>> GOOD AFTERNOON. WELCOME TO TODAY'S GRAND ROUNDS. OUR TWO SPEAKERS WILL BE PRESENTING ON TOPICS RELATED TO ORAL PHARYNGEAL CANCERS. THE FIRST SPEAK, DR. EVA SZABO, CHIEF OF THE LUNG AND UPPERAIRE DIGESTIVE CANCER RESEARCH GROUP OF NCI DIVISION OF CANCER PREVENTION. SHE RECEIVED HER UNDERGRADUATE DEGREE IN MOLECULAR BIOCHEMISTRY FROM -- TRAINED AT NYU MEDICAL CENTER BEFORE COMING TO NIH AS A MEDICAL STAFF FELLOW IN THE NCI CLINICAL ONCOLOGY PROGRAM IN 1989. SHE IS A MEDICAL ONCOLOGIST, BASIC RESEARCH BACKGROUND AND TREATS PATIENTS WITH LUNG, HEAD AND NECK CANCER IN THE NCI THORACIC ONCOLOGY CLINIC. LEADS THE NCI DIVISION OF CANCER PREVENTION PHASE 1 AND 2 CANCER PREVENTION CLINICAL TRIALS PROGRAM AND THE LUNG AND HEAD AND NECK CANCER PREVENTION PROGRAM. HER LEADERSHIP ROLES HAVE INCLUDED HEADING THE LUNG CANCER PREVENTION COMMITTEE FOR THE AMERICAN ASSOCIATION OF CANCER RESEARCH PREVENTION TASK FORCE. CHAIRPERSON FOR THE AMERICAN ASSOCIATION FOR CANCER RESEARCH FROND TEARS AND -- FRONTIERS AND INTERNATIONAL 2010 INTERNATIONAL MEETING AND CURRENT POSITION AS CHAIR OF THE AMERICAN SOCIETY CLINICAL OBCOLOGY CANCER PREVENTION COMMITTEE. HER INTERESTS INCLUDE EFFECTIVE AGENTS FOR LUNG AND HEAD AND NECK CANCER PREVENTION, ASSESSING EFFICACY IN EARLY PHASE CANCER PREVENTION CLINICAL TRIALS AND DEVELOPING NEW CLINICAL TRIAL MODELS. OUR SECOND PRESENTER, J. SILVIO GUTKIND, CHIEF OF THE ORAL AND PHARYNGEAL CANCER BRANCH WITH THE NATIONAL INSTITUTE OF FACIAL AND CRANIAL RESEARCH. RECEIVED HIS Ph.D. IN PHARMACY AND BIOCHEMTRY IN ARGENTINA. TRAINED AS A POSTDOC TROPICAL FELLOW AT THE NATIONAL INSTITUTE MENTAL HEALTH LABORATORY CLINICAL SCIENCE AND LABORATORY OF CELLULAR DEVELOPMENT AND ONCOLOGY. HIS RESEARCH INVESTIGATORS THE MOLECULAR BASIS OF CANCER WITH EMPHASIS ON BASIC MECHANISMS OF SIGNAL TRANDUCTION AND CELL GROWTH CONTROL. AND DISREELINGS IN CARCINOGENESIS AND AIDS MALIGNANCIES, CURRENTLY LEADING A MULTI INSTITUTIONAL EFFORT AIMED AT EXPLORING THE BIOCHEMICAL CONSEQUENCES AND BENEFITS OF TREATING NEWLY DIAGNOSED HEAD AND NECK CANCER PATIENTS WITH M TORE INHIBITORS. >> THANK YOU VERY MUCH. THANK YOU FOR THE TUNE TO GIVE THIS TALK. AND ESPECIALLY WITH MY COLLEAGUE AND FRIEND. SO LET ME BEGIN WITH THE DISCLOSURES. I HAVE NONE. I WILL BE DISCUSSING OFF LABEL INVESTIGATIONAL USE OF LACTOSE. THE LEARNING OBJECTIVES TO DESCRIBE THE RATIONAL FOR CANCER PREVENTION, TO RECOGNIZE THE IMPORTANCE OF RISK BENEFIT ANALYSIS AND DESCRIBE THE ONGOING EFFORTS FOR CANCER PREVENTION. LET ME BEGIN WITH STATISTICS TO LAY THE GROUNDWORK. SO IN THE YEAR 2012, IT'S ESTIMATED THAT THERE WILL BE OVER 50,000 NEW CASES OF HEAD AND NECK CANCER. NOT JUST ORAL. IN ABOUT A QUARTER TO FIFTH OF THOSE PEOPLE WILL ACTUALLY DIE FROM THEIR CANCER THIS YEAR. THE FIVE YEAR SURVIVAL OVERALL IS 63%. IT'S HIGHER IN EARLY STAGES. DEFINITELY ARE SOME RACIAL DISPARITIES AND SOCIOECONOMIC DISPARITIES. HOWEVER, 2/3 PRESENT WITH REGIONALLY ADVANCED OR METASTATIC DISEASE. IT'S CLEARLY NOT CURABLE. ALTHOUGH THERE IS DECREASING INCIDENTS AND DEATH RATES OVER THE YEARS THIS IS ASSOCIATED WITH AN INCREASE IN HUMAN PAPILLOMA VIRUS ASSOCIATED ORO PHARYNGEAL CANCER AND DECREASE IN TOBACCO RELATED ORAL CANCERS. ANYBODY THAT HAS EVER SEEN A PATIENT WHO HAS HAD SURGERY FOR THIS, EVEN IF CURED MORBIDITY IS TREMENDOUS AND MORTALITY IS A REAL ISSUE. THAT'S WHERE I'VE GOTTEN INTO CANCER PREVENTION. THE RATIONALE IS THE FACT THAT METASTATIC CANCER IS NOT CURABLE, RARELY, AND ESPECIALLY FOR EPITHELIAL CANCERS. AS AN EXAMPLE, THE PROGRESS THAT WE'VE MADE IN LUNG CANCER, WHICH IS WHERE I SPEND THE BULK OF MY DAY WORK IS ACTUALLY NOT AS GREAT AS WE WOULD LIKE. THE FIVE YEAR SURVIVAL WAS 5%, 60 YEARS AGO. IT'S NOW A WHOOPING 15%. WE HAVE A LONG WAY TO GO. AND ALTHOUGH, AGAIN, ORO PHARYNGEAL CANCER AND ORAL CANCER, THE SURVIVAL HAS IMPROVED BUT IT'S NOT A HOME RUN BY ANY STRETCH. WE ALSO NOW KNOW CANCER IS PREVENTABLE. WE HAVE CLINICAL TRIALS, NOT JUST ANIMAL MODELS BUT CLINICAL TRIALS IN BREAST CANCER AS WELL AS OTHERS THAT SHOW THAT YOU CAN REDUCE THE INCIDENCE OF NEW BREAST CANCERS IN PEOPLE THAT ARE AT RISK. AND WE ALSO KNOW FROM THE BIOLOGY THAT THERE IS ACTUALLY A LONG PRECLINICAL PHASE FOR MANY EPITHELIAL CANCERS, ORAL CANCERS. INCREASING HISTOLOGIC AND MOLECULAR ABNORMALITIES AND WE CAN IDENTIFY SPECIFIC POPULATIONS AND TARGET FOR INTERVENTIONS. SO HOW DO WE FIND NEW AGENTS? AND POTENTIAL STRATEGIES? IF YOU