The Genetic Basis of Kidney Cancer: Targeting the Metabolic Basis of Disease


>>>GOOD AFTERNOON, EVERYONE. WELCOME TO A SPECIAL WEDNESDAY AFTERNOON LECTURE. THE ANNUAL ASTUTE CLINICIAN LECTURE. AND ONE OF OUR OWN. DR. MARSTON LINEHAN WILL BE SHORTLY COMING UP TO THE PODIUM TO TELL YOU ABOUT HIS REMARKABLE RESEARCH OBSERVATIONS IN THE AREA OF KIDNEY CANCER. IT’S MY PLEASURE TO HAVE A CHANCE TO INTRODUCE HIM, SOMEBODY I HAVE KNOWN FOR PROBABLY 15 OR 20 YEARS, WHO IS ABSOLUTELY A LEADER IN THIS FIELD THAT HAS CONTRIBUTED AMAZING INSIGHTS INTO THIS COMMON FORM OF CANCER AND SOMEONE WHO BOTH RUNS AN AMAZING LABORATORY, OFTEN THE PLACE WE BRING SPECIAL DIGNITARIES TO, LIKE THE PRESIDENT OF THE UNITED STATES, FOR INSTANCE. BUT WHO ALSO IS AN ACTIVE SURGEON DOING IT ALL, AND DOING IT WITH THE MOST REMARKABLE PERSONAL INVOLVEMENT THAT YOU WOULD EVER WANT TO SEE AND A DOCTOR WHO IS ALSO TAKING CARE OF PATIENTS AND TREATING EACH SPECIAL HUMAN INDIVIDUAL WITH A SPECIAL NEED FOR A MEDICAL AND SURGICAL CARE. MARSTON GOT HIS UNDERGRADUATE DEGREE AT BROWN UNIVERSITY. WENT ON TO GET THE MD AT THE UNIVERSITY OF OKLAHOMA AND YOU MIGHT NOTICE IN HIS PRESENTATION THERE IS SOME REMNANT OF THAT PART OF THE COUNTRY THAT STILL IS AUDIBLE. HE DID A YEAR OF MEDICINE AT OKLAHOMA AND WENT ON TO DUKE AND SURGERY AND ULTIMATELY BECOMING CHIEF RESIDENT IN UROLOGIC SURGERY AND AFTER THAT, HE CAME BACK HERE TO THE MECCA AS A SENIOR INVESTIGATOR IN THE SURGERY BRANCH WHERE HE IS NOW THE CHIEF OF THIER LOGIC ONCOLOGY BRANCH. HE ALSO HAS APPOINTMENTS AT GW BUT MOST OF HIS WORK IS DONE RIGHT HERE IN THIS REMARKABLE CLINICAL CENTER. HE HAS BEEN RECOGNIZED BY VARIOUS AWARDS, INCLUDING THE DR. NATHAN DAVIS AWARD OF THE AMERICAN MEDICAL ASSOCIATION AND AN ELECTED MEMBER OF THE INSTITUTE OF MEDICINE. HIS LONGSTANDING INTEREST IN KIDNEY CANCER AND THE GENETIC BASIS OF THIS DISEASE HAS RESULTED IN REMARKABLE REVELATIONS, INCLUDING THE BON HIPEL LIN DO YOU GENE, THE GENE FOR HEREDITARY PAP LARRY RENAL CARCINOMA, THE FLCN GENE, HE WILL TELL YOU MORE ABOUT THESE THINGS I’M PRETTY SURE. A TOTAL OF FIVE NEW DISEASES THAT HAVE COME OUT OF THIS RESEARCH EFFORT. AS I’M SURE HE WILL REFLECT ON, BECAUSE THE TITLE HERE POINTS TO IT, WHAT WE ARE LEARNING THROUGH THIS IS NOT ONLY WHAT IS GOING ON IN TERMS OF THE INSIGHTING EVENT. KIDNEY CANCER, BUT HOW THAT CONNECTS IN A WAY THAT NONE OF US WOULD HAVE SUSPECTED A FEW YEARS AGO WITH MET LOLLIC PATHWAYS THAT KIDNEY CANCER AND METABOLIC BASE OF DISEASE ARE IN FACT TIGHTLY INTERLINKED AS THEY ARE IN HIS TITLE. SO WE COULD IS NOT A BETTER PERSON FOR OUR ASTUTE CLINICIAN LECTURE THIS PARTICULAR YEAR. IT’S MY GREAT PLEASURE TO ASK YOU TO HELP ME WELCOME DR. MARSTON LINEHAN. [ APPLAUSE ]>>THANK YOU DR. COLLINS FOR THE VERY, VERY KIND INTRODUCTION. I REALLY APPRECIATE IT AND ALSO I’D LIKE TO ACTUALLY EXTEND MY THANKS TO THE WONDERFUL MEN AND WOMEN I HAD THE OPPORTUNITY TO WORK WITH HERE FOR THE LAST 32 YEARS AND ALSO PARTICULARLY TO DR. JOHN GAL IN AND THE CLINICAL CENTER AND HIS STAFF FOR MAKING THIS A PLACE FOR SOMEONE LIKE ME, SOMEONE LIKE US, OUR GROUP, COULD PURSUE THESE IDEAS, STUDY THESE PATIENTS, OVER THESE YEARS IN THIS MARVELOUS ENVIRONMENT. SO, I WANT TO TALK ABOUT KIDNEY CANCER AND KIDNEY CANCER EFFECTS WORLDWIDE ABOUT 300,000 PATIENTS AND IS RESPONSIBLE FOR ABOUT 100,000 DEATHS PER YEAR WORLDWIDE. IN THE U.S. IT IS ABOUT 65,000 AFFECTED AND 13,000 DIE. NOW AS DR. COLLINS MENTIONED, I’M A UROLOGIC SURGEON. SO IN OUR AREA, WE WORK ON PROSTATE CANCER, BLADDER CANCER, KIDNEY CANCER. NEW KIDNEY CANCER HAPPENS TO BE THE MOST LETHAL DISEASE AMONG THOSE THREE. GI CANCER ABOUT 25% OF HUMAN CANCER. BUT KIDNEY IS THE ONE THAT CAUSES LOST YEARS OF LIFE. SO REALLY THE MOST LETHAL CANCER. WE ESTIMATE THERE ABOUT 200,000 ALIVE IN THIS COUNTRY TODAY WITH KIDNEY CANCER. NOW, IN THE SPIRIT OF THIS WONDERFUL AWARD WHICH I’M SO TOUCHED TO BE ASKED TO GIVE THIS LECTURE, I’M GOING TO SORT OF WALK YOU THROUGH REALLY, OUR JOURNEY OVER THE LAST 30 YEARS IN STUDYING KIDNEY CANCER. WHEN I CAME HERE AS A YOUNG GUY, A YOUNG PERSON, IN THE EARLY 80s, I LOOKED AT KIDNEY CANCER AND I SAID, KIDNEY CANCER, IF SOMEONE COMES WITH LOCALIZED KIDNEY CANCER TO SOMEONE LIKE ME, A UROLOGIC SURGEON, WE CAN TAKE THAT OUT AND WE DON’T USE THE C WORD, THE CURE WORD, BUT WE CAN GIVE THEM 95% 5-10 YEAR SURVIVAL. PRETTY MUCH AS NOW, IF THEY CAME TO US WITH ADVANCED DISEASE, 82% OF THEM DIED WITHIN 24 MONTHS. SO WE SAID, IS THERE A WAY WE CAN DO SOMETHING TO CHANGE THIS? WE SET OUT EARLY IN THE 80s WITH MY WONDERFUL COLLEAGUE, BURT, TO STUDY KIDNEY CANCER, AND OUR HOPE WAS TO IDENTIFY WE THOUGHT WAS THE GENE FOR KIDNEY CANCER. WE HAD NO IDEA IT WOULD BE GENES. AND ONE OF THE THINGS IF YOU REMEMBER ONE THING DURING THIS TALK PROBABLY IS THIS SLIDE AND THE NEXT ONE, THAT IS KIDNEY CANCER IS NOT KIDNEY CANCER. IN THOSE DAYS, WE TREATED ALL PATIENTS WITH KIDNEY CANCER THE SAME. THE SAME OPERATIONS, GAVE THEM THE SAME DRUGS IF THEY HAD METASTATIC DISEASE, NONE OF WHICH WORKED. NOW WE KNOW THAT KIDNEY CANCER IS NOT A SINGLE DISEASE. IT’S A NUMBER OF DIFFERENT TYPES OF CANCER THAT JUST HAPPEN TO OCCUR IN THIS ORGAN. THEY HAVE DIFFERENT HISTOLOGIES, DIFFERENT CLINICAL COURSES AND RESPOND DIFFERENTLY TO THERAPY AND ARE CAUSED BY DIFFERENT GENES. NOW WE STARTED OUT, WATER AND I AND OUR COLLEAGUES, MICHAEL AND A NUMBER OF OTHER PEOPLE AND WE WERE SEEING A LOT OF PATIENTS IN THE CLINICAL CENTER WITH KID FEE CANCER AS PART OF THE IL-2 PROGRAM, STEVE ROSENBURG IN THE SURGERY BRANCH IN THOSE DAYS. AND WE LOOKED AT TUMORS FROM PATIENTS WITH LOCALIZED KIDNEY CANCER AND WE SHOWED THAT THERE WAS A CONSISTENT LOSS OF A CHROMOSOME. OF CHROMOSOME 3 IN THOSE TUMORS FROM PATIENTS WITH CLEAR CELL KIDNEY CANCER. AND WE WERE SO HAPPY ABOUT THIS. WE PUBLISHED THIS IN “NATURE” AND WE STARTED TO MAP AND SAID WE ARE GOING TO FIND THIS GENE AND THIS LOCATION. WE MAPPED AND MAPPED AND MAPPED AND SPENT ABOUT THREE YEARS DOING THIS. AND YOU NEVER FORGET THINGS. I NEVER WILL FORGET WE SPENT SIX MONTHS TRYING TO REFINE OUR STRATEGY. WE TALKED TO EVERYBODY WE COULD. WE SAW BURT VOGELSTEIN AND TALKED TO ALL SORTS