WHAT WOULD BE A BETTER ENVIRONMENT AND SET UP TO DO THAT? SO I JUST WANT TO SHOW YOU VERY BRIEFLY WHAT WE HAVE BEEN DOING IN THE CLINIC UP TO NOW AND WHERE IS THIS TAKING US PROBABLY AND STIMULATE SOME QUESTIONS FROM YOU THAT OVER AT THE CLINIC WE MIGHT BE ABLE TO ANSWER. SO YOU ALL KNOW WHAT THIS IS. INTROGASTNAL TUMOR, WHICH IS THE TUMOR IN THE GASTRO INTESTNAL TRACT AND IT IS FROM THE PACEMAKER. AS MOST OF YOU KNOW, MOST OF THESE TUMORS HAVE A MUTATION IN GENES AND THE REASON WHY YOU ARE HERE IS BECAUSE YOU DON'T HAVE IT. THERE ARE OTHER PATIENTS WHO DON'T HAVE THE MUTATIONS IN THESE GENES. NOW PATIENTS WHO DO HAVE A VERY GOOD RESPONSE TO IMACNI THAT LEADS TO A NICE REDUCTION IN TUMOR GROWTH. BUT HOW ABOUT THE TENTATIVE 10% OF PATIENTS WHO DO NOT HAVE THE MUTATIONS? THIS IS WHAT WE HAVE BEEN CALLING UP TO NOW WILD AND INDICATE IN CERTAIN OPPORTUNITIES WITH DIFFERENT DEGSS OF SUCCESS -- DEGSS OF -- DIFFERENT DEGREES OF SUCCESS ARE LESS EFFECTIVE. MOREOVER, 85% OF CHILDREN WHO HAVE THIS DO NOT HAVE THE MUTATIONS. SO SINCE WE WERE AGAIN USING THE TWO YOUNG TEAMS AND THE REST OF THE TEAMS' INITIATIVE, IT WAS CURIOUS ABOUT WHAT IS THE NATURAL HISTORY AND HOW CAN WE BETTER HELP THE PATIENTS WHO HAVE THESE UNIQUE WILD. THE CLINIC HAD THE BIG GOAL OF OBTAINING CLINICAL AND RESEARCH DATA THAT WILL HELP US DESIGN THE PROT KOLESSES TO GATHER DATA AND TO MOVE FROM THERE TO SEE WHAT CAN WE DO TO IMPROVE THE OUTCOME, TO IMPROVE THE LANDSCAPE. SO WHAT HAVE WE LEARNED SINCE 2008? WE'VE LEARNED THAT WHILE IT IS DIFFERENT FROM ADULTS MUTATED DISKS AND SOME OF THE DOSES WERE PRESENT HERE HAVE SHARED THE -- SOME OF THE DOCTORS WHO WERE PRESENT HERE HAVE SHARED THE INFORMATION ABOUT WILD TYPE GENES MISSING AND HYDROGENATE. SO HOW DO WE -- THESE ARE THE SLIDES, VERY FINE SLIDES AS THEY LOOKED AT THE MICROSCOPE OF TUMORS AND YOU CAN SEE HERE IN BROWN IS A PROTOCOL CALLED FDHB. SO PATIENTS WHO HAVE THE MUTANT DICKS HAVE NO PROBLEMS WITH HDAH. HOWEVER AT THE BOTTOM YOU SEE THERE THERE IS NOTHING IN BROWN HERE. WE CANNOT FIND THE PRODDING. AND THEY GAVE US AN INITIAL LEAD ABOUT THE BIOLOGY AND HOW CAN WE MOVE FROM LEARNING ABOUT BIOLOGY TO MOVE TOWARDS TREATMENT. SO WHAT DOES THIS MEAN? WHAT IS THE ADHD? SO IT'S THE MACHINE INSIDE THE CELLS THAT ALLOW CELLS TO CONVERT PUT A NUTRIENT INTO READY-TO-USE ENERGY SO WHENEVER WE EAT CARBS, FAT, PROTEIN, ALL THESE NUTRIENTS GET BROKEN DOWN INTO VERY SMALL PIECES AND GET TRANSFERRED INTO THE CELLS AND THE CELLS HAVE TO PROCESS THEM SEQUENTIALLYLY IN ORDER TO PRODUCE THE ENERGY TO GROW AND SURVIVE. AND THE WAY THE CELLS DO THIS IS IS TO GO THROUGH THESE CYCLES, TRANSFORMING THESE NUTRIENTS INTO DIFFERENT MOLECULES. AND