KNOW THE BIOLOGY, IF YOU KNOW THE MECHANISM, THAT'S THE FIRST STEP. WE HAVE THAT SITUATION CERVICAL CANCER. IT'S AN INFECTION FOR THE DEVELOPMENT AND THE VACCINE ACTUALLY DECREASES THE INCIDENCE OF PRECURSOR LESIONS, LEADING TO A DECREASE IN CERVICAL CANCER AND DEATH FROM CERVICAL CANCER. FOR MOST OTHER TUMORS WE DO NOT KNOW THIS. ALTHOUGH WE KNOW TOBACCO IS REALLY IMPORTANT, EXPOSURE IN THE PATHOGENESIS OF ORAL CANCER, NOT EVERYBODY WHO SMOKES GETS CANCER. MOST PEOPLE DON'T. AND SO A LOT MORE IS NEEDED -- A LOT MORE KNOWLEDGE IS NEEDED. WE TURN TO PRECLINICAL MODELS. IN OUR TALKS YOU WILL SEE EXAMPLES OF THIS. AGAIN, IN SOME CASES THEY VARY -- THEY TRACK VERY NICELY WITH CLINICAL DATA. IN OTHER CASES, NOT QUITE AS WELL. WE TURN TO OBSERVATIONAL EPIDEMIOLOGY. WE'VE PICKED UP SIGNALS, FOR INSTANCE, ASPIRIN, NON STEROIDAL ANTIINFLAMMATORIES. WE LOOK AT SECONDARY ENDPOINTS. SO I WILL GO TO SOME OF THESE TO SHOW YOU OUR RATIONALE FOR HOW WE HAVE SETTLED ON STUDYING THIS. ONE OTHER POINT TO MAKE AS BACK GROUND, WHEN YOU TALK ABOUT PREVENTION, THIS IS A VERY DIFFERENT SITUATION FROM TREATMENT OF INVASIVE CANCER. AND ALTHOUGH RISK AND BENEFIT ARE THE BUZZ WORDS FOR ANY MEDICAL INTERVENTION, THE BALANCE IS QUITE DIFFERENT IN THE SETTING OF PREVENTION. EFFICACY IS OBVIOUSLY CRITICAL, IF YOU CAN PREVENT CANCER, YOU NEED TO KNOW THIS AND NEED TO HAVE GOOD EVIDENCE THAT THIS WILL HAPPEN. BUT THE RISKS BECOME MUCH MORE IMPORTANT. SO YOU NEED TO LOOK AT THE ADVERSE SIDE EFFECTS WHICH COULD INCREASE MORTALITY. IN OTHER WORDS, TIP THE SCALE. THOSE ARE OFTEN RARE EVENTS. AND YOU LOOK TO A TOLERABILITY. IF PEOPLE GET LOW GRADE DIARRHEA. THEY'RE NOT GOING TO TAKE THEIR DRUGS. EVEN THOUGH IT'S NOT LIFE THREATENING, IT WILL PREVENT COMPLIANCE AND THIS WILL NOT BE A GOOD STRATEGY. SO THESE ARE ALL THE THINGS THAT YOU NEED TO THINK ABOUT AS YOU CONTEMPLATE PREVENTIVE INTERVENTION. LET ME TURN TO WHAT WE'RE DOING, HOW WE GOT THERE. THESE ARE DATA THAT HAVE BEEN RECENTLY PUBLISHED LOOKING AT SEQUENCING OF HEAD AND NECK CANCERS. AND ONE OF THE THINGS THAT CAME OUT, WHICH IS QUITE INTERESTING, ABOUT A THIRD OF THE CASES HAD MAJOR MUTATIONS IN GENES THAT REGULAR GEMIS DIFFERENTIATION. THIS IS WHERE I CAME TO THE ACTIVATED RECEPTOR GAMMA, WHICH ACTUALLY IS VERY IMPORTANT IN INDUCTION OF DIFFERENTIATION AND REGULATION OF DIFFERENTIATION IN MULTIPLE MODEL SYSTEMS. SO PPR FAMILIARA IS A MEMBER OF THE NUCLEAR HORMONE RECEPTOR FAMILY, PARTICULARLY IMPORTANT. IT HAS A ROLE VERY KEY REGULATOR OF ADPO GENESIS, BUT IT'S THE TARGET OF A WHOLE CLASS OF ANTI-DIABETES DRUGS. THERE ARE -- THERE IS A LOT OF FASCINATING BIOLOGY WHICH I'M NOT GOING TO GO INTO. BECAUSE THERE IS AVAILABLE DRUG AND THIS IS SOMETHING THAT I WILL SHOW YOU, DOES MODULATE DIFFERENTIATION. THIS IS HOW WE GOT TO HEAD AND NECK CANCER PREVENTION. THIS OLD WORK WE DID IN THE LAB LOOKING AT LUNG CANCER, NOT HEAD AND NECK CANCER, SHOWS THAT PPAR-GAMMA IS HIGHLY EXPRESSED IN TUMORS AND TREATMENT OF CELL LINES INVOTETRO IN CELL TISSUE CULTURE MODULATES DIFFERENTIATION STATUS. GENERAL MARKERS ARE INCREASED, INCREASED IN MULTIPLE MODEL SYSTEMS, NOT JUST IN LUNG CANCER. IN PROGENITOR MODELS, CC10, SEVERAL OTHERS, ALL DECREASED IN THE CELL LINES THAT EXPRESS THESE MARKERS. SO THIS WAS A CLUE THAT PERHAPS THIS TARGETING RECEPTOR COULD BE USEFUL FOR MODULATING DIFFERENTIATION IN SOLID TUMOR SYSTEMS. I SAID SIMILAR DATA EXISTS IN OTHER ORGAN TYPES. THERE IS ALSO EPIDEMIOLOGY, LIMITED, BUT IT'S THERE. DEALING WITH DIABETICS. THERE ARE TWO STUDIOS HERE. THEY BOTH -- STUDIES HERE. THEY BOTH CENTER ON A V.A., VETERAN'S ADMINISTRATION DATABASE OF DIABETICS COMPARING THOSE TO TOOK THE DRUGS VERSES THOSE WHO DID NOT. AND WHAT THESE DATA HAVE SHOWN, THERE IS A 33% DECREASE IN LUNG CANCER WHO PEOPLE WHO TOOK THE LIGANDS VERSES THOSE WHO DIDN'T. A VERY SIMILAR LEVEL OF DECREASE IN HEAD AND NECK CANCER AS WELL. THERE ARE ANIMAL MODEL SYSTEMS, CARCINOGENESIS MODEL SYSTEMS. YOU'LL SEE MORE OF THESE USING OTHER DRUGS. THAT ALSO SHOW THAT IF YOU TREAT ANIMALS WITH A CARCINOGEN, GIVES YOU TONGUE CANCERS, THESE WRATH IN THIS CASE, THEN YOU FEED THEM THE LIGANDS, IN THIS CASE, ONE OF THE FIRST MEMBERS OF THE CLASS WHICH IS NO LONGER ON THE MARKET, YOU CAN REDUCE THE INCIDENCE OF TUMORS TEN FOLD AND ALSO REDUCE THE MULTIPLICITY OF TUMORS. THIS IS LUNG CANCER, BUT A SHARED PATHOGENESIS, TOBACCO EXPOSURE. I'M SORRY. FIRST LET ME SAY IN ADDITION, NOT