OF PEOPLE AND CAME TO THE CONCLUSION THAT OUR LAB WORKING 13 HOURS A DAY SIX DAYS A WEEK AND BURT’S LAB WORKING THE SAME, WITH THE TOOLS WE HAD AVAILABLE TO US IN THE MIDDLE 80’S, WE COULD DEFINITELY FIND A GENE IN THIS LOCATION WITHIN 54.5 YEARS. SO WE KIND OF ASSUMED THAT WE THOUGHT WE WERE NICE PEOPLE BUT ASSUMED THEY WOULDN’T FUND US FOR THAT LONG. SO WE TALKED TO A BUNCH OF PEOPLE. DR. ANNUITIES ON SAID IF IS THERE A HEREDITARY VERSION OF YOUR CANCER, NEWT SON — YOU COULD STUDY FAMILIES AND MAKE YOUR OWN PROBES. SO THAT IS WHAT WE DID. WE SET UP A HEREDITARY CANCER PROGRAM AND AGAIN, SOMEONE LIKE ME — WE COULD HAVE NEVER DONE THIS ANYWHERE ELSE OTHER THAN HERE AT THE CLINICAL CENTER. I MEAN, THIS IS JUST TO HAVE ALL THESE PEOPLE TO WORK WITH. I THINK MY ASSISTANT TOLD ME THE OTHER DAY THAT — SHE SAID, YOU WORK WITH 147 DIFFERENT PEOPLE FROM 29 LABS AND BRANCHES FROM NINE DIFFERENT INSTITUTES AT NIH. THIS IS REALLY A TRANS-NIH PROJECT. THERE IS A WHOLE NUMBER OF PEOPLE WHO COULD BE STANDING UP HERE GIVING THIS TALK BESIDES ME. BUT THIS WAS IN THE DAYS BEFORE THERE WAS A FRANCIS COLLINS OR BEFORE FRANCIS COLLINS WAS HEAD OF THE GENOME PROJECT, LET’S PUT IT THAT WAY. THERE WAS NO GENOME PROJECT. SO WE HAD TO BE OUR OWN GENOME PROJECTED. THERE WAS NO OTHER WAY. SO WE SET UP A PROGRAM TO BRING IN FAMILIES AND EVALUATE THEM AND DETERMINE WHO IS EFFECTED AND WHO WASN’T SO WE COULD DO GENETIC LINKAGE ANALYSIS. THIS TOOK A ARMY OF COLLEAGUES TO WORK WITH. I’M GOING TO TALK ABOUT FIVE DIFFERENT TYPES OF INHERITED KIDNEY CANCER THAT WE WORKED ON. VHL, HEREDITARY RENAL CARCINOMA, BITTER HOG DUBE, HLRCC AND SDH. AND I’LL SHOW YOU HOW EACH ONE IS CAUSED BY A DIFFERENT GENE BUT ALSO HOW VERY DIFFERENT THEY ARE. AGAIN, OVER THE YEARS, WE HAD THE UNBELIEVABLE OPPORTUNITY TO EVALUATE NEARLY 1000 FAMILIES WITH MULTIPLE MEMBERS OF KIDNEY CANCER. A LIST UP HERE, WE CALL THIS FRC. THIS IS FAMILIAL RENAL CANCER. WHEN WE STARTED, WE STARTED WITH VHL. SO WE HAD VHL AND THEN WE HAD FRC. WE DIDN’T KNOW WHAT THE DISEASES WERE. THEY WEREN’T NAMED. WE DIDN’T HAVE ANY GENES FOR THEM. SO, EVERYYEAR WE TAKE MORE PEOPLE OUT OF THE FRC CATEGORY AND PUT THEM IN NAMED GENE SYNDROMES. SO WE ARE GOING TO START WHERE WE OTHER STAKED, WHICH WAS VHL, VON HIPEL LIN DO YOU, HEREDITARY CANCER SYNDROME. PATIENTS ARE AT RISK, AUTOSOMAL DOMINANT. PATIENTS ARE AT RISK AND DEVELOP TUMORS IN A NUMBER OF LOCATIONS INCLUDING OF COURSE BILATERAL KIDNEY CANCER. THESE PATIENTS ARE AT RISK TO DEVELOP BILATERAL MULTI-FOCAL KIDNEY CANCERS AND CYSTS IN THE KIDNEYS. IN SCIENCE, WE DON’T SAY ALWAYS OFTEN. BUT THESE ARE ALWAYS CLEAR CELL KIDNEY CANCER. WE HAVE SEEN THOUSANDS OF THESE TUMORS THAT DR. MARINO HAS LOOKED AND THE THEY ARE ALWAYS CLEAR CELL. THESE PATIENTS ALSO GET CYSTS IN THEIR KIDNEYS AND INSIDE THOSE CYSTS THIS YELLOW MATERIAL IS CLEAR CELL KIDNEY CANCER. NOW AGAIN, WE HAVE I THINK 700 KNOCKOUT MICE. WE HAVE ABOUT 500 CAGES OF XENOGRAPHED MODELS. WE HAVE GREAT CELL LINE MODELS IN THE LAB. BUT THIS IS OUR MODEL. THE HUMAN MODEL. THIS SATURDAY MODEL WE STUDIED OVER THESE YEARS AND THIS IS THE MODEL THAT ENABLED US TO MAKE ANY PROGRESS WE MADE. WHEN WE LOOK AT THESE PATIENTS TUMORS OR KIDNEYS, WE ASK IF THEY HAVE ALL SORTS OF TUMORS. WE ESTIMATE THEY GET UP TO 600 TUMORS PER KIDNEY. THEREFORE, WHEN WE DO SURGERY, WE ARE NOT CURING THESE PEOPLE. WE ARE SETTING BACK THE CLOCK. THAT’S OUR APPROACH. TO GET THEM THROUGH THEIR LIVES WITH THEIR NORMAL KIDNEYS AND OF COURSE NORMAL PAN COUNTRIES AND ADRENAL IN TACT. PANCREAS. IT USED TO BE SAID THAT VHL ASSOCIATED KIDNEY CANCER WASN’T AGGRESSIVE LIKE REAL KIDNEY CANCER. IN MY FIELD THAT WAS PUBLISHED IN THE ABILITIES. MY FIELD JUST DIDN’T UNDERSTAND THE TERM, LEAGUE TIME BIAS. THESE ARE EXACTLY THE SAME AS SPORADIC NON-HEREDITARY KIDNEY CANCERS. WE ESTIMATE — THIS IS A PATIENT WHO CAME TO US WITH A LARGE VHL TUMOR T SPREAD TO HER CHEST. METASTATIC DISEASE. WE ESTIMATE FROM THE TIME OF THE — THIS IS ON THE BASIS OF ABOUT 17,000 TUMOR MEASUREMENTS. FROM THE TIME OF THE SECOND HIT IN THIS CANCER GENE, TO TWO CENTIMETERS, WE ESTIMATE THAT TIME IS ABOUT 25 YEARS. SO THIS IS LIKE A LITTLE BIT LIKE PROSTATE CANCER. VERY SLOW-GROWING CANCER. BUT WHEN IT GOATS A CERTAIN SIZE, IT CAN SPREAD. SO WE HAVE MANAGED THESE PATIENTS NOW OVER 27 YEARS, VERY CAREFUL CONSECUTIVE MANAGEMENT HERE AT NCI OR NIH. AND WE HAVE DEVELOPED A CLINICAL APPROACH. NOW THE FIRST PATIENT I SAW WITH VHL, I WAS A YOUNG KID HERE. AND THE WAY WE MANAGED CANCER IN MY FIELD, AND I TALKED TO EVERYONE HERE AND ALL OF MY COLLEAGUES AND READ LITERATURE THE WAY YOU HANDLE KIDNEY CANCER, YOU REMOVE THE KIDNEY. WELL, I TOOK OUT BOTH OF THAT PATIENT’S KIDNEYS. AND YOU KNOW, YOU NEVER FORGET SOME THINGS. I’LL NEVER FORGET I TOOK THAT PATIENT DOWN IN THE OLD ENTRANCE TO THE HOSPITAL, I TOOK HIM DOWN, PUT HIM IN A TAXI CAB, SENT HIM HOME TO BE ON DIALYSIS. AND I SAID, I DON’T CARE WHAT THEY SAY, I’M NEVER DOING THIS AGAIN. AND WE STARTED THEN DOING PARTIAL REFLECT MES. I GOT A LOT OF GAS FOR A WHILE BUT AFTER A WHILE IT BECAME ACCEPTED. WELL, WE OPERATED AND PEOPLE WOULD GET NEW TUMORS AND WE WOULD OPERATE AND THE GET NEW TUMORS AGAIN. I REMEMBER ONE TIME DURING ONE OF THESE CASES AND WE WERE DOING A PATIENT FOR THE THIRD TIME ON THE SAME KIDNEY AND IN ABOUT 5 YEARS WE ARE GOING TO HAVE TO PUT ZIPPERS IN THESE PEOPLE. SO WE STARTED AN APPROACH THEN, WE DID A BUNCH OF CALCULATION BUSY METASTASES. WE DEVELOPED AN APPROACH TO DO ACTIVE SURVEILLANCE. WE WOULD NOT OPERATE — I KNOW TODAY THAT SOUNDS KIND OF NOT SO UNUSUAL. BUT WHEN WE DID THIS, IT WAS — WE HAD A LOT OF CRITICISM, LET’S PUT IT THAT WAY ABOUT THIS APPROACH. NOT OPERATE ON CANCER. WE STARTED TO DO ACTIVE SURVEILLANCE UNTIL THE LARGEST TUMOR REACHED THREE CENTIMETERS. AT THREE CENTIMETERS WE RECOMMEND INTERVENTION. NOW, IN 27 YEARS, AS OF NOVEMBER 20, 2013, WHEN USING THIS STRATEGY, WE HAVE NOT YET HAD ONE SINGLE PATIENT DEVELOP METASTATIC DISEASE. NOW SURGICALLY FOR YEARS, WE WOULD DO OPEN OPERATIONS. WE NOW HAVE GONE TO A ROBOTIC APPROACH. AND WALLY RECENTLY TOOK OUT 54 TUMORS FROM A SINGLE PATIENT’S KIDNEY WITH THIS