THIS IS AN ESCHEMEA THAT SHOWS IN THE PROCESS OF TRANSFORMATION, A COMPOUND CALLED SUCTIONINATE IS TRANSFORMING FUMORATE AND CONTINUES TO SPIN AROUND IN ORDER TO BE ABLE TO LIBERATE ALL THE ENERGY FROM THE NUTRIENTS TO THE CELLS TO BE READY TO USE. THERE ARE KEY COMPONENTS OF THE CELL METABOLISM THAT HELP THESE CYCLES TO OCCUR AND SOME OF THEM -- NOT ALL OF THEM, ARE DEPICTED HERE. ONE OF THEM IS FDH, WHICH IS THE SAME THAT IS MISSING IN THE SAMPLES OF THE TUMORS. NOW, WHILE THE CELL IS BUSY TRYING TO GET ENERGY OUT OF FOOD, THERE ARE OTHER THINGS THAT ARE HAPPENING. THERE IS A BALANCE IN BETWEEN GROWTH AND PROLIFERATION UNTIL DEATH TRYING TO KEEP THE MECHANISMS THAT ALLOW CELLS TO GROW IN CHECK. SOME OF THE FACTORS THAT HELP THE CELLS TO GROW ARE CALLED HYPOINDUCEABLE FACTORS AND THESE HELP THE CELLS PRODUCE GROWTH FACTORS THAT ULTIMATELY LEAD TO TUMOR GROWTH AND SURVIVAL. SOME OF THESE GROWTH FACTORS WE DON'T KNOW WHAT THEY ARE. SOME OTHERS WE ARE STARTING TO KNOW BETTER, AND ARE CALLED VEGA, WHICH IMPEL BLOOD VESSELS TO GROW AND EGFR, WHICH IS A PARTICULAR KIND OF GROWTH FACTOR THAT IS INVOLVED IN MANY DIFFERENT TUMOR TYPES AND BASICALLY THESE FACTORS ARE ABLE TO STIMULATE THE PRODUCTION OF THESE THINGS AND ALLOW THE CELLS TO GROW AND SURVIVE. IF THESE WERE NOT CONTROLLED, IT WOULD BE VERY EASY TO GET TUMOR CELLS IN THE BODY. SO THERE ARE MANY MECHANISMS THAT CONTROL THIS TO MAKE SURE THAT THE HIGH UPON NEWSABLE FACTORS THAT ARE IN CHECK ARE BEING DESTROYED AND DEGRADED AND THE LEVEL NEVER BUILT UP SO WE HAVE A BALANCE HERE AND IT DOESN'T ACCUMULATE. NOW, HOW DOES IT RELATE TO THE MECHANISMS BY WHICH CELLS ARE GETTING ENERGY FROM FOOD? IT TURNS OUT THAT IF FDH IS NOT PRESENT, SDH CANNOT KEEP IT AROUND AND A BUILDUP STARTS TO OCCUR. AND WHEN YOU RESEARCH IS TEACHING US THAT THIS ACCUMULATION IS ABLE TO RECEIVE THE MECHANISM THAT KEEP THESE IN CHECK. SO WHEN BEFORE WE HAD A TON OF DIFFERENT PRODDING TRYING TO KEEP THESE HIGH UPON NEWSABLE FACTOR AT A LOW LEVEL AND IN CHECK WITH A VERY CLOSE REGULATION OF THE CELL GROWTH AND PROLIFERATION, THE BUILDUP AFFECTS THIS IN THAT MANNER IN A MANNER SUCH THAT THE FACTORS START TO BUILD UP. PROBABLY MANY OTHER THINGS THAT WE STILL DON'T KNOW ABOUT START TO BUILD UP AND WE BELIEVE THAT THIS IS A FACTOR THAT NEEDS TO BE ON THE PROGRAM, THAT MEANS THE SIGNALS THAT TELL THE CELLS THAT THIS CAN GROW WITHOUT CONTROL AND POSSIBLY LEAD TO TUMORS. SO THIS IS OUR HYPOTHESIS. WE LEARNED FROM ALL THE SAMPLES AND ALL THE INFORMATION SHARED BY MANY GENEROUS PATIENTS LIKE YOU. WE HYPOTHESIZED THAT FDH DEFICIENCY LEADS TO INCREASED HEAT ACTIVITY, ICHB CREASED ACTIVITY AND OTHER THINGS AND ULTIMATELY TUMOR GROWTH. SO