ONLY DO YOU DECREASE THE NUMBER OF TUMORS, YOU ALSO DECREASE THE PRENO PLASTIC FORCEI. YOU SEEM TO BLOCK BEFORE THE DEVELOPMENT OF INVASIVE TUMORS OCCURS. THIS IS A DIFFERENT MODEL SYSTEM. THESE ARE MICE THAT ARE TREATED WITH A DIFFERENT CARCINOGEN, VINE THE CARBA MATE. THIS IS FROM THE COLLEAGUES IN OUR DIVISION. WHERE THEY GAVE VINYL CARBONATE TO NICE THAT WERE WILDTYPE FOR P53 AND ALSO MUTANT. THE REASON TO GO WITH THE MUTANT MICE IS THAT P53 IS COMMONLY DISREGULATED IN LUNG CARCINOGENESIS AND ALSO HEAD AND NECK CARCINOGENESIS. YOU GET LARGER TUMORS QUICKER AND MORE TUMORS. AND WHAT YOU SEE HERE IS THAT TREATMENT OF THESE CARCINOGEN TREATED MICE, WITH PI GRID ZONE, LEADS TO A MASSIVE INHIBITION OF LUNG TUMOR LOAD, NOT JUST IN THE WILDTYPE BUT ALSO THE P53 MUTANT ANIMALS. I BRING THIS UP BECAUSE THIS IS ACTUALLY A SCENARIO THAT P35 ANIMALS ARE QUITE HARD TO USE IN THIS SETTING. AND MOST INTERVENTIONS THAT WORK IN WILDTYPE ACTUALLY DO NOT WORK NEARLY AS WELL IN THE MUTANT MICE. NOW, IN THIS PARTICULAR STUDY, THERE WAS NO EFFECT ON INCIDENTS BECAUSE THE TREATMENT WAS STARTED WELL AFTER CARCINOGEN WHICH WE THINK ACTUALLY REFLECTS THE HUMAN CONDITION. WE'RE OFTEN NOT -- WE'RE PROBABLY NEVER GOING TO BE GIVEN ANY KIND OF INTERVENTIONS WHEN YOU GET YOUR FIRST EXPOSURE TO THE CARCINOGENS. IT'S LIKELY TO BE AFTER YOU HAVE THE ESTABLISHMENT. TRYING TO UNDERSTAND WHAT HAPPENS WHEN YOU TREAT WITH PIGLID AZONE, THERE IS REDUCTION OF APOPTOSIS. THERE IS A DECREASE IN PROLIFERATION, ONLY IN THE WILDTYPE ANIMALS. WHY DO I MENTION THIS? THESE ARE THINGS THAT WE WILL BE LOOKING AT IN OUR HUMAN TRIALS. SO THE MOUSE MODEL GIVES US A INDICATOR OF EFFICACY, BUT ALSO, HOW WE CAN MONITOR EFFECTS. IN THE SAME PAPER THE DOCTOR USED A DIFFERENT CARCINOGEN, WHICH GIVES SQUAMOUS CELL CARCINOMAS. THAT HAS BEEN HARD TO MODEL IN MICE. THIS IS ONE OF THE FEW WAYS OF DOING IT. IT'S QUITE HARD TO QUANTIFY BECAUSE THESE TUMORS GROW ALONG THE BRONCHIAL AIRWAYS AND TRACHEA, SO IT'S TECHNICALLY A LITTLE BIT MORE DIFFICULT THAN JUST COUNTING ADENOMAS IN THE PERIPHERAL LUNG. BUT AGAIN IN THIS CASE, THE SAME DRUG GIVES ABOUT A 35% DECREASE IN SQUAMOUS CELL TUMORS. THIS IS, AGAIN, NOT NUMBERS BUT IT'S A QUANTITATION OF THE VOLUME. AND THE EFFECT SEEMS PRIMARILY TO BE AN INDUCTION OF APOP APOPTOSIS, NOT INILL OF PROLIFERATION. THIS IS THE BACKGROUND AS TO HOW WE MOVE FORWARD. SO AS WE WERE GETTING ALL THESE DATA, HAD SOME ALREADY, WE DECIDED TO START A TRIAL. THIS IS WHAT'S CALLED A PHASE 2A TRIAL. EVERYBODY GETS TREATED. IT WAS A SMALL STUDY, PILOT STUDY, REALLY, WITH PEOPLE AT HIGH RISK FOR ORAL CANCER. WHO ARE THEY. THEY HAVE A LESION, A WHITE PATCH IN THE MOUTH, KNOWN TO HAVE UP TO 10% OR SO INCIDENCES OF DEVELOPMENT INTO CANCER. ORAL CANCER. OVER A FAIRLY LONG PERIOD OF TIME. 8 OR MORE YEARS. SO SUBJECTS WITH ORAL LEUKOPLAQUIA HAD A BIOPSY TAKEN WITH RESIDUAL LESION, TREATED FOR THREE MONTHS WITH THE HIGHEST FDA APPROVED DOSE AND HAD A PORT-AU-PRINCE AGAIN. THERE WERE MEASUREMENTS, PHOTOS PREAND POST TREATMENT. BUT THE PRIMARY ENDPOINT SIZE AND GRADE OF THE LESION, LOOKING AT PROLIFERATION AND APOPTOSIS THAT WE'VE LOOKED AT IN ANIMAL MODELS AS WELL AS DIFFERENTIATION STATUS. FRANK AT THE UNIVERSITY OF MINNESOTA DID THIS TRIAL IN COLLABORATION WITH US. BY CONTRACT. THERE WERE 22 PEOPLE WHO WERE ENTERED. 21 WERE VALUABLE, THEY FINISHED BOTH BIOPSIES BEFORE AND AFTER TREATMENT. THE CLINICAL RESPONSE RATE WAS ACTUALLY QUITE IMPRESSIVE. IT WAS 81%. WITH SOME ACTUAL COMPLETE RESPONSES. SOME -- I'M SORRY. YES. WITH MANY MORE PARTIAL RESPONSES. SOME STABILITY AND NOBODY ACTUALLY HAD A LARGER LESION UPON FINISHING TREATMENT. THE HISTOLOGIC RESPONSES WERE MUCH LESS STRIKING. 14% OF PEOPLE HAD REGRESSION OR LOWER STAGE OF DISPLASIA OR HYPERPLASIA. THE MAJORITY WERE STABLED. SOME PEOPLE ACTUALLY PROGRESSED IN TERMS OF HISTOLOGY. OF COURSE WE HAVE ABANSWER TO WHY WE THINK THIS IS SO. THERE ARE MANY POSSIBLIES, ONE THAT IT DOESN'T EFFECT THE LEVEL OF DISPLASIA, BUT ANOTHER ONE IS THE FACT THAT WHEN YOU GO AND BIOPSY, YOU BIOPSY WHAT'S THERE. AND THESE LESIONS ARE ACTUALLY HETEROGENEOUS. AND ALTHOUGH THE SURGEON WILL GO AND BIOPSY WHAT HE THINKS LOOKS THE WORST, IF YOU'RE GOING TO ACTUALLY CUT THROUGH THE ENTIRE LESION, THERE ARE VARYING GRADES OF ABNORMALITY. SO ONE POSSIBILITY IS THAT BY GOING TO THE RESIDUAL LESION, EITHER IT'S THE AREA THAT DIDN'T RESPOND, THE AREA THAT MAYBE WAS EVEN