ROBOT. WE HAVE DONE AS MANY AS 74 WITH AN OPEN OPERATION. I WANT TO SHOW YOU THIS BECAUSE MANY OF YOU ARE NOT CANCER PEOPLE. I WANT TO SHOW YOU WHEN THEY LOOK LIKE. AND ALSO I WANT TO SHOW YOU THIS. THIS IS PART OF THE PHENOTYPE. IN OTHER WORDS, I’M GOING TO SHOW YOU THIS IS HOW WE MANAGE THE ONES WITH WITH VHL MUTATION WITH THE NEXT GENE WHICH WILL BE MET AND THE THIRD GENE WHICH WILL BE FALICAL AND DR. COLLINS MENTIONED, BUT THIS IS VERY DIFFERENT. FROM THE WAY WE MANAGE PATIENTS WITH CREPE CYCLE ENZYME MUTATIONS AND SECTION HYDROGENASE. THIS IS A ROBOTIC PARTIAL NEPHRECTOMY. YOU CAN SEE THE TUMOR HERE AND WITH THE ROBOT JUST COMING RIGHT AROUND THIS, LIKE PETER PINTO IS DOING THIS CASE. IT WAS JUST COMING RIGHT AROUND THIS TUMOR AND AS YOU CAN SEE, WE ARE NOT GETTING MUCH OF A MARGIN: NOW, WE KNOW THIS TUMOR. WE KNOW THIS GENE. AND WE KNOW HOW THIS BEHAVES. AND WE HAVE NEVER HAD A PROBLEM WITH THIS AND WE HAVE NOT HAD ONE PATIENT DEVELOP METASTATIC DISEASE. NOW I’LL SHOW THAT YOU IS VERY, VERY VERY DIFFERENT FROM A COUPLE OF TYPES OF KIDNEY CANCER I’LL SHOW YOU IN A MINUTE. THESE PATIENTS ALSO DEVELOP TUMORS IN THE ADRENAL GLANCED. YOU CAN SEE HERE THIS IS AN 8-YEAR-OLD CHILD. ALSO IN THE PANCREAS. THEY GET PANCREATIC CYSTS AND THEY GET PANCREATIC NEURAL ENDOCRINE TUMORS. WHICH ARE MA LIGNANT TUMORS WHICH CAN SPREAD. THESE PATIENTS ALSO GET TUMORS IN THE BRAIN AND SPINE. CEREBELLAR BLASTOMA. THESE ARE SPINAL BLASTOMAS. THIS PATIENT HAS TWO. WE HAVE PATIENTS WHO HAVE HUNDREDS. IF YOU WANT TO HAVE A SNAPSHOT IN YOUR MIND ABOUT WHAT THIS GENE PATHWAY IS, THIS IS A GOOD PICTURE. SO THIS IS ONE THAT ED OLE’ FIELD WAS DOING. THIS IS THE SPINAL CORD AND THIS IS THE SPINAL BLASTOMA AND YOU CAN SEE IT’S VASCULARITY. IT IS EXTREMELY VASCULAR. VHL GENE AS I WILL SHOW YOU, IS AN OXYGEN SENSOR. SO, WHEN A CELL THINKS IT IS SHORT OF BREATH, IT NEEDS MORE VASCULATURE AND NEEDS MORE ENERGY, IT NEEDS MORE BLOOD, A BUNCH OF THINGS. I’LL SHOW THAT YOU IN JUST A MINUTE. THESE PATIENTS I MIGHT ALSO ADD THAT WE COULDN’T HAVE THOUGHT ABOUT DOING THIS WORK WITHOUT OUR WONDERFUL COLLEAGUES ED OL FIELD, RUSS LOONSER, MORE RECENTLY, KAREN ZAG POL AND. [ INDISCERNIBLE ] FROM THE NEUROLOGICAL SUCH REBRANCH AND WE ARE APPRECIATIVE OF THEIR SUPPORT OF THEIR WORK AS WE ARE OF JEFF NORTON AND OUR COLLEAGUES IN GENERAL SURGERY. AND IN OPTHALMOLOGY, EMILLIE CHEW HAS BEEN WITH US HELPING TO MANAGE THESE PATIENTS AND WITHOUT THEM, WE NEVER WOULD HAVE EVER HAVE BEEN ABLE TO DO THE PHENOTYPE ASSESSMENT AND NEVER BEEN ABLE TO MANAGE THESE PATIENTS OVER THE YEARS. THESE PATIENTS ALSO DEVELOPED RETINAL ANGIOAS. THESE ARE BENIGN TUMORS EXTREMELY VASCULAR. THIS IS THE FIRST MANIFESTATION OF VHL. YOU CAN SEE THESE IN ONE-YEAR-OLDS. THAT’S WHY WE RECOMMEND GERMLINE MUTATION TESTING AT AGE ONE. BECAUSE PHOTO DYNAMIC THERAPY CAN ALSO SAVE VISUAL FIELDS AND IT REALLY MAKES US SICK TO SEE A PATIENT WHO LOST THEIR VISION BECAUSE THEY WEREN’T DETECTED EARLY AND DIDN’T HAVE EARLY TREATMENT. THESE PATIENTS ALSO DEVELOP INNER EAR TUMORS, 12% OF OUR PATIENTS DEVELOP WHAT IS CALLED AN EN DOE LYMPHATIC SAC TUMOR WHICH IS IN THE CANAL, IT’S A BENIGN PAP LARRY TUMOR. IF IT PROGRESSES, THESE PATIENTS CAN LOSE THEIR HEARING. OUR NEUROSURGEONS AND OUR ENTs ARE DOING A STUDY TO SEE IF EARLY SURGICAL INTERVENTION WILL PRESERVE HEARING IN THIS PATIENT POPULATION. SO, WE WANTED TO FIND THIS GENE. WE BROUGHT PATIENTS HERE TO THIS WONDERFUL CLINICAL CENTER, PERFORMED GENETIC LINKAGE ANALYSIS AND AGAIN, THIS IS WITH BETTER AND MIKE AND A NUMBER OF COLLEAGUES. AND WE WERE ABLE TO EVALUATE DNA FROM 4,312 PATIENTS TO DO THIS. THIS ACTUALLY TOOK US ABOUT 10 YEARS TO DO THIS PROJECT. LOCALIZED, THE GENE TO THE SHORT ARM OF CHROMOSOME 3 AND THEN IN THE SPRING OF 1993, WE WERE ABLE TO LOCALIZE AND IDENTIFY THE 7th CDNA WE LOOKED AT, G7, WHICH TURNED OUT TO BE THE VHL GENE, THE 6th HUMAN CANCER GENE IDENTIFIED WHEN WE FOUND THIS. WE NOW LOOKED AT 371 FAMILIES AND DETECTED VHL MUTATION IN EVERY SINGLE ONE OF THEM. THE MUTATIONS WE SEE ARE REALLY A CATALOG FOR GRAD STUDENTS IN GENETICS. TWO-THIRDS OF OUR TUMORS ARE FRAMESHIFTS, NONSENSE, ABOUT A THIRD ARE DELETIONS, ABOUT TWO-THIRDS OF THOSE ARE PARTIAL DELETION AND ABOUT A THIRD ARE COMPLETE DELETION AND ABOUT 5% OF OUR MUTATIONS ARE MECHANICAL AND ARE SPLICING DEFECTS. THEN WE WANTED TO SEE WAS THIS THE GENE WE LOOKED FOR FOR SO LONG? NOT A GIVEN THIS WILL BE THE CASE. THE LADIES IN THE FAMILIES OR THE LADY WHO IS NOT IN A HEREDITARY BREAST FAMILY WHO HAS BREAST CANCER, IT’S NOT OB CLAWS BRCA1 OR 2 WILL BE INVOLVED IN HER CANCER. SO WE JUST DIDN’T KNOW. BUT IT TURNED OUT AND WE LOOKED AT TUMORS FROM PATIENTS WITH NONHEREDITARY, SPORADIC CLEAR CELL KIDNEY CANCER, WE FIND A HYPE PERCENTAGE OF MUTATIONS OF THIS GENE. WE FIND MUTATION OF THE GENE AND LOSS OF THIS GENE MOST RECENT STUDY, WAS WITH MIKE NICKERSON AND LEE MOORE OUT OF NCI AND THAT WAS ABOUT 412 TUMORS AND NEARLY 90% HAVE EITHER MUTATION OR METHYLATION OF THAT GENE. RECENT STUDY OUT OF JAPAN SHOWED A 95% RATE EVER MUTATION METHYLATION OR MUTATION OF ONE OF THE PARTNERS OF VHL GENE. SO, I THINK IT IS CLEAR TO SAY THAT VHL IS THE CLEAR CELL KIDNEY CANCER GENE. SO WE FIND THAT, WE FOUND THAT HERE IN CLEAR CELL BUT WE DON’T FIND IT IN TYPE I PAP LARRY AND TYPE II PAP LARRY AND CHROMOPHOBE, ONCOCYTOMA COLLECTING. THE OTHER TYPES OF KIDNEY CANCER. SO THE FIRST INCLINATION THAT THERE WAS A GENETIC DIFFERENTIATION AMONG THE DIFFERENT TYPES OF KIDNEY CANCER. SO WHAT KIND OF GENE WAS THIS? IT TURNED OUT TO BE A CLASSIC TWO HIT TUMOR SUPPRESSOR GENE. WE HAVE MUTATION OF THE GENE AND LOSS OF THE SECOND COPY OF THAT GENE. SO, WE MADE A CELL LINE OF THE FIRST LINE THAT WAS DESCRIBED AS A VHL OR AS A CLEAR CELL KIDNEY CANCER LINE WITH THE VHL MUTATION, PUT IT IN A MOUSE. WE MADE ONE SINGLE CHANGE IN THOSE CELLS. ONE CHANGE. WE PUT A NORMAL COPY OF THAT GENE BACK IN THOSE CELLS AND WE GET NO TUMOR OR VERY SMALL TUMOR. SO, VERY STRONG DATA. THIS IS A LOSS OF FUNCTION TUMOR SUPPRESSOR GENE. THEN WE WANTED TO KNOW HOW DOES THIS GENE WORK? WE HAD NO IDEA IN THE WORLD WHAT THIS DID. SO WE STARTED TO WORK WITH RICK