WHAT WE DO AS SCIENTISTS AS TO START THINKING HOW ARE WE GOING TO TEST THE HYPOTHESIS? IN OTHER WORDS, HOW DO WE KNOW IF WE ARE RIGHT? SO TYPICAL WAYS TO DO THAT IS TO USE A CELL SQLICHBLET CELL LINES ARE CANCER CELLS THAT ARE GROWING ON PLASTICS AND WE CAN EXPERIMENT WITH THEM AND ADD DIFFERENT DRUGS AND SEE HOW THEY RESPOND. AND EVEN THOUGH IT'S NOT ALWAYS VERY LINEAR AND WE HAVE TO BE CAREFUL ABOUT DOING THAT, WE CAN DRAW CONCLUSIONS. UNFOURJ, WE DO NOT -- UNFORTUNATELY, WE DO NOT HAVE THE CELL LINES AVAILABLE. WE ARE WORKING REALLY HARD IN TRYING TO GENERATE THEM. WE'RE WORKING REALLY HARD IN HAVING THESE CELLS ATTACHED TO PLASTIC, LOOKING AT THEM GROW AND TRYING TO MANIPULATE THEM AND TRYING TO INHIBIT THEIR GROWTH. BUT THESE KINDS OF MODELS ARE AVAILABLE FOR OTHER TUMORS BUT AS TO THIS POINT NOT YET FOR WILD -- OTHER WAYS TO GO AROUND AND-T AND WHAT IS DONE IN SOME OTHER TUMORS IS TO THINK ABOUT WHAT WE CALL AN ANIMAL MODEL. IS THERE ANY ANIMAL MODEL THAT WE CAN COMPASSIONATELY USE IN ORDER TO STUDY GENES AND THEIR CONCLUSIONS FROM IT? UNFORTUNATELY, NOT THERE YET. THERE ARE NO ALVIN MAL MODELS OF WILD TYPE GENES. SO THE NEXT THING ON THE LIST IS HOW ABOUT OTHER TUMORS THAT COULD HAVE SIMILAR MECHANISMS? IS THERE ANY OTHER TUMOR THAT COULD BEHAVE IN A SIMILAR WAY, WHERE WE COULD EXTRAPOLATE AND LEARN FROM IT? AND THERE IS A VERY SPECIFIC TYPE OF KIDNEY CANCER WHERE A VERY SIMILAR MECHANISM HAPPENS. IF YOU REMEMBER, I JUST SHOWED YOU HOW THESE GUYS, SFH, WAS ABSENT IN PATIENTS WITH WILD TYPE GENES. NOW, THERE IS A CERTAIN TYPE OF KIDNEY CANCER WHERE THE PROTEIN ABSENT IS THE NEXT ONE DOWN THE CHAIN, FH. AND WHEN THIS IS ABSENT, THIS ENERGY-PRODUCING MACHINERY, IT BUILDS UP AND WE KNOW IT IS ABLE TO INHIBIT ALL THE CONTROL MECHANISMS OF THE FACTOR AND IT TURNS INTO TUMOR GROWTH AND SURVIVAL. SO I THINK I AM DOING SOMETHING WRONG. SO WE THOUGHT HOW CAN WE USE THIS INFORMATION IN ORDER TO TRY TO BRING NEW THERAPIES TO THE CLINIC? WE ASKED THE DOCTORS WHO ARE ADVISING RESEARCHING KIDNEY CANCER AND WHAT THEY SAW WAS -- IS THAT EVEN THOUGH THEY CANNOT INHIBIT THE PROCESS AT THIS LEVEL, WHEN THEY BLOCK THE PRODDING, VEGA AND EGFR, THEY SAW A STRIKING REDUCTION IN TUMOR GROWTH AND SURVIVAL IN THESE PATIENTS WITH FH-DEFICIENT KIDNEY CANCER. SO THE QUESTION THAT WE ARE ASKING OURSELVES IS CAN WE STOP WILD TYPE GENES GROWTH BY INHIBITING THESE TWO PRODINGS, EGFH AND INVESTIGATEFHR? AND HOW WOULD WE DO THAT? SO IT TURNS OUT THAT WE ARE VERY FAMILIAR WITH A DRUG THAT INHIBITS THOSE TWO PRODINGS AND OTHER PRODINGS AS WELL THAT ARE IN IMPORTANT IN OTHER CANCERS SUCH AS A PARTICULAR TYPE OF CANCER AND I BRING THIS UP BECAUSE THIS DRUG WAS F.D.A. HAN