WORST HISTOLOGY OR IT'S POSSIBLE THIS DOESN'T WORK. THOSE ARE THE DATA THAT WE HAD AND THEY ARE ACTUALLY QUITE PROMISING. ADVERSE EVENTS ON THIS SMALL TRIAL WERE VERY FEW. OF THE 22 PARTICIPANTS WE SAW THREE WHAT WE CALL GRADE TWO EVENTS. MODERATE SEVERITY. WE DID SEE SOME SWELLING, THE LOWER EXTREMITIES, MUSCULAR SKELETAL CHEST PAGE. WITH YOU PERSON WHO HAD ECZEMA HAD EXASPERATION OF THAT. THIS IS JUST AN EXAMPLE OF ONE OF THE CASES. YOU CAN SIGHT THE WHITE LESION, AND WHAT'S LEFT IS NOTHING THAT I CAN SEE ON THE PHOTO. THAT'S OBVIOUSLY ONE OF THE BEST CASES. BUT IN ALL CASES WHERE THERE WAS A RESPONSE, RESPONSE WAS GREATER THAN 50% AND THE AVERAGE WAS REALLY MORE 80% REDUCTION IN SIZE OF THE LESION. SO BASED ON THIS WE'VE GONE ON TO A PHASE 2B STUDY WHICH IS VERY SIMILAR, EXCEPT IT'S NOW A SIX MONTH STUDY, SO LONGER INTERVENTION. IT'S ALSO RANDOMIZED PLACEBO CONTROLLED DOUBLE BLIND. THIS IS THE GOLD STANDARD IN ASSESSING WHAT IS OTHERS WITH A BIOISED APPROACH. IF YOU KNOW EVERYBODY IS GETTING THE DRUG. SO THIS STUDY, WHICH IS, AGAIN, DONE UNDER CONTRACT, FROM DCP TO JAY BIOLOGICAL, FRANK ANDRE, THE CO-PI SAID, A STUDY OF 100 PEOPLE ALL OF WHOM HAVE LEUKOPLAQUIA, BEING DEFINED AS THE WHITE PATCH THAT HAS DYSPLASIA AND THAT CAN BE ANYWHERE IN THE ORAL CAVITY, OR HYPERPLASIA. THAT'S ONLY AT HIGH RISK SITES, SUCH AS THE TONGUE AND THE FLOOR OF MOUTH. OR ALEGITIMATERO PLAQUIA, A RIB PATCH. TENDS TO HAVE -- HAS AN EVEN GREATER PROGNOSIS RATE TO CARCINOMA. MOST PEOPLE HAVE LEUKOPLAQUIA. AND PEOPLE ARE BIOPSIED. SO MODERATE -- THEY'RE RANDOMIZED AND REBIOPSIED AFTER SIX MONTHS. THE PRIMARY ENDPOINT IS LESION REGRESSION OF BOTH CLINICAL AND HISTOLOGIC. THERE ARE MULTIPLE SECONDARY ENDPOINTS ON THE TISSUES. SO THIS STUDY IS ONGOING. THERE ARE 11 SITES INVOLVED. 100 PEOPLE DOESN'T SOUND LIKE A LOT BUT IT'S EXCEEDINGLY DIFFICULT TO ACCRUE ON TO A STUDY LIKE THIS. ONE OF THE THINGS THAT I THINK WE'RE DOING THAT IS FAIRLY INTERESTING IS BECAUSE WE DO HAVE ALL THESE SITES, WE HAVE DEVELOPED A WEB BASED CENTRAL PATHOLOGY REVIEW. ADELE AT M.D. ANDERSON IS THE PRIMARY PATHOLOGIST. THIS IS SOMEWHAT PRAGMATIC APPROACH IN THAT WE HAVE THE PRIMARY READING AT THE LOCAL -- WHEREVER THE LOCAL PATHOLOGIST IS. SLIDES ARE, THEN, SCANNED IN TO A WEB BASED SYSTEM, AT ONE PLACE IN MINNESOTA. A DOCTOR READS THE SLIDES. IF THERE IS CONCURRENCE, THEN HIS REPORT IS CONSIDERED THE FINAL. IF THERE ISN'T, THEN THERE IS A SECONDARY CENTRAL PATHOLOGIST WHO IS ASKED TO REVIEW THE SLIDES AS WELL. WE HAVE A TISSUE REPOSITORY. AND PATHOLOGY IS ONE OF THOSE THINGS THAT PEOPLE LOVE TO BASH. BUT IT'S OBVIOUSLY VERY IMPORTANT. WE MAKE CLINICAL DECISIONS BASED ON PATHOLOGY. SO WE WANTED TO MAKE SURE THAT THIS SYSTEM IS WORKING, SO WE LOOKED AT THE FIRST 17 CASES. THERE ARE MULTIPLE BIOPSIES FROM EACH CASE. WE WERE LOOKING AT NORMAL -- VISUALLY NORMAL EPITHELIUM. AND SO WE REVIEWED THESE CASES TO SEE WHAT'S THE RATE OF REFERRAL TO A SECONDARY PATHOLOGIST? WHAT'S THE CONCURRENCE? WE FOUND ABOUT A QUARTER OF THE CASES INITIALLY WERE REFERRED TO THE SECONDARY PATHOLOGIST. USUALLY THERE IS ONE OUT OF TWO OR MORE SLIDES THAT WAS NOT -- THAT WAS NON CONCURRENT. SO ACTUALLY, TURNED OUT TO BE IF YOU LOOK AT THE NUMBER OF BIOPSIES, 6 OUT OF 40 REQUIRED A SECOND CENTRAL PATHOLOGY REVIEW, OR 15%. AND INTERESTINGLY ENOUGH, THERE WAS MOST LIKELY TO BE ADDITIONAL REVIEW WITH -- MOST LIKELY NEEDED IF THE HISTOLOGY WAS WORSE. IN OTHER WORDS, LOW CARCINOMA, OR MORE THAN MODERATE DYSPLASIA DIAGNOSIS FOR HYPERPLASIA AND MILD DYSPLASIA, WHICH IS WHERE YOU EXPECT TO HAVE LESS CONCURRENCE. THERE WERE NOT AS MANY PROBLEMS. SO THE EARLY CONCLUSION WAS THAT THE SYSTEM IS WORKING. AND WE'RE CONTINUING WITH IT. OBVIOUSLY ONE OF THE THINGS WE'RE GOING TO BE LOOKING AT VERY CAREFULLY IS HOW DOES EVERYBODY LOOK AT THIS PATHOLOGY? BUT WHAT WE LIKE ABOUT THE FACT IS THAT IT'S ONE CENTRAL -- OR TWO CENTRAL PATHOLOGISTS, BUT IT'S A WHOLE NUMBER OF DIFFERENT PATHOLOGISTS IN MANY INSTITUTIONS. IT GIVES YOU A READ ABOUT THE FIELD. I WANT TO MENTION ONE OTHER STUDY THAT WE HAVE ONGOING, WHICH IS NOT AN ORAL CANCER BUT IT'S QUITE COMPLEMENTARY. THIS IS A STUDY USING THE SAME DRUG, A BIOMARKER TRIAL. MAYO IS THE P.I. ON THIS. THREW CONTRACTS. AND THIS IS A STUDY THAT IS LOOKING AT PEOPLE ARE RESECTABLE LUNG CANCER. GOING TOWARD SURGERY. WE'RE DOING BIOPSIES ON THE TUMOR AS WELL AS BRON COSPIES, LOOKING AT NORMAL BIOPSIES. AND