CLOUZNER IN THE MIDDLE 90s. AND ROXANNE A POSTDOC IN OUR LAB WORKING WITH RICK AND HIS COLLEAGUES AND DID A PRETTY STRAIGHTFORWARD EXPERIMENT, IPVHL AND PULLED DOWN THESE TWO BANDS HERE. WE WORKED WITH BILLY UP AT THE RED CROSS AND BILLY SLEPT IN THE LAB FOR 5 1/2 DAYS TO DO THIS SEQUENCING. AND SHOWED THAT THIS BAND HERE, WHICH HAD JUST BEEN PUT IN THIS SEQUENCE, SOMETHING CALLED ELONG IN C. WE CALLED THAT WEEKEND, RON AND JOHN CONWAY, MEDICAL RESEARCH FOUNDATION AT OKLAHOMA CITY, OKLAHOMA, AND THEY WERE DUMBFOUNDED BY WHY WE WERE CALLING THEM. WE TOLD THEM THIS AND WHATEVER THIS GENE IS, BINDS VHL AND WE HAD ANOTHER GENE WE DIDN’T KNOW — WE HAD ANOTHER PROTEIN WE DIDN’T KNOW WHAT THAT WAS. WE E-MAILED THAT TO THEM AND THEY SAID THAT IS ELONG IN B. WHICH THEY HASN’T PUT OR COMMUNICATE THE ANYWHERE YET. SO, WE PUBLISHED THIS AND PUBLISHED THIS IN “SCIENCE” AND WE WERE VERY HAPPY ABOUT THAT AND PROUD OF THE WORK BUT IT DIDN’T HELP US TO UNDERSTAND THE FUNCTION OF THIS GENE OR THIS PATHWAY. UNTIL THIS WILL GEL, WHICH WAS RUN BY ARM AMIN RICK CLOUZNER’S LAB AND ARM AMHAD IPVHL AND RAN A BIGGER GEL. AND RAN ACROSS THIS BAND RIGHT HERE THAT HE SEQUENCED, WHICH WAS A PROTEIN CALLED CULIN 2. IT WAS AT THE TIME A RECENTLY IDENTIFIED TUMOR SUPPRESS ARE GENE FAMILY IN HELMET. ONCE YOU PUT CUL2 ALONG C AND BVHL TOGETHER, THEN YOU CAN GO BACK TO THE MODEL AND MAKE SENSE OF THIS. THAT VHL IS PART OF AN E3 UBIQUITIN LIGASE COMPLEX THAT TARGETS CERTAIN TARGET PROTEINS IN THE MOST WELL STUDIED ARE HYPOXIA INDUCIBLE FACTORS, HIF 1 AND 2 FOR UBIQUITIN MEDIATED DEGRADATION. THIS WAS DONE BY THE KALE IN AND MAXWELL GROUP AND OVER THE YEARS, WE HAVE COME TO UNDERSTAND THIS IS SIMPLY AN OXYGEN SENSING SYSTEM. WHEN THERE IS NORMAL OXYGEN IN THE CELL, THE COMPLEX CAN TARGET HIF, DEGRADE IT FOR UBIQUITIN MEDIATED DEGRADATION. WHEN IT’S HYPOXIC, NOT ENOUGH OXYGEN, VHL COMPLEX CAN’T SEE HIF TO DEGREAT IT AND HIF ACCUMULATES AND THEN TRIBES THINGS SUCH AS VEGF, GLUTE 1, GLUTE 4, THINGS WE KNOW OF AS CANCER. HOWEVER, IN OUR CLEAR CELL KIDNEY CANCERS, WHERE THE VHL MUTATION, IT’S LIKE THE CELL THINKS IT IS SHORT OF BREATH. SO NO MATTER WHAT THE OXYGEN LEVEL IS, HIF IS NOT DEGRADED AND IT ACCUMULATES AND YOU GET A VASCULAR CELL, A CELL THAT IS MAKING PLATELET-DERIVED GROWTH FACTOR AND ALL SORTS OF THINGS TO STIMULATE GROWTH IN THE CELLS NEXT TO IT AND ITSELF. SO THIS PROVIDED THE FOUNDATION FOR THE DEVELOPMENT OFAVE THERAPEUTIC APPROACH FOR PATIENTS WITH ADVANCED CLEAR CELL KIDNEY CANCER, IE TARGETING THE VHL PATHWAY. SO AS OF TODAY, SEVEN DIFFERENT TARGETED THERAPEUTIC DRUGS APPROACHES, HAVE BEEN APPROVED BY THE FDA FUR THE TREATMENT OF PATIENTS WITH ADVANCED KIDNEY CANCER, PRIMARILY ADVANCED CLEAR CELL KIDNEY CANCER. SO, AS THRILLED AS WE ARE ABOUT THIS, WE ARE NOT HOME YET. YOU CAN SEE DRAMATIC RESPONSE. YOU CAN SEE INCREASE IN SURVIVAL. BUT, MOST PATIENTS EVENTUALLY OR MOST OF THE TIMES THIS THERAPY EVENTUALLY FAILS THESE PATIENCE AND EVEN THOUGH YOU CAN SEQUENCE THESE DRUGS, MANY TIMES THEY GO ON TO DIE OF THIS DISEASE. JUST RECENTLY, THE CANCER GENOME ATLAS, WHICH OF COURSE IS A WONDERFUL PROJECT, I’D SAY IT’S THE DREAM OF A LIFETIME, THIS PROJECT, THIS CO-SUPPORTED BY THE NHGR I AND NCI AND WE WERE INVOLVED IN THE ONE YOU’RE LOOKING AT, CLEAR CELL KIDNEY CANCER. AND ANOTHER GENES ON CHROMOSOME 3 WHICH HAVE PREVIOUSLY BEEN SEEN. THESE GENES ON CHROMOSOME 3 THAT ARE CENTRAL MERIC TO WHERE VHL IS, THESE ARE CHROMATIN REMODELING GENES. PBRM1 SET D2 AND BAF1. PRETTY REMARK AGE. AND THESE TWO GENES SET B2 AND BAF1 WHEN THEY ARE MUTATED, THAT CORRELATES WITH AN AGGRESSIVE PHENOTYPE AND DECREASES SURVIVAL. SO YOU ARGUE THAT VHL’S EARLY THING BUT OVER THE YEARS, SOMEHOW THESE OTHER GENES HELP TO SPREAD OR BECOME MORE AGGRESSIVE. AND RECENTLY, WE LOOKED AT A FAMILY AND THIS WAS WORK DONE WITH LAURA SUBMIT AND KATHY VOKE AND A NUMBER OF NEME OUR GROUP ALONG WITH JAMES AT TEXAS SOUTHWESTERN AND A FAMILY WE HAVE BEEN FOLLOWING FOR 11 YEARS, LINDSAY COULDN’T FIND VHL MUTATION. WE COULDN’T FIND SDH MUTATIONS. THIS FAMILY CARRIES THE MUTATION OF THAT GENE I SHOWED YOU BAF1 ON CHROMOSOME 3. SO WE KNOW NOW THAT THIS GENE ALSO CAN CAUSE CLEAR CELL KIDNEY CANCER. THIS FAMILY HERE. BUT THE OTHER THING THAT WE FOUND, AND THIS WAS WORK THAT REALLY CHRIS REALLY PUT TOGETHER, AND THAT IS THAT WE THOUGHT THIS WAS GOING TO BE THE CASE BUT WE WERE SHOCKED WHEN SEE SAW THIS. AND THAT IS THAT HIGH-GRADE, HIGH-STAGE, VERY AGGRESSIVE KIDNEY CANCER IN PATIENTS WITH LOW SURVIVAL, IN OTHER WORDS BAD DISEASE, THESE PATIENTS TUMORS UNDERGO A METABOLIC SHIFT. AND THIS SHIFT LOOKS VERY MUCH LIKE COUPLE OF OTHER TYPES OF KIDNEY CANCER I’LL SHOW YOU IN A MINUTE, WHERE THE TCA CYCLE ENZYMES ARE SUPPRESSED SUGGESTING DECREASE IN OXIDATED PHOSPHORYLATION. THE ENZYMES FOR GLYCOLYSIS ARE WAY UP. ENZYMES FOR THE PHOSPHATE ARE WAY UP. SO SUGGESTING DEFENSE AGAINST OXIDATIVE STRESS. AMPK IS DOWN, THAT’S GOING TO BE REOCCURRING THEME. I’LL COME BACK TO THAT. AND YOU HAVE EVIDENCE OF REDUCTIVE CAR BOXALATION OF GLUTAMINE-DEPENDENT APPROACH FOR MAKING FATTY ACIDS. AND INCREASING CELLULAR SINCE SIS. SO WE SAW THAT BY DOING THIS VERY COMPLEX INTEGRATIVE ANALYSIS OF 480 TUMORS THAT ONLY PROJECT LIKE TCGA CAN DO. SO WHAT I HAVE SHOWN YOU IS THAT VHL CLEAR CELL KIDNEY CANCER, OXYGEN SENSOR. OKAY? NOW HOW ABOUT THE OTHER TYPES? THAT’S ABOUT 75% OF KIDNEY CANCER IS CLEAR CELL. NOW HOW ABOUT THE OTHER TYPES OF KIDNEY CANCER? I THOUGHT I’D JUST WALK YOU THROUGH HOW WE GOT A LITTLE BIT WHERE WE ARE AND AGAIN, IT WAS ALL PATIENTS SEEN RIGHT HERE IN THIS BUILDING. SO THIS WAS THE FIRST ONE. THIS WAS A LITTLE GIRL OR YOUNG WOMAN, 21-YEAR-OLD. SHE CAME HERE FROM OHIO WITH HER MOM, HER WORRIED MOM, WITH THIS TUMOR IN HER KIDNEY. I TOOK THIS OUT. SHE WENT ON TO DIE EIGHT MONTHS LATER OF METASTATIC DISEASE. I WENT OVER TO SEE MARINO, I WORKED WITH SO CLOSELY AND I SAID, MARIA WHAT KIND OF KIDNEY CANCER IS THAT? SHE SAID, IT’S PAP LARRY KIDNEY CANCER. I SAID, ALL RIGHT. SO THEN IN 89, IN MAY, I SAW ANOTHER YOUNG WOMAN WHO CAME UP WITH HER MOM FROM CHARLOTTESVILLE, AND SHE HAD THIS TUMOR IN HER LEFT KIDNEY. AND I TOOK