PROVED LAST YEAR AND THANKS TO THAT WE HAVE A WHOLE LOT OF INFORMATION ABOUT SAFETY AND MECHANISM OF FACTOR. WE ARE STARTING TO LEARN A WHOLE LOT, SO IT WAS APPROVED AND WE HAD THE LUXURY OF ADMINISTERING TO CHILDREN HERE AT THE NCI IN A PHASE ONE OF TRIAL, WHICH IS MEANT TO SEE THE C CB IN PATIENTS WITH THESE KINDS OF DISEASE. SO WE ARE STARTING TO LEARN A LOT ABOUT IT AND THE PEOPLE WHO RUN THE TRIAL IN THE CARCINOMA IS ALSO INVOLVED IN TRYING TO HELP US HOW TO FIGURE OUT THE BEST WAY TO DESIGN A SAFE AND EFFECTIVE TRIAL DEDICATED TO THESE PATIENTS. ONE OF THE ADVANTAGES IS THAT IT'S ADMINISTERED AS A DAILY PILL AND SOME PRECLINICAL DATA AND BY THAT I MEAN DATA IN THE LABORATORY WITH THE REAGENTS THAT ARE AVAILABLE SUCH AS KIDNEY CANCER AND SO FORTH, SHOW THAT THIS KIDNEY CANCER CELL LIFE ARE SENSITIVE TO IT MESSAGE THAT WHEN YOU TREAT THEM THE TUMOR WILL START GROWING IN PLASTIC, WHICH IS ENCOURAGING. THE NUMBER ONE QUESTION IS ALWAYS ASKED IS SIDE EFFECTS AND EVERY DRUG HAS ZPEFKTS THIS IS NO EXCEPTION. DIREIA HAS BEEN SEEN IN MORE THAN -- RASH, NAUSEA, HIGH BLOOD PRESSURE THAT WE HAVE HAD NO PROBLEM TREATING IN THE PEDIATRIC POPULATION BUT IT'S SOMETHING DEFINITELY TO CONSIDER. FATIGUE, HEADACHE, AND THEN FROM THERE THERE ARE LIKE A SERIES OF SIDE EFFECTS THAT ARE AT A LOWER FREQUENCY, BUT OF COURSE, CAN BE FULLY DISCOVERED ANY TIME. SO THIS IS WHAT WE ARE DOING NOW. WE ARE GATHERING MORE AND MORE INFORMATION AND TALKING VERY ACTIVELY TO THE PHARMACEUTICAL COMPANY THAT HOLDS THIS DRUG TO TRY TO PUT TOGETHER A PHASE TWO CLINICAL TRIAL OF A DRUG I WAS JUST DISCUSSING IN CHILDREN AND ADULTS WITH WILD TYPE GAST TROINTESTNAL TRAUMA TUMORS. WE ARE JUST STARTING THIS PROCESS AND THERE ARE MANY THINGS THAT ARE GOING TO BE ADJUSTED BUT WE ARE HOPING TO HAVE IT OPEN FAIRLY SOON. AND ONE OF THE BIG THINGS IS HOW ARE WE GOING TO BE ABLE TO MEASURE RESPONSE ADDIATLY -- ADEQUATELY AND ANSWERING THE QUESTIONS THAT WE ARE ASKING AND WHAT FUTURE QUESTIONS WE CAN POSE FOR THE FUTURE? SO UP TO NOW WHAT I CAN SAY IS THAT I AM REALLY HONORED TO BE HERE, REALLY HONORED TO BE PART OF A TEAM THAT HAS LED -- THAT HAS HELPED ME BUILD UP A QUESTION AND HOPEFULLY TOGETHER WE WILL BE ABLE TO FIND ANSWERS THAT CAN BENEFIT THE COMMUNITY. SO WITH THAT, I REALLY WANT TO THANK YOU ALL FOR YOUR ATTENTION AND I HOPE TO SEE YOU ALL TOMORROW IN CLINIC AND I AM FREE TO ANSWER ANY QUESTIONS. [APPLAUSE] >> ANY QUESTIONS? >> THIS IS VERY EXCITING. THIS IS HOW WE ENVISIONED AND WE WANTED TO BASICALLY START AND MOVE IT INTO CLINICAL PROTOCOL AND WHERE THE DOCTOR HAS DONE IS GOING TO HELP NUS THAT ENDEAVOR. SO EVERYONE, LET'S GO EAT AND THEN WE CAN JUST TALK AND GO IN THERE.