GETTING NORMAL BRONCHIAL BRUSHINGS. THEN THEY'RE TREATED FOR A SHORT PERIOD OF TIME, 2-6 WEEKS. THEN AT SURGERY YOU GET A MUCH LARGER CHUNK OF TISSUE AS WELL AS REPEATING ALL THE WRONG OSPY AND NORMAL BRUSHINGS. IN THIS CASE THE PRIMARY ENDPOINT IS TUMOR PROLIFERATION. WE'RE LOOKING AT A WHOLE BUNCH OF OTHER MARKERS. AND THE MARKER THAT -- OR THE ANALYSIS THAT I THINK IS THE MOST COMPLEMENTARY TO THE ORAL LEUKOPLAKIA STUDY IS THE GENE EXPRESSION ANALYSIS THAT'S GOING TO BE DONE ON NORMAL BRONCHIAL BRUSHINGS. WHY DO I BRING THIS UP? IT'S BECAUSE OF DATA FROM BOSTON UNIVERSITY, SPEAKERA'S DATA LOOKING -- SPERRA'S DATA, LOOKING AT THE PATHWAYS DISREGULATED. HIGH FOUND THAT THE PI3 KINASE PATHWAY IS ACTUALLY ACTIVATED IN LUNG CANCERS. AS WELL AS IN THE ENTIRE FIELD IN SMOKERS WHO HAVE PREMALIGNANTCY, WHO HAVE DYSPLASIA. THIS IS GENE EXPRESSION ANALYSIS, LOOKING AT NORMAL BRONCHIAL BRUSHINGS. AND LOOKING AT WHAT PATHWAYS ARE ACTIVATED. HEALTHY SMOKERS, YOU SEE ONE PATTERN, SMOKERS WITH DISPLASIA, YOU SEE PI3 KINASE ACTIVATION. THERE IS A PILOT COMPONENT TO THE STUDY. WE USED A DIFFERENT INTERVENTION. I DIDN'T PUT IN MY CME DISCLOSURE. I WON'T SAY WHAT IT IS. BUT PEOPLE WHO HAD REGRESSION OF DYSPLASIA ALSO HAD REVERSAL OF THE PI3 KINASE ACTIVATION. THIS IS A MECHANISM TO LOOK AT EARLY CHANGES IN THE EPITHELIUM. AND SO THE LUNG CANCER STUDY WILL BE LOOKING, AGAIN, AT THE NORMAL BRONCHIAL EPITHELIUM. I THINK IT WILL GIVE US A LOT OF INFORMATION THAT IS COMPLEMENTARY TO WHAT WE'LL BE FINDING FROM THE ORAL DYSPLASIA STUDY WHERE WE'RE LOOKING AT HISTOLOGIC AND CLINICAL RESPONSES, AND SOME CONCRETE CHEMICAL MARKERS. SO THAT'S WHERE WE ARE WITH THE ONGOING STUDIES. I DO WANT TO ADDRESS THE SAFETY PRO FINAL OF THIS DRUG OF THE THESE ARE STILL WHAT I CONSIDER PILOT EARLY PHASE STUDIES. SO PIBRIT AZONE -- WHEN WE STARTED THIS, NOT ALL OF THIS WAS KNOWN. IS FDA AGENT. IT'S QUITE WELL TOLERATED. WE HAD NO PROBLEMS GIVING PEOPLE THE MAXIMUM DOSE. THERE IS NO HYPOGLYCEMIA. THIS IS INSULIN SENSE TIESER BUT DOES NOT GIVE YOU LOW BLOOD PRESSURE LEVELS. IT IS WELL-KNOWN TO INDUCE FLUID RETENTION, CAN EXACERBATE CONGESTIVE HEART FAILURE. THERE WAS NO INCREASE IN MORTALITY. WHEN YOU TAKE IT OUT TO THE GENERAL COMMUNITY WHERE PEOPLE ARE SICKER AND DON'T MEET THE CRITERIA, THE STRICT ENTRY CRITERIA, THAT COULD BE MUCH WORSE. A FEW YEARS AGO THERE WAS A BIG TO DO ABOUT THE MYOCARDIAL INFARCTION RISKS. HOWEVER, THERE ARE VERY GOOD DATA SHOWING THAT THERE IS NO INCREASED RISK OF M.I. WITH IT. THE STUDY ADDRESSING THAT IN HIGH RISK DIABETICS SHOW THERE WAS A DECREASED RISK OF CHEST PAIN, ET CETERA. NEVERTHELESS, THERE ARE NEGATIVE. BONE FRACTURES. INCREASED WITH LONG TERM USE. MORE SO IN MEN THAN WOMEN. LITTLE BIT ODD. MORE RECENTLY, AN ASSOCIATION WITH BLADDER CANCER HAS BEEN SHOWN AFTER MORE THAN TWO YEARS OF USE, HIGH DOSES. THIS ALL CAME AFTER. WE -- LONG AFTER WE STARTED OUR STUDY. BUT THE OTHER BENEFIT IS THE DECREASED PROGNOSIS TO AVERT DIABETES IN PERSON WITH METABOLIC SYNDROME. NO DRUG IS PERFECT. ARE WE GOING TO GIVE THIS FOR 20 YEARS TO PEOPLE FOR THE PREVENTION OF CANCER? I DON'T THINK. BUT THE PILOT STUDIES ARE HELPING US IDENTIFY THE MECHANISMS, AND HELPING US TO GO TO HOPEFULLY BETTER SECOND GENERATION AGENTS AND LET US LEARN MORE ABOUT THE DISEASE. SO WITH THAT, I JUST WANT TO THANK YOU COLLABORATORS WHO HAVE BEEN INVOLVED, THE ANIMAL STUDIES. I'M GOING TO END WITH THIS. I'LL BE HAPPY TO ANSWER ANY QUESTIONS. [APPLAUSE] >> THANK YOU EVA FOR YOUR WONDERFUL PRESENTATION. TO PROVIDE BASIS FOR WHAT I WILL BE PRESENTING. THE FIRST ONE, I HAVE NO FINANCIAL ISSUES TO DISCLOSE. I WILL BE DISCUSSING OFF LABEL USE OF RAPAMYCIN. AND METFORMIN. YOU WILL SEE AT THE END, I HOPE BY THE END OF THIS PRESENTATION YOU WILL RECOGNIZE THE IMPORTANCE OF THE IMPORTANCE OF P13K-mTOR IN THE PATH AWAY. WE'RE A SIGNALING LAB. WE WORK IN MOLECULICALS, HOW THEY TALK TO EACH OTHER. HOW THEY FIND EACH OTHER. HOW THEY FORM AN ORGANIZING NETWORK WITH ORGANIZING PATHWAYS. SO -- BUT FOR THIS PARTICULAR PRESENTATION, I WOULD FOCUS ONLY FEW OF THEM. THERE WILL NOT BE ANY TEST, DON'T WORRY. I WILL FOCUS ON VERY FEW OF THEM. PARTICULARLY, I WILL FOCUS ON TWO MOLECULES. LET ME START SAY, THE MAJORITY HAVE REALLY HIGH OVEREXPRESSION OF EGF RECEPTOR. 