THIS OUT. AND SHE WENT ON TO DIE 10 MONTHS AFTER THAT OF METASTATIC KIDNEY CANCER AND HER MOM DIED 14 MONTHS AFTER THAT OF METASTATIC KIDNEY CANCER. I SAID, MARIA, WHAT IS THIS? AND SHE SAID, MARSDEN, IT’S PAP LARRY KIDNEY CANCER. I SAID, ALL RIGHT. SO THIS IS A PATIENT THAT WE SAW, THIS FAMILY WE SAW IN MARCH OF 92. SO THIS MAN CAME UP AND HE WAS 71 YEARS OLD. HE HAD METASTATIC KIDNEY CANCER AND HE HAD TUMORS IN BOTH KIDNEYS. DISEASE IN HIS CHEST, EVENTUALLY WEPT ON TO DIE OF METASTATIC DISEASE. HIS SISTER CAME UP WITH THEM AND SHE HAD TUMORS IN BOTH KIDNEYS, GROW TO BE VERY LARGE TUMORS AND HIS SON CAME UP WHO AT THE TIME WAS 42. AND HE HAD TUMORS IN BOTH HIS KIDNEYS. SO I START WITH THIS GUY, WITH THIS DISORDER FIRST. THIS WAS PAP LARRY. I SAID MARIA, WHAT IS THIS? SHE SAID T IS PAP LARRY KIDNEY CANCER. SO THIS OBVIOUSLY RAN IN FAMILIES. THIS HAD NOT BEEN DESCRIBED. YOU CAN SEE OWL THE MEMBERS WHO HAD KIDNEY CANCER ON IT. AUTO ZOOMAL HEREDITARY KIDNEY CANCER. ULTRARARE DISORDER. BILATERAL MULTIFOCAL TUMORS IN THE KIDNEY. YOU CAN SEE THIS. YOU CAN SEE WE ESTIMATE THESE PEOPLE GET UP TO 2000 TUMORS PER KIDNEY. IT’S ALWAYS TYPE I PAPILLARY KIDNEY CANCER. AGAIN, WE DEVELOPED A SIMILAR APPROACH AND THAT IS, IF WE HAD PEOPLE WITH METASTATIC DISEASE, YES, WE HAVE. BUT WE DEVELOPED AN APPROACH HERE TO INTERVENE WITH A LARGEST TUMOR REACHES THREE CENTIMETERS AND 21 YEARS SINCE 1992, WE HAVE NOT HAD ONE PATIENT DEVELOP METASTASES WHO WERE MANAGED IN THIS FASHION. SO, WE BROUGHT PEOPLE TO THIS MARVELOUS CLINICAL CENTER AND DID GENETIC LINKAGE ANALYSIS, PRIMARILY LAURA SMITH AND BURT AND MIKE NICKLESON, AND LOCALIZED THIS TO LONG ARM OF CHROMOSOME 7. LOOKED AT A NUMBER OF THINGS, INCLUDING THESE CANDIDATE GENES AND THE GENE FOR THIS DISORDER TURNED OUT TO BE MET. MET AS YOU KNOW, AND WHICH IT WAS — WHICH DONBA TAROT HAD SHOWN THAT HGF IS THE LIGAND FOR THIS CELL SURFACE RECEPTOR CALLED MET. SO THIS IS WHAT WE FIND IS MUTATIONS IN THE TYROSINE KINASE DOMAIN OF THIS. SO THIS IS A DOMINANT GENE. VHL TUMOR SUPPRESSOR GENE. THIS IS AN ONCOGENE: SO THESE ARE THE ACTUAL MUTATIONS WE SEE IN THE TYROSINE KINASE DOMAIN OF THIS GENE. SO WE LOOKED AT AND ANALYZED DNA AND SEEN 12 FAMILIES. THERE IS ONLY 25 FAMILIES KNOWN IN THE WORLD. SO THIS IS A ULTRARARE DISEASE BUT AN IMPORTANT DISEASE IN MANY WAYS BECAUSE MET IS NOW SUCH AN IMPORTANT DISEASE IN LUNG CANCER, STOMACH CANCER AND A NUMBER OF THINGS. SO, WE DESCRIBED AN EARLY ONSET FORM OF THIS DISEASE. LAURA SUBMIT DID. AND THESE MUTATIONS WERE HERE IN THE ATP BINDING DOMAIN SO THAT COULD EXPLAIN WHY WE SEEN SUCH AN AGGRESSIVE PHENOTYPE IN THOSE PATIENTS WITH THAT MUTATION. SO WE WERE HAPPY ABOUT THAT AND HAPPY TO FIND THE GENE AND HAPPY TO BE ABLE TO TELL PATIENTS WHO IT EFFECTED WHO WASN’T HAPPY TO MAKE THE DIAGNOSIS. HOWEVER, WHAT WE REALLY WANTED TO DO WAS TO HOPEFULLY WITH ALL OF THESE DISORDERS, TO DEVELOP AN APPROACH FOR THERAPY. SO, THIS SHOULD BE STRAIGHTFORWARD. AND I’D SAY IT WILL BE BUT IF YOU THINK IT WOULD BE IN A WAY. SO, RON IN OUR GROUP, HEAD OF OUR MOLECULAR THERAPEUTICS PROGRAM, CONDUCTED A TRIAL USING A DRUG CALLED FRET NIB, DUAL KINASE VEGF RECEPTOR AND MET RECEPTOR INHIBITOR. SO I’LL JUST SHOW YOU ONE PATIENT. SO THIS IS THAT FIRST FAMILY I SAW. THIS WAS THE 42-YEAR-OLD SON. WHEN WE SAW HIM IN THE SPRING OF 92, I’D SEEN THESE OTHER FAMILIES WITH HORRIBLY AGGRESSIVE DISEASE AND HAD THESE PEOPLE DIE. WE DIDN’T KNOW THE DIFFERENCE THEN BETWEEN THIS TYPE OF HEREDITARY PAPILLARY KIDNEY CANCER — KNOWN DID — AND THE OTHERS. SO I TOOK OUT THIS PATIENT’S LEFT KIDNEY. I WOULDN’T DO IT AGAIN. I WOULD DO A PASSIONATE. BUT IN THE SPRING OF 1992 I TOOK OUT HIS LEFT KIDNEY YOU SEE HERE. IN JUNE OF THAT YEAR, OF 92, WE TOOK OUT 12 TUMORS FROM HIS REMAINING RIGHT KIDNEY. SOLITARY RIGHT KIDNEY. SO DID FINE. GOING BACK AND FORTH TO SCHOOL, BACK AND FORTH TO PTA MEETINGS AND BACK TO WORK TO LITTLE LEAGUE BASEBALL GAMES. DEVELOPS TUMORS AGAIN AS WE HAVE COME TO UNDERSTAND HAPPENS, AND IN THE FALL OF 2000, WE TOOK OUT 59 ADDITIONAL TUMORS FROM HIS REMAINING RIGHT KIDNEY. THAT’S 71 TUMORS SO FAR. THAT’S OKAY. HE HAS A LITTLE RENAL INSISTY. HIS EGFR IS 51 OR 54. HE IS DOING OKAY. HOWEVER, IN ABOUT 2006, HE STARTS TO DEVELOP NEW TUMORS IN THAT KIDNEY AND HIS LARGEST TUMOR IN THAT RIGHT KIDNEY REMAINING RIGHT KIDNEY IS 3.4 CENTIMETERS. WE DON’T LIKE THAT. WE DON’T WANT HIM TO DIE OF METASTATIC DISEASE LIKE HIS FATHER DID. SO, RON PUT HIM ON THIS DRUG. WHEN HE CAME BACK THE FIRST TIME, HIS TUMOR HAD GONE FROM 3.4 TO 2.5. AND THE UROLOGIC ONCOLOGY FELLOW SAID, DR. MARSTON LINEHAN, WAIT A MINUTE. THIS GUY’S TUMOR IS 2.5. HE SAID, HE IS NO LONGER A SURGICAL CANDIDATE. I SAID, RIGHT. I SAID, THAT’S WHAT WE ARE WORKING TOWARDS. WE ARE WORKING TOWARDS MAKING THESE NON-SURGICAL DISEASES. SO, AFTER 49 CYCLES OF FORET NIB, HIS TUMORS BECAME ALMOST NONDEDUCTIBLE. THIS WAS HIS LARGEST DOWN TO 1.4. HE HAD A NUMBER OF OTHER TUMORS WHICH BASICALLY DISAPPEARED. NOW ARE WE HOME YET? NO. BUT, THIS WAS THE FIRST TRIAL TARGETING A PAPILLARY KIDNEY CANCER GENE SHOWING THAT THIS IS PROOF OF PRINCIPLE OF AN EFFECT AND I’LL JUST SHOW YOU THIS SLIDE. THIS IS 39 TUMORS IN NINE DIFFERENT PATIENTS. AS YOU CAN SEE, EVERY SINGLE ONE OF THEM HAS GOTTEN SMALLER WITH THERAPY. SO WE GET READY TO START A NEW TRIAL WITH A PURE MET INHIBITOR AND WE HAVE A NUMBER OF OTHER APPROACHES THAT WE HAVE DEVELOPED HERE. SO WE WILL SEE. I’M HOPEFUL. THE THIRD ONE IS — THIS WAS THAT FIRST PATIENT I MENTIONED TO YOU, THE ONE FROM OHIO. THAT WAS PAPILLARY KIDNEY CANCER. SO, WE MADE A CELL LINE FROM THIS. AND WITH COLIN COOPER — WE SHOWED THAT THERE WAS A TRANSLOCATION FROM THE FIRST CHROMOSOME TO THE X CHROMOSOME. AND THEN, WITH COLIN COOPER IN ENGLAND, SHOWED WHAT WAS HAPPENING HAPPENING IS A GENE ON CHROMOSOME 1 WAS GOING TO A GENE ON THE X CHROMOSOME CALLED TFE3. AND THIS WAS THE FIRST DESCRIPTION OF TFE3 KIDNEY CANCER. WE NOW KNOW THAT TFE3 IS PART OF A FAMILY OF TRANSCRIPTION FACTORS. TFE3, TFEB AND MITF WHICH CAN ALL CAUSE KIDNEY CANCER. MITF A GERMLINE ALTERCATION THAT CAUSES KIDNEY CANCER IN MELANOMA AND WE NOW KNOW THAT TFE3 KIDNEY CANCER IS