYLE CHANGE WHICH UNFORTUNATELY DOESN’T WORK SO WELL. QUE DON’T HAVE WE DON’T HAVE LARGE STUDIES TO LOOK AT THE MICROBIOME. IF YOU TAKE HUNDREDS OF PEOPLE AND PUT THEM ON A DIET AND MAYBE A YEAR LATER ONLY A SMALL NUMBER WILL REALLY SUSTAIN THE WEIGHT LOSS. YOU DON’T HAVE MUCH POWER.>>ANYTHING ELSE? OKAY. THANK YOU, NEIL.>>THANK YOU.

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