90% REALLY LARGE EXPRESSION OF EGF RECEPTORS, 20-50%, ONLY 20-50% IS OVERLY ACTIVE. THAT MAY EXPLAIN WHY SOME OF THE INITIAL ATTEMPTS TO USE [INDISCERNIBLE] FOREIGN INHIBITORS OR ANTIBODIES AS A FIRST LINE AGENTS -- IN MANY CASES THEY WORK BUT HAVE NOT REALLY SHOWN EFFICACY THEY WERE INITIALLY EXPECTED. IN ONE OF THE ISSUES, SOME OF THE [INDISCERNIBLE] ARE ACTIVATED DOWN STREAM FROM EGF RECEPTORS ACTIVATED EVEN AT YOU BLOCK. SO WE'LL FOCUS ON AKT FIRST. THIS IS A KINASE. IT'S ACTIVATED UPON RECRUITMENT TO THE MEMBRANE BY A FORCEFUL LIPID, AND THEN INITIALLY IN A POSITION [INDISCERNIBLE], SECONDARY, I WILL NOT EXPLAIN TOO MUCH. YOU NEED ANOTHER, 473. INITIAL STUDIES, MANY YEARS AGO, LIKE MANY OF YOU IN THE AUDIENCE, WE WENT PACK INTO ANALYSIS WHAT WAS REALLY -- NOT REALLY FUNCTIONAL IN TERMS OF SIGNALING IN USING ANTIBODIES. WE RECOGNIZED THE ACTIVATORS. WE FOUND ROUGHLY 90% OF THE HUMAN CONCEPT -- THERE IS OVERACTIVITY OF AKT. HERE, IN BROWN, IT'S POSITIVE. IF YOU DON'T SEE THE STAINING IN NORMAL TISSUES, EVEN IN DISPLASIA, YOU REALLY SEE ACTIVATION. INCLUDING DIFFERENTIATATED AND POORLY DIFFERENTIATED. WHY AKT ACTIVATED? YOU WILL SEE LATER. [INDISCERNIBLE] 5% OF MUTATIONS IN RAT, LEADING TO ACTIVATION OF AKT. 40% IMPLIINDICATION -- IMPLICATION. SO I'M TALKING ABOUT 7-10 COPIES OF PI3 KINASE JEAN. 10%. [INDISCERNIBLE] EXPRESSION OF P SO, THEY'VE REMOVED THE PHOSPHATE AND INACTIVATE AKT. WE HAVE ACVATION OF AKT. SO AKT KIN NASES, A LARGE NUMBER OF TARGETS MANY OF WHICH YOU MAY BE STUDYING. WE MADE A DECISION A FEW YEARS AGO TO FOCUS ON THE mTOR PATHWAY. YOU WILL SEE ACTIVATION OF THESE INITIAL KINASE. EMPTOR. THEY HAVE MANY -- mTOR. ONE I WILL NOT BE DISCUSSING, BLOCKS [INDISCERNIBLE]. THE OTHER ONE IS I76 THAT LEADS TO THE FOS PHOSPHORYLATION. SO 6 IS VERY, VERY USEFUL. THEY'RE ANTIBODIES THAT YOU CAN RECOGNIZE THE PHOSPHORYLATED FORM OF 6 IN THE IMMUNOCHEMISTRY, SO YOU CAN IDENTIFY THEM. IN EARLIER STUDIES IN 2005 WE SHOW, AGAIN, ACTIVATION [INDISCERNIBLE] WAS VERY TYPICAL IN BOTH DISPLASIA AS WELL AS IN ADVANCED [INDISCERNIBLE]. ANOTHER STUDIES, WE STARTED TO PUT THESE PIECES TOGETHER. WHAT IS DRIVING THIS ACTIVATION? AT THIS STAGE AGAIN I WILL TELL YOU IT'S [INDISCERNIBLE] OF EVENTS. BUT WHAT WE STARTED TO DO IS REALLY ASKING HOW PROMINENT THAT IS, ACTIVATION OF THIS PATHWAY. AS PART OF WHAT WE CALL THE INTERNATIONAL [INDISCERNIBLE] INITIATIVE IN COLLABORATION WITH NCI WE COLLECTED AROUND 600 CASES, CANCER CASES FROM ALL OVER THE WORLD. AND PREPARED FROM THE TISSUE BLOCKS, [INDISCERNIBLE] AND THEN ARRANGED THEM IN WHAT IS CALL TISSUE ARRAYS. AND THEN YOU CAN DO IMMUNOSTAINING FOR TISSUES AND GIVE A LOT OF INFORMATION FOR EVERY SINGLE MARKER THAT YOU STUDY. USING THIS WE FOCUS ON THE PATHWAYS ASAND YOU CAN TELL WHEN YOU DO CLUSTER ANALYSIS, THE NORMAL TISSUES WE CLUSTERED ALONE. THEY DON'T HAVE TOO MUCH ACTIVATION. TO DO POSITIVE SUSTAINING. THE VAST [INDISCERNIBLE] AROUND 90% OF THE ACTIVATION OF AKT. [INDISCERNIBLE] THE STATUS OF THE 53, PERHAPS MORE CLINICALLY RELEVANT, SUGGESTING THAT BY THE TIME A PATIENT IS DIAGNOSED, IS VERY LIKELY THE ACTIVATION OCCUR ALREADY DOWNSTREAM FROM EG5 RECEPTOR. WHY IS THIS PATHWAY IMPORTANT? THERE ARE MOLECULES, SMALL MOLECULE INHIBITOR OF THE PATHWAY, ONE THAT I WILL NOTES FOCUS ON IS RAPAMYCIN. THERE ARE MANY NEW DRUGS ON THE MARKET. RAPAMYCIN HAS BEEN APPROVED IN 1999. THERE IS A LOT OF EXPERIENCE WITH THE USE OF RAPAMYCIN IN THE CLINIC. AND THIS DRUG -- SORRY. BLOCKS mTOR IN DIRECT FASHION BY RUNNING A PROTEIN CALLED FKB12 IN -- WHEN YOU USE -- YOU WILL SEE IN A SECOND, [INDISCERNIBLE] RAPAMYCIN VERY IMPORTANTLY BLOCKS INTERACTVATION. YOU CAN DO THIS BY CHEMISTRY AND YOU CAN DO BY WESTERN BLOCK. SO MORE IMPORTANT, IF YOU USE RAPAMYCIN, [INDISCERNIBLE] YOU SEE VERY, VERY QUICKLY TUMOR REGRESSION. LET ME TELL YOU, THIS IS TYPICAL CASE OF -- ONE SECOND. I KNOW YOU CANNOT DRINK, BUT SPEAKERS ARE ALLOWED TO. THIS IS VERY TYPICAL. AS I WAS MENTIONING, THAT YOU CAN HAVE ACTIVITY IN TUMOR XENOGRAPH. THE QUESTION YOU CAN ASK YOURSELF, HOW MANY OF THESE [INDISCERNIBLE] THAT IS WHERE WE THOUGHT -- INSTEAD OF JUMPING INTO THAT, AND OF COURSE WE HAVE NOTHING APPROVED, SO WE DECIDED TO MAKE A REAL CONCERTED EFFORT IN DEVELOPING GENETICALLY AND CHEMICALLY DRIVEN MOTORS OF HEAD AND NECK CANCER TO [INDISCERNIBLE] SPECIFICALLY RAPAMYCIN WERE EFFECTIVE FOR CANCER BUT THE IDEA WAS TO CHALLENGE WHETHER THAT WAS THE CASE. SO WE STARTED OWE WITH SOME OF THEM. SO THE IDEA WAS AT THAT TIME TO FOCUS ON [INDISCERNIBLE] PATHWAY, [INDISCERNIBLE] SO FIRST OF ALL, AS EVA WAS