ONE PENALTY 5% OF KIDNEY CANCERS BUT IN THE CHILDREN AND YOUNG ADULTS, IT’S 20-45%. SO THIS IS THE MOST COMMON TYPE OF KIDNEY CANCER IN CHILDREN AND YOUNG ADULTS. AND WE ARE WORKING VERY HARD AND YOU’LL BE DEVELOPING A THERAPEUTIC APPROACH TARGETING TFE3 AND WE ARE VERY ENCOURAGED ABOUT THE PRECLINICAL RESULTS WE HAVE AND WE ARE HOPING TO START CLINICAL TRIALS THIS YEAR TARGETING THIS TYPE OF KIDNEY CANCER. SO THIS IS THESE 3 GENES HERE. SO NEXT, I’M GOING TO SHOW YOU OUR FOURTH TYPE OF KIDNEY CANCER AND KIND OF HOW WE GOT INTO THIS. SO, WE WERE SAYING WE WILL SEE ANYBODY WITH MULTIPLE MEMBERS OF THE FAMILY WHO HAVE KIDNEY CANCER. AND WE SAW THIS FAMILY WHO AT THE TIME WAS THOUGHT TO HAVE BILATERAL MULTI-FOCAL, ONCOCYTOMA, AND THESE IDENTICAL TWINS. AND WE FOUND A TUMOR IN THE FATHER. SO WE THEN SENT LETTERS OUT TO PHYSICIANS AROUND THE COUNTRY ASKING FOR FAMILIES WITH FAMILIAL ONCOCYTOMA. AND WHAT HAPPENED WAS THE FOLLOWING: WE SAW A PATIENT, GLAD IN R.IS GLENN WAS WORKING WITH US AT THE TIME. AND SHE CALLED ME AND SAID, MARSDEN, WE HAVE A PATIENT UP HERE IN THESE ONCOCYTOMA FAMILIES THAT HAS FUNNY SKIN BUMPS. I SAID, LET’S BIOPSY THEM AND SEE WHAT PAUL DERA, THE PATHOLOGIST AT THE TIME HERE AT NCI, THINKS. WE DID. PAUL CALLED ME AND SAID, MARS DEN, THESE PEOPLE HAVE SOMETHING THAT RUNS IN FAMILIES. I SAID, I KNOW IT. IT RUNS IN MY FAMILY. HE SAID NO, IT RUNS IN FAMILIES. I SAID, I HAVE A FAMILY HERE. HE SAID NO, IT’S BEEN DESCRIBED. HE SAID IT WAS DESCRIBED BY THREE GUYS IN 1977. IT’S CALLED BURT HOG DUBE. THEY DESCRIBE CUTANEOUS LESIONS THAT RUN IN THESE FAMILIES. SO WE THEN WENT ON TO — THESE PATIENTS CAN GET VERY OBVIOUS CUTANEOUS FIBROFA LICK GNOMA OR GET SUBTLE ONES. THEY ARE BENIGN TUMORS. WE RECRUITED THESE FAMILIES AND SHOWED KIDNEY CANCER RUNS IN THESE FAMILIES. THEY CAN BE SOLITARY. THEY CAN BE BILATERAL, MULTIFOCAL. THEY CAN BE LARGE. THEY CAN METASTASIZE. THE PATHOLOGY HERE IS DIFFERENT. YOU CAN GET DIFFERENT TYPES OF PATHOLOGY. VHL IS ALWAYS CLEAR CELL. WITH HPRC, IT’S ALWAYS TYPE I PAP. HERE, WE SEE ABOUT A THIRD GET CHROME PHOBE KIDNEY CANCER. ABOUT 60% HYBRID ONCOCYTIC KIDNEY CANCER AND WE SEE A FEW CLEAR CELLS AND A FEW ONCOCYTOMEAS. WE CAN SEE THOSE DIFFERENT HIS TOLLAGES IN THE SAME FAMILY AND SAME PATIENTS. SOMETIMES IN THE SAME KIDNEY. WE ESTIMATE THESE PATIENTS GET UP TO 3000 TUMORS PER KIDNEY. SO, AGAIN, OUR SURGERY IS NOT CURING THEM BUT WE ARE SETTING BACK THE CLOCK BUT USUALLY IF WE DO GOOD SURGERY, MOST OF THESE PATIENTS, ONLY NEED ONE KIDNEY OPERATED ON PER LIFETIME. SO WE DO THREE CENTIMETERS. WE RECOMMEND SURGICAL INTERVENTION AND AGAIN THIS IS 96, 17 YEARS NOW, NOT ONE PATIENT DEVELOPED METASTATIC DISEASE WHEN MANAGED IN THIS FASHION. SO, WE WANTED TO FIND THE GENE AND WE BROUGHT THEM INTO THIS MARVELOUS FACILITY. AGAIN, THIS WAS WITH LAURA SMITH, BURT, MICHAEL NICKERSON. WE USED THE FIBROFOLLIC LOMAS AS OUR MARKER. AND LOCALIZED THIS TO THE SHORT ARM OF CHROMOSOME 17 AND IN THE FALL OF 2002, IDENTIFIED THE FLCN GENE AND WE DETECTED MUTATION OF FLCN NOW IN 97% OF 229 FAMILIES IT’S PRETTY REMARKABLE CHANGE AS WE SEE IN THIS GENE. WITH VHL, WE SEE NONSENSE, MISSENSE, FRAMESHIFT, COMPLETE DELETION, PARTIAL. HERE, MOST OF THE MUTATIONS, ALMOST ALL OF THEM, ARE MUTATIONS PREDICTED TO TRUNCATE THE PROTEIN. USUALLY IT’S A FRAMESHIFT OR A STOP. IT IS PRETTY UNBELIEVABLE. WHY THAT IS, WE DON’T KNOW EXACTLY. WE ARE HAPPY TO BE ABLE TO MAKE THE DIAGNOSIS AND TELL IN THESE FAMILIES WHO IS EFFECTED AND WHO IS NOT AND WHO NEEDS SCREENING AND WHO DOESN’T. WE AND OTHERS HAVE SHOWN THESE PEOPLE ALSO GET LUNG CYSTS. 92% OF OUR PATIENTS GET PULMONARY CYSTS. YOU CAN SEE THEY CAN BE VERY PROMINENT. THIS IS ONE DAVE OPERATED ON FOR US. TWO OF THEM. BUT WHAT WE WANTED TO DO WAS UNDERSTAND WHAT KIND OF GENE THIS IS. IS THIS A TUMOR SUPPRESSOR GENE? IS IT AN ONCOGENE? KATHY VOGUE DID THIS STUDY WHERE SHE LOOKED AT A NUMBER OF TUMORS FROM PATIENTS LIKE THIS PATIENT THAT WE OPERATED ON. AND SHE FOUND 70% OF THEM HAD A SECOND HIT. NOW IN OTHER WORDS THIS IS A TWO-HIT MODEL. SO YANG MADE A CELL LINE, THE ONLY ONE IN THE WORLD, FOLLIC LEGAL DEFICIENT CANCER CELL LINE. MAKES TUMORS IN MICE. FOLLIC LIN WAS PUT BACK IN AND IT’S LIKE VHL, YOU GET NO TUMOR OR VERY SMALL TUMOR. SO WE WANTED TO KNOW HOW THIS GENE FUNCTIONS. SO, THIS IS THE WORK OF LAURA SCHMIDT AND A NUMBER OF OTHERS. AND A BABA RAN THIS GEL WHERE IPd FLICK LIN AND PULLED DOWN THIS PROTEIN HERE WHICH TURNED OUT TO BE A PROTEIN WE NAMED FLICK LIN INTERACTING PRO TIN 1. FNIP1 AND THIS BAND RIGHT HERE IN THIS CHANGE — THIS ONE BAND CHANGED OUR ENTIRE FOCUS. OUR ENTIRE DIRECTION OF OUR WORK IN KIDNEY CANCER BECAUSE THIS PULLED DOWN THE GAMMA SUBUNIT OF AMPK. AND AS YOU KNOW, AMPK IS THE GRAND CENTRAL STATION OF ENERGY SENSING IN THE CELL. SO THIS REALLY WAS WHAT GAVE US THE FIRST INCLINATION THAT KIDNEY CANCER IS FUNDAMENTALLY A METABOLIC DISEASE. SO WE NOW KNOW THAT FLICK LIN BINDS FNIP1 AND 2 WHICH BIND AMPK AND THIS PUTS THIS THEN IN THE LKB1, TS1TS2 mTOR PATHWAY. NOW THERE IS A LOT WE DON’T KNOW BUT IS THERE SAY LOT WE DO KNOW AND AGAIN, WE HAVE SHOWN THAT DEFICIENT FLICK LIN KNOCKED OUT, YOU GET TO, 1 AND TO, 2 ACTIVATED AND — TORQUE 1 AND TORQUE 2. AND THE CURRENT WORK SHOWS THIS COMPLEX IS RIT CALL TO ACTIVATION OF AMPK, CERTAINLY BY THINGS LIKE FIN FORM AND METFORMIN. SO WE THINK THAT MAYBE THROUGH LKB1, NOT TOTALLY SURE BUT WE WILL SEE. BUT THIS IS A BASICALLY A FUNDAMENTALLY METABOLIC PATHWAY. SO, WE ARE WORKING ON THE FOLLOWING APPROACH AND WE ARE GEARING UP TO DO POTENTIALLY DO CLINICAL TRIALS TARGETING EITHER TORC1 OR 2 IN THIS HEREDITARY CANCER SYNDROME AND WORKING ON OTHER PATHWAYS. BACK TO THIS 18-YEAR-OLD YOUNG WOMAN THAT CAME UP FROM CHARLOTTESVILLE. AFTER SHE DIED, HER MOM DIED, WE TRIED AND TRIED. YOU REGRET THINGS YOU DO IN LIFE AND I REGRET I DIDN’T DRIVE TO CHARLOTTESVILLE AND GO TO THE POLICE OFFICE AND TRY AND FIND THIS FAMILY. WE COULDN’T FIND THEM. WE LATER FOUND OUT WHAT HAPPENED. THE CHILDREN WEPT WITH THE STEPFATHER WHO HAD A DIFFERENT LAST NAME. WE COULDN’T FIND THEM. BETWEEN THE TIME WE SAW HER AND WHEN WE SAW HER FIRST COUSIN, HER BROTHER DIED, HER MOTHER DIED, HER UNCLE DIED, HER GRANDMOTHER HAD DIED AND HER GREAT-AUNT AND LATER ON, HER COUSIN. VERY ADVANCED DISEASE AND ENDED UP DYING OF THIS DISEASE. SO THIS IS A VERY LETHAL FORM OF KIDNEY CANCER WHICH WE INITIALLY DESCRIBED IN 95 WHICH WAS REDESCRIBED AND RENAMED, BETTER DESCRIBED IN 1999 AND GOES NOW BY THE NAME OF HEREDITARY LIOMATOSIS RENAL CELL CANCER. THESE PATIENTS ARE AT RISK TO DEVELOP BOTH CUTANEOUS AND UTERINE BIOMIOMAS AND AN AGGRESSIVE FORM OF KIDNEY CANCER. AUTO SOMAL DOMINANT HEREDITARY CANCER SYNDROME. THESE CUTANEOUS LESIONS ARE TUMORS OF THE. [ INDISCERNIBLE ] WHICH IS IN THE BASE OF THE HAIR FOLLICLE. THIS IS LIKE AN ENERGY SENSOR. NORMALLY WHEN YOU GET COLD, THIS CONTRACTS. YOUR HAIR STAND ON END AND TRAPS HEAT. HERE, IT’S LIKE IT NEVER STOPS CONTRACTING AND THEY FORM THESE TUMORS. AND WE WORKED WITH MARIA TURNER AND SO HAPPY NOW TO WORK WITH ED ON THIS AND THIS IS THE PATIENT WE SAW JUST RECENTLY. THESE CAN BE EXTREMELY SYMPTOMATIC. WE LOST A PATIENT — IT WAS A FAMILY MEMBER OF ONE OF OURS WHO TOOK HIS LIFE. JUST COULDN’T DEAL WITH IT. THESE CAN BE VERY SIMPLE MATTIC AND WE ARE HOPING TO DEVELOP A BETTER APPROACH TO THERAPY. APOLOGIZE FOR THAT. THESE PATIENTS ALSO GET UTERINE LIE OH, MY OHMS. — LEIOMYOMAS. THEY ARE VERY EARLY ONSET. 89% OF OUR WOMEN WHEN THESE FAMILIES ARE AFFECTED WITH UTERINE LEIOMYOMAS AND 50% OF THE WOMEN HAD HYSTERECTOMIES IN THEIR 20S. CATASTROPHIC PHENOTYPE FOR WOMEN. CURRENTLY, OUR GUIDELINECOLOGICKIC SURGEONS, PAM AND HER COLLEAGUES, DO — GYNECOLOGIC — WE HAD FOUR BABIES HERE AFTER MYOMECTOMIESES. THEY GET VERY AGGRESSIVE KIDNEY CANCERS. A 21-YEAR-OLD CAME UP FROM MIAMI. I TOOK OUT THAT WITH JEFF NORTON. A BIG OPERATION. TOOK THAT OUT. THIS YOUNG MAN LIVED 17 MONTHS, DIED OF METASTATIC DISEASE. THIS IS A PATIENT WHO CAME, YOU CAN SEE THE COUPTANEOUS — THEY DON’T TEND TO CROSS THE MID LINE. THEY DON’T TEND TO. YOU CAN SEE WE BIOPSIED IT. HE WAS 32 YEARS OLD AND HIS FATHERED DIED AT AGE 35 OF METASTATIC DISEASE. WE SCREENED HIM AND FOUND THIS. THEY GET CYSTS IN THEIR KIDNEY AND GET SOLID TUMORS AND THEY CAN GET TUMORS INSIDE THE CYSTS. HE HAD THAT. HE HAD THIS ASSIST WITH A VERY SMALL TUMOR, 1/2 CENTIMETER. NOW WHEN HE SHOWED UP, WE WERE JUST SCREENING HIM AND HE ALREADY HAD A LARGE TWO CENTIMETER NODE. SO THESE SPREAD EARLY. VERY DIFFERENT THAN THE OTHER ONES I SHOWED YOU. MARIA HAS DESCRIBED THIS AND THIS IS PRETTY MUCH OF A — I DON’T FINISH I SAY UNIQUE BUT PATHOPNEUMONIC PICTURE FOR THIS. SHE CAN JUST LOOK AT THE PATH AND TELL YOU WHAT THIS IS. THIS IS A FORM OF TYPE II PAPILLARY KIDNEY CANCER CHARACTERIZED BY A RANGE OF NUKE OLE’ I WITH THESE VERY PROMINENT PERRY NUCLEAR HALO. WE SEE THIS DISEASE IN 10-YEAR-OLDS. WE SEE IT IN 77-YEAR-OLDS. THIS IS A LIFE-LONG RISK FOR CANNER. CANCER. VERY TRICK TOW MANAGE CLINICALLY. THIS PATIENT WAS 24. CAME TO US WITH THIS CT SCAN, I DON’T KNOW. I CAN’T CALL THAT. IS THAT JUST A ASSIST OR SOMETHING INSIDE THATANIST SO WE SAID COME BACK IN THREE MONTHS AND LET’S DO AN MRI. WE DID AN MRI AND WE COULDN’T CALL THAT. SO WE SAID COME BACK IN NINE MONTHS. WE DID THIS CT AND I CAN’T CALL THAT. I DON’T REALLY KNOW. WE DID THE MRI AND WE SAID, WE DHAL A DOUBLE BUMP. SO WE OPERATED. WHEN WE OPERATED, AND THIS OPERATION WAS DONE BY NETTY, WE WENT WAY WIDE ON THIS KIDNEY. THIS WAS LOWER POLE. WE WENT ALL THE WAY UP TO THE HIGH LAND AND ALMOST DID A MEME — HEMINEPHRECTOMY. YOU CAN SEE — HANG ON. THERE WE GO. SO, YOU CAN SEE WE DID BASICALLY A HEMINETERRIFIC ME. WHEN MARIA CALLED ME, SHE SAID YOU HAVE TO LOOK AT THIS. SHE SAID, THAT 24-YEAR-OLD YOU OPERATED ON SHE SAID, YOU GOT TUMOR HERE IN THE ASSIST LIKE YOU EXPECTED. BUT LOOK AT THIS. YOU HAVE TUMOR INFILTRATING THROUGHOUT THE FRENCH MAN. I SAID DON’T TELL ME — PA REVEREND MA. YOU HAVE A 4 CENTIMETER MARGIN. BUT THIS IS HALFWAY THERE. I SAID WE COULDN’T SEE IT ON IMAGING. YOU COULDN’T SEE THE MARGIN SURGICALLY. SHE SAID, YES. SO WE MANAGED THESE VERY DIFFERENT THAN THE OTHER TYPES. THIS WAS ONE THAT ADAM DID RECENTLY. IS THAT ANYTHING? IT’S HARD TO KNOW. SO WEAR ON THE SIDE OF INTERVENE FIGURE WE ARE NOT SURE. IS THERE SOMETHING IN THERE? HE DID A PARTIAL. MAYBE. THE PARTIAL NEPHRECTOMY ON THAT AND MARIA SAID YOU HAVISTS AND TUMORS IN THE CYSTS. SO I SAY THAT IS AN ALLIGATOR WASN’TING TO POUNCE AND THEN YOU ALSO HAVE TUMOR INVASIVE IN THERE. THIS HAS TO BE HANDELED WITH KID GLOVES. A VERY FRIGHTENING DISORDER. IN THE INTEREST OF TIME, I’M GOING TO SKIP OVER THIS PATIENT AND TALK ABOUT THIS ONE. SO WE RECOMMEND IMAGING EVERY YEAR. THIS IS A LADY WE ASKED IF YOU DO IT EVERY YEAR, WE FIND SMALL LESIONS WE GET THEM OUT. PATIENTS DO FINE. THIS LADY WE ASKED OR SAW HER IN ’03. HER IMAGING WAS FINE. NOTHING THERE. IN ’06 SHE HAD IMAGING ON THE OUTSIDE. THREE YEARS LATER. EVERYTHING WAS FINE. AND THEN IN DECEMBER OF 2010, I GOT A CALL FROM THE UNIVERSITY OF MARYLAND. THEY SAID WE THINK WE HAVE ONE OF YOURS THERE. I SAID, WHAT DO YOU GOT? THIS LADY HASN’T HAD IMAGING IN FOUR YEARS. THESE NOSED. 10-59 NOSED POSITIVE. SHE IS NOW BEING TREATED FOR ADVANCED DISEASE. SO WE DO NOT RECOMMEND ACTIVE SURVEILLANCE. WE TREAT THESE VERY DIFFERENTLY THAN THE OTHER TYPES OF KIDNEY CANCER. AND WE DO SURGERY AND GO VERY WIDE. THIS GENE IS ON CHROMOSOME 1. THE GENE FUMEERATE HYDROTAZE. WE EVALUATED 186 FAMILIES. WE FOUND FH MUTATION IN 98% OF THESE FAMILIES. THIS IS A TWO-HIT LOSS OF FUNCTION TUMOR SUPPRESS ARE GENE. THIS IS THE HLRC KIDNEY CANCER CELL LINE. YOU PUT FH BACK IN, NO TUMORS. IT’S PRETTY REMARKABLE. JUST A ENZYME. SO, WE SAID, HOW ON EARTH COULD LOSS OF CREB CYCLE ENZYME — WHY DIDN’T THAT KILL THE CELL? WE SHOWED JUST THE OPPOSITE THAT THESE CELLS IS NO LONGER A CYCLE. IT’S LINEAR. BUT THESE CELLS SHIFT TO A GLUTAMINE DEPENDENT REDUCTIVE CAR BOXALATION PATHWAY, WHICH BY THE WAY GIVES US A NUMBER OF NOVEL TARGETS ALONG THE WAY WHICH WE CAN TARGET. AND WE SHOWED IN THE LAB AND PRIMARILY YANG DID THIS WORK, THAT THE FH DEFICIENT CLEAR CELL KIDNEY CANCER DOESN’T TAKE UP OXYGEN. THESE CELLS OXIDATIVE PHOSPHORYLATION, THE TCA CYCLE, ELECTRON TRANSPORT CHAIN ARE IMPAIRED AND THESIS CELLS RAMP UP