MENTIONING, NOW WITH THE KNOWLEDGE GAIN THE FROM THE JOANMIC LANDSCAPE -- GENOMIC LANDSCAPE, ALL THE MUTATIONS HAVE BEEN IDENTIFIED IN THESE FULL SEQUENCING FROM TWO DIFFERENT LABS. ALL FITTING INTO A [INDISCERNIBLE] 1/8 PAY. SO THE FIRST STUDIES, INITIALLY WE USED P10 TO [INDISCERNIBLE] DRUG IF I. AND THEN -- WE DID THIS IN THE EPITHELIAL LAYERS. K14, THAT IS A TECHNICAL ISSUE. YOU CAN SEE CLEARLY, THE PHENOTYPES OF THIS MICE. MORE IMPORTANT, IT WILL DIE RELATIVELY SOON. WE KEEP THE MICE ON VERY LOW DOSE OF RAPAMYCIN FOR ONE YEAR, TYPICAL GENETIC [INDISCERNIBLE] WE WENT INTO OTHER, ONE THAT'S VERY STRIKING. USING TAMOXIFEN. WE CAN USE OTHER DRUGS THAT LEAD TO ACVATION OF ONE [INDISCERNIBLE], IN SOME CASES [INDISCERNIBLE]. SO THE MICE WITH THE SINGLE ACTIVATED, THE DIE FROM LARGE TUMORS. PROTECTED MICE IN WHICH RATS WAS ACTIVATED, AS WELL AS PROTECTED RATS. WE FOLLOWED THAT UP WITH SEVERAL OTHER STUDIES, SOME IN COLLABORATION WITH OUR INSTITUTE USING P10, MODELS. [INDISCERNIBLE] USING [INDISCERNIBLE]. CONFIRMING SEVERAL GENETICALLY DEFINED [INDISCERNIBLE]. HOWEVER, YOU CAN NOW AGAIN ASK THE QUESTION HOW MANY PATIENTS WILL GO TO THE CLINIC WITH ONE OR TWO SINGLE CHANGES, ONE OR TWO SINGLE JEANS? VERY, VERY FEW. WE DECIDED TO GO -- BACKWARDS, MORE COMPLEX. PROBABLY RESEMBLE MORE OF THE COMPLEXITY OF THE CLINICAL SETTING. SO WE TRIED TO PERSUADE OUR MICE TO SMOKE. IT DID NOT WORK. SO INSTEAD, WE USED A DRUG THAT WAS MENTIONED BY EVA, IT WAS USED PRIOR TO THE STUDIES, USED IN RATS, NOT MICE. [INDISCERNIBLE] EXTREMELY SIMPLE PROCEDURE. THE MAISTRING THE WATER THEY -- THEY DRINK THE WATER, PHYSICALLY ACCUMULATING TO THE TONGUE. THEN WE START DEMONSTRATION, THEN MONITOR TUMOR FORMATION. WHAT'S INTERESTING, MOST OF THE MICE BY THE END OF THE 16 WEEKS EXPOSURE, WILL START DEVELOPING TUMORS, THE TUMORS WILL PROGRESS, THE NUMBER WILL CONTINUE TO GROW. THESE ARE REALLY DIVERSE TUMORS, SQUAMOUS CARCINOMA, AS WELL AS PLASTIC DISPLASIAS. USING THIS SYSTEM WE APPLY RAPAMYCIN. IMPACT WAS JUST REMARKABLE. THE NUMBER OF SQUAMOUS CARCINOMA DECREASED THE TUMOR SIZE, REMARKABLE HOW THEY WERE DECREASE CREASED. THE TYPICAL EXAMPLE HERE, THE TONGUES OF THE MICE WITH RAPAMYCIN. SO THAT IS ONE OF THE IMPACTS OF RAPAMYCIN. IN ANOTHER ISSUE PUBLISHED RECENTLY, WE HAVE SQUAMOUS CARCINOMA TYPICALLY METASTASISED TO THE LYMPH NODES, MOST IMPORTANT DIAGNOSTIC MARKER. WE ASKED IF IT CAN BLOCK METASTASES. WE CHECKED THE TUMOR CELLS INTO THE -- INJECTED THE TUMOR CELLS INTO THE TONGUE. THESE ARE EXTREMELY [INDISCERNIBLE]. YOU CAN SEE THE LYMPH FATIC VESSELS. THEN WE CAN USE IN COLLABORATION OF [INDISCERNIBLE] GROUP, WE CAN USE TWO-FOLD MICROSCOPY, AND SEE HOW THIS BEHAVES WITHIN THE TUMOR. WE CAN SEE THE TUMOR ITSELF, LABELED ACCUMULATING INTO THE LYMPH NODES. USING THIS SYSTEM USING RAPAMYCIN YOU SEE A REMARKABLE DECREASE IN THE NUMBER OF METASTASES. WE CAN QUANTIFY PER MICE. INTO MORE SURVIVOR. UNISSUE THAT WAS MENTIONED, INCREASED NUMBER OF POSITIVE HIDDEN CANCERS, WILL EMBARK INTO OUR TISSUE ARRAY, USING THE P16 -- I KNOW IT'S NOT PERFECT. WE FOLLOW THIS IS A LARGE COLLECTION OF WELL CHARACTERIZED POSITIVE AND NEGATIVE TUMORS. WE CAN SEE THEY RUN 20% OF THE TISSUE STATE WE ANALYZE IN THE WORLD ARE POSITIVE FOR HPV. THIS IS ACROSS THE BOARD, REGARDLESS OF THE COUNTRY. AND THEN YOU SEE CANCER CELLS IN THIS CASE, DRIVEN FROM IPV PBS. THERE IS REAL -- HPV PATIENTS. IN SOME CASES IT WAS MORE REMARKABLE THAT BE HPV NEGATIVE TUMORS. WITH RAPAMYCIN OR OTHER ANALOGS, CAME TO USE FOR HPV PATIENTS. NOW GOING BACK TO EVA'S PRESENTATION. PREVENTION IS MORE IMPORTANCE. IF YOU DON'T HAVE A TUMOR, BETTER THAN TREATING THEM AFTERWARDS. THANK YOU. SO WE DECIDED TO INSPIRE BY THIS POTENTIAL USE OF RAPAMYCIN AND DRUGS FOR PREVENTION. WE OPTIMIZE THIS MODEL. WHAT WE DID WAS TO CHANGE THE TIME OF EXPOSURE TO FOREIGN Q FOR DIFFERENT TIME, AND THEN MONITOR ENOUGH FOR HOW MANY CANCERS THEY HAD. USING THIS PROCEDURE, WE IDENTIFIED A TIME POINT IN WHICH THE MICE DID NOT HAVE ANY SQUAMOUS CARCINOMA, BUT HIGH GRADE DYSPLASIAS. AND THEN AT THE END OF THE OBSERVATION PERIOD, THESE MICE WILL STILL HAVE DYSPLASIAS. ROUGHLY MORE OR MORE OR LESS FOLLOWING 1-HAVE RATIO. IN THIS SYSTEM, THE USE OF RAPAMYCIN IS QUITE DRAMATIC. IT REALLY BLOCKS. BUT AS EVA WAS MENTIONING, IT'S VERY UNLIKELY THAT YOU WILL [INDISCERNIBLE] BEFORE YOU FOUND A PATIENT WITH PREMALIGNANT LESIONS FOR MANY YEARS, RAPAMYCIN. SO WE DECIDED TO GO INTO CAN WE BLOCK mTOR IN AN INDIRECT FASHION. THE USE OF THE DRUG, THIS USE FOR MORE THAN ONE MILLION IN THE U.S., MILLIONS AROUND THE WORLD FOR TYPE II DIABETES. IN AN INDIRECT FASHION WE BLOCK mTOR SUNSHINE ACTING ON THE MITOCHONDRIA WOULD INDUCE DECREASE AND INCREASE. [INDISCERNIBLE]. THAT LEADS TO DECREASE. SO OUR ANNUAL MODEL, OF A HIGH GRADE DISPLASIA, YOU CAN SEE NOW IT ACCUMULATES IN THE TUMOR EVERYWHERE. IN THE -- EVEN DYSPLASIA. IN HIGH GRADE DISPLASIAS WHERE YOU SEE, USUALLY A COMBINATION OF [INDISCERNIBLE]. IN THE BASAL LAWYER OF THE CELLS. -- LAYER OF THE CELLS, OF THE LESION. WHEN USED WHEN FORMING, ALL THESE CELLS [INDISCERNIBLE] LIKELY THE TUMOR [INDISCERNIBLE] ARE GONE. SO IT'S THE MATURITY YOU DON'T SEE FOR [INDISCERNIBLE] SO IT'S VERY EFFECTIVE IN REDUCING THE ACCUMULATION IN THE BASIL CELL LAYER. THIS IS PROPOSED TO BE THE MAJOR IMPACT OF METFORM THING. ONE OF THE REASONS IS IN COLLABORATION WITH ABRAHAM SCHNEIDER. WHAT WE FOUND WAS IN THE BASAL LAYER OF THE NORMAL TISSUES, THIS IS HIGHLY EXPRESSION OF A MODEL CALLED OTC 3, A TRANSPORT. SO THIS CAN BE TRANSPORTED AND HAVE ACTIVITY IN THE TISSUES NOT ONLY BASED ON REDUCING [INDISCERNIBLE]. THE IMPACT INTO TERMS [INDISCERNIBLE] TUMOR WAS SUCH, AGAIN REMARKABLE. THE NUMBER OF TUMORS, THE NUMBER OF SQUAMOUS CARCINOMA WAS ALMOST ABOLISHED. [INDISCERNIBLE] SO ALL OF THIS EFFORT CAME TO US FROM THE BELOVED [INDISCERNIBLE] USING T.O.R. INHIBITORS IN HEAD AND NECK CANCER. HOPEFULLY THIS IS A STORY, BENCH TO BEDSIDE PROJECT HERE AT NIH. A CLINICAL TRIAL WAS APPROVED ONE YEAR AGO, VERY CLOSE COLLABORATION BETWEEN OUR LAB AND NCI, PARTICULARLY INITIALLY [LIST OF NAMES]. PHASE I/2 TREATMENT. WE SCREAMED THE PATIENTS. -- SCREENED THE PATIENTS. PATIENTS RECEIVE RAPAMYCIN ONCE A DAY FOR 21 DAYS, AND THEY BE [INDISCERNIBLE] TAKEN. THE SURGERY OCCURS 1-2 WEEKS BEGINNING ON THE SCHEDULE WHEN THERE IS NO MORE IMPACT OF RAPAMYCIN IN THE BLIND. SO THE CRITERIA FOR THE STANDARD. WE HAVE FOLLOWING A NUMBER OF BOTH THE CLINICAL AND BIOCHEMICAL AND MOLECULAR ENDPOINTS. THIS IS AN ACTIVE TRIAL. I HAVE TO MENTION, SO THE FOUR PATIENTS HAVE BEEN SEEN ALREADY RECEIVED RAPAMYCIN TREATMENT. THREE IN SOUTH CAROLINA, ONE AT THE NIH. SO FAR, AGAIN THIS IS [INDISCERNIBLE]. QUITE, QUITE REMARKABLE. SO THESE ARE OUR FIRST PATIENTS. THE -- THIS IS OUR FIRST PATIENT. CT SCAN AND PET SCAN. THE FIRST PATIENT, THREE WEEKS. THERE WAS NO EVIDENCE OF TUMOR REMAINING. AND NO PATHOLOGICAL EVIDENCE OF ANY CANCER INTO THE TISSUES. THE PATIENT 2 AND 4 HAD A PARTIAL RESPONSE. MORE THAN 50% TUMOR REDUCTION IN 50, MORE THAN 50% REDUCTION IN BOTH CASES. ONE OF THE PATIENTS, WE [INDISCERNIBLE], AGAIN THIS IS PRELIMINE DATA. WE ARE OBTAINING EARLY EVIDENCE AND BY THE TIME BEING, ACCEPTABLE TOXICITY PROFILE. IN CONCLUSION, THERE IS A WE HAD SPREAD ACTIVATION OF KINASE IN HEAD AND NECK CANCER, SOMETHING WE ARE WORKING ON. THIS -- HEAD AND NECK CANCER MAY ARISE FROM EPITHELIAL STEM CELLS THAT HAVE ESCAPED FROM mTOR DEPENDENT. SO WE THINK THAT CELLS MAY FIRST BYPASS THESE mTOR SIB NECESSARIANCE. AND THAT MAY BE ONE OF THE REASONS THAT THE CELLS BECOME MARKED. FROM THAT POINT ON IT MAY BECOME ADDICTED TO AND DEPENDENT ON THE KINASE mTOR FOR SURVIVAL. THIS INFORMATION CAN BE EXPLOIT ED IN USING [INDISCERNIBLE] PREVENTED STRATEGIES IN CRIMINAL OPTIONS FOR HEAD AND NECK CANCER, SPECIFICALLY, THE [INDISCERNIBLE]. MANY NEW ANALOGS THAT HAVE BEEN TESTED. FOR HEAD AND NECK CANCER TREATMENT. THIS IS ALSO POSSIBLE TO EXPLORE WHICH WE ARE GOING TO TRY TO DO SOON. INHIBITION, INDIRECT INHIBITION OF mTOR IN PREMALIGNANT LESIONS FOR PREVENTION IN AVERAGE PATIENTS. BOTH TREATMENT AND PREVENTION CAN BE GOOD CANDIDATES. IF IT'S A SINGLE MESSAGE I WOULD LIKE YOU ALL TO TAKE HOME, THE FIGHT AGAINST CANCER IS NOT IN THE LAB, IT'S NOT IN THE CLINIC. IT'S A REAL TEAM EFFORT. THIS IS REALLY THE GROUP OF PEOPLE I'M JUST PRESENTING IT. THESE ARE THE PEOPLE, MEMBERS OF -- MANY MEMBERS OF OUR LAB. PAST MEMBERS THAT ARE WORKING ON RELATED ISSUES IN THE U.S. AND ALL AROUND THE WORLD. OUR COLLEAGUES, PARTICULARLY FOR THE CLINICAL TRIAL AND EVA SZABO. [LIST OF NAMES] MANY MIGHT BEES OF THE NIH HAVE -- MANY MEMBERS OF THE NIH. [INDISCERNIBLE] TO SUPPORTING OUR ACTIVITIES. THE EXCELLENT COLLABORATIONS WITH MANY MEMBERS OF OUR COMMUNITY, PARTICULARLY IN THE CLINIC, WHO'S DEVOTION TO THE CONCEPT OF PATIENTS ARE -- HAVE REALLY INSPIRED ALL OF OUR WORK. THANK YOU.