GLYCOLYSIS. SO THIS IS A SHIFT TO AEROBIC GLYCOLYSIS. IT’S LIKE A WARBERG MODEL. YANG SHOWED THAT IF YOU TAKE A VHL KIDNEY CANCER CELL LINE, CLEAR CELL, A V MUTATION AND YOU GROW IT IN CULTURE AND PUT TO THE IN LOWS GLUCOSE T LAUGHS AT YOU. BUT IF YOU TAKE THESE CELLS, MOST ACTIONER AGGRESSIVE TYPE, THEY ARE SENSITIVE. SHE NUTS A LOW GLUCOSE THEY ALL DIE. SO THEY ARE VERY SENSITIVE TO THIS. CLINICALLY, WHAT WE FOUND IS THIS FRANCEALATES STEP-BY-STEP TO OUR PATIENTS. SO, THESE PEOPLE — TRANSLATES. THEY LIGHT UP LIKE A CHRISTMAS TREE. IT’S SAD. YOU CAN PICK UP EVERY ONE OF THESE TUMORS. THIS PATIENT GROWS TO METASTATIC DISEASE. RON IS LOOKING AT THE PET SCANNING ON THESE PATIENTS. YOU CAN SEE THIS PATIENT AND THIS WAS THOUGHT TO BE NORMAL. THE CT SCAN. IS THIS VASCULAR OR SOMETHING? WE DID A PET SCAN AND MAN. 54-YEAR-OLD RADIOLOGIST. THIS PATIENT HERE IS THERE SOMETHING IN THERE? WE ARE NOT SURE. WHY YES, THERE IS. WELL, IF YOU LOOK AT THIS CHEST, I DON’T KNOW. THESE VESSELS. WHICH ONE OF THESE? WHAT IS GOING ON? THE CELL IS RIGHT THERE. EVEN THIS SKIN LIGHTS UP. REMEMBER THIS GUY? LOOK AT THIS. UTERUS IN THESE LEIOMYOMAS LIGHT UP. THEY LOSE THE SECOND ALLELE AND SHIFTED TO AEROBIC GLYCOLYSIS. SO TRACY SHOWED THE FOLLOWING. THAT IN THESE CELLS, THIS IS COUNTERINTUITIVE. BUT WHAT HAPPENS IS, THEY BECAUSE OF GLYCOLYSIS, EVEN THOUGH OX PHOS IS SHUT DOWN AND EVEN THOUGH THIS IS INEFFICIENT, GLYCOLYSIS GOES UP SO MUCH THAT THEY MAKE A LOT OF AT. AND AMPS SUPPRESSED IT’S INHIBITEDDED. THAT TELLS THE CELL TO GROW. IT SAYS, I GOT A LOT OF ENERGY. SO IT HAS A LOT OF EFFECT, DROWN STREAM EFFECTS ON THE IRON TRANSPORTERS STABILIZING HIF. HOWEVER, JUST KEEP THIS IN MIND. DECREASE AMPK. NOW, CAROL TREATED THESE CELLS WITH METFORMIN AND NOW LOOKING AT OTHERS AND SAW VERY DRAMATIC EFFECT. SHE COULD HAVE A HUGE EFFECT ON THE INVASION OF THESE CELLS AND WHEN SHE IS COMBINED IT IN PRECLINICAL MODELS IN VITRO AND IN-VIVO, WITH OTHER TARGETED AGENTS TARGETING OTHER PARTS OF THIS PATHWAY, YOU CAN CURE-ALL THESE ANIMALS. SO, THIS, WE THINK, TARGETING THE METABOLIC BASIS OF THIS HAS SOME SIGNIFICANT POTENTIAL. NOW, WITH LIN AND JEN ISSACS, WE SHOWED THAT WHEN HYDROTAZE IS KNOCKED OUT, FUMEERATE GOES UP. AND FUMEERATE IS FUNDAMENTALLY AN ONCOPROTEIN. AND THIS WAS THE FIRST STUDY TO SHOW THIS. FUMEERATE OUTCOMPETES FOR BINDING HYDROXYLASE AND ESSENTIALLY POISONS IT. SO WHAT YOU END UP WITH THEN IS A VHL INDEPENDENT MECHANISM FOR DYSREGULATION OF HIF DEGRADATION AND FUMER EIGHT HYDROTAZE DEFICIENT KIDNEY CANCER. SO, THESE CELLS THEN DEVELOP, OR THEN GET A LOT OF VEGF GLUTE 1 AND GLUTE 4 GOES UP. WE SAY, THESE GUYS NEED THAT. THEY NEED THE VASCULATURE. THESE CELLS MIGHT BE SENSITIVE TO TARGETING VASCULATURE BECAUSE THEY ARE SO DEPENDENT ON GLUTAMINE FOR THEIR SURVIVAL EVEN THOUGH THEY ARE SO AGGRESSIVE. SO, RON RAN A PILOT TRIAL. NOW DOING A BIGGER TRIAL WITH TARGETING WITH BEVACIZUMAB TO ELOT NIB. AND POTENTIAL TOW TARGET MAYBE GLUCOSE TRANSPORT GLYCOLYSIS. NOW, HOW CAN I PUT THIS. TWO DIFFERENT SITE REVIEWS I WAS TOLD THIS DOESN’T WORK. WHAT DO YOU THINK? AND I SAID, WAIT A MINUTE, YOU’RE TALKING ABOUT CLEAR CELL KIDNEY CANCER. THAT’S A DIFFERENT GENE. A DIFFERENT DISEASE. HERE IT MIGHT. AND WE SEEN DRAMATIC RESPONSE. THIS IS ONE OF THE FIRST PATIENTS. UP UNTIL THIS POINT, THIS DISEASE, WE LOST EVERY ONE OF THEM TO METASTATIC DISEASE. IT WAS REALLY NOT TREATABLE. THIS IS THE WOMAN WHO CAME TO US 42-YEAR-OLD, WHO HAD SURGERY ON THE OUTSIDE AND THE DOCTOR DIDN’T REALIZE IT WAS HLRC AND DIDN’T REALIZE HU TO GO WIDE. HE DID A REGULAR PARTIAL NEFRACT ME AND LEFT A LOT OF DISEASE ON THE KIDNEY AND HER ABDOMEN. WE HAD POPSY PROOF AND EVERYTHING ELSE. AND YOU CAN SEE IT ON THE PET SCAN. NOW BOTH HER SISTERS DIED OF METASTATIC KIDNEY CANCER AS DID HER FATHER. RON PUT HER ON THIS APPROACH WITH BEVACIZUMAB AND ELOT NIB. AFTER THREE MONTHS SHE HAD A COMPLETE RESPONSE. SHE LATER DEVELOPED A NEW SMALL TUMOR IN ABOUT 3 1/2 YEARS AND WE TOOK OUT, INDEPENDENT SEPARATE TUMOR. SHE IS NOW SEVEN YEARS OUT AND WE CANNOT FIND EVIDENCE OF DISEASE. SO, I THINK WHAT I’M GOING TO DO IS CONCLUDE BY SAYING THAT WHAT I HAVE SHOWN YOU IS THAT KIDNEY CANCER IS FUNDAMENTALLY A METABOLIC DISEASE MADE UP OF A NUMBER OF DIFFERENT TYPES OF CANCER, DIFFERENT HISTOLOGIES AND DIFFERENT CLINICAL COURSES CAUSED BY DIFFERENT GENES, AND THAT EACH OF THE KIDNEY CANCER GENES THAT ARE CURRENTLY KNOWN, EACH ONE OF THEM, EFFECTS THE CELL’S ABILITY TO SINCE OXYGEN, IRON, OR NUTRIENTS OR MOST OBVIOUSLY IN THE TCA CYCLE, CREB CYCLE, FUMEERATE AND DEHYDROGENASE ENERGY. AND IT’S OUR HOPE THAT TARGETING THE METABOLIC BASIS OF KIDSNY CANCER WILL PROVIDE THE FOUNDATION FOR THE DEVELOPMENT OF AN EFFECTIVE FORM OF THERAPY FOR PATIENTS WITH THIS DISEASE. I WANT TO ACKNOWLEDGE MY WONDERFUL COLLEAGUES. I HAD THE HON OUR TO WORK WITH AND MY COLLEAGUE, BURT ZA BAR, MY COLLEAGUES, IN OUR GROUP AND ULB AND ALSO LYNN KNICKERS AND DON AND KATHY AND TRACY AND HER GROUP, OUR COLLEAGUES IN NEUROSURGERY, ENT, GENERAL SURGERY, OPTHALMOLOGY, ENDOCRINOLOGY, WHO WE COULDN’T HAVE DONE THIS WORK WITHOUT. I ALSO WANT TO MENTION DR. RAM. PETER PINT OH, ADAM, MARIA MERRINEO WHO HAS BEEN BY OUR SIDE FOR 27 YEARS MANAGING THESE PATIENTS, PETER AND BRAD, THE TWO BEST RADIOLOGISTS I EVER MET, AND THE MOST SENSATIONAL GROUP OF UROLOGIC ONCOLOGY FELLOWS AND FINALLY THE MOST GIFTED, ACCOMPLISHED, TALENTED AND COMMITTED GROUP OF INDIVIDUALS TO WORK WITH US, TO MANAGE OUR PATIENTS, OUR NURSING AND PATIENT MANAGEMENT STAFF, OUR PHYSICIANS ASSISTANTS AND RNs AND AN INCREDIBLE GROUP OF PATIENT CARE COORDINATORS AND DATA MANAGERS. THANK YOU VERY MUCH. [ APPLAUSE ]>>THANK YOU, HAS DIN FOR TYPIFYING WHAT WE HOPED THIS LECTURE WOULD BE AND DOING IT SO ELEGANTLY. THE HOUR IS GETTING A LITTLE LATE SO WHAT WE ARE GOING TO RECOMMEND IS, WE ARE GO GOING TO HAVE A RECEPTION FOR MARSDEN IN THE LIBRARY HERE, IN THE LOUNGE. YOU ARE ALL WELCOME TO COME AND DISCUSS INFORMALLY WITH MARSDEN AND EACH OTHER, THE INCREDIBLE OPPORTUNITIES FOR KIDNEY CANCER THAT HE DESCRIBED. SO THANK YOU VERY MUCH. [ APPLAUSE ]

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