>> GOOD AFTERNOON. WE'LL GET STARTED. SO TODAY WE'RE GOING TO HEAR A PRESENTATION ON HEAD AND NECK CANCER. IT'S ROUGHLY THE FIFTH, SIXTH OR SEVENTH MOST COMMON KIND OF CANCER, AND DUE TO THE FACT THAT IT INVARIABLY ARISES INVOLVING THE MOUTH OR THE TONGUE, THE PHARYNX, THE LARYNX. THESE ARE AREAS THAT ARE NOT ACCESSIBLE THROUGH WHAT YOU MIGHT CALL SIMPLE SURGERY. FURTHERMORE, THERE ARE AREAS THAT ARE VERY INTIMATELY INVOLVED WITH IMPORTANT FUNCTIONS. LIKE SPEECH, DENTAL HYGIENE, SWALLOWING. AND DYSFUNCTION IN THESE AREAS CAN BE EQUALLY OR MORE DISTRESSING THAN SY SYMPTOMOLOGY OF THE TUMOR MASS ITSELF. THIS IS REALLY A VERY COMPLEX AREA OF CANCER. AND FOR THAT MATTER, TYPE OF CANCER. SO AT LEAST IN MY DAY, WE WERE TAUGHT THAT THE RISK FACTORS FOR CANCER OF THE MUT MOUTH AND PHARYNX AND SO FORTH WERE SMOKING AND CHEWING TOBACCO. ALCOHOL WAS ALWAYS LISTED. I DON'T KNOW HOW ACCURATE THAT WAS EVEN DEEM LOGICALLY BU EVEN DEEM EPIDE MIOLOGICALLY. THAT'S THE WAY IT STOOD. VERY DIFFICULT TREATMENT. NOT VERY MUCH KNOWN THAT COULD PREVENT. THAT'S GOING TO BE THE SUBJECT OF TODAY'S BRIDGING SCIENCE AND MEDICINE. THE TWO MAJOR THINGS YOU'RE GOING TO HEAR ABOUT IS BASICALLY ONE IS THE ROLE OF INFECTION IN MANY CASES CASES OF NASO PHARYNGEAL CANCERS, THE VIRUS THAT'S PREVENTIBLE BY VACCINATION. WHOLE COMPLICATED STORY AND I'M SURE IT WILL COME UP IN THE DISCUSSIONS. THIS HAS BECOME NOW A MAJOR NEW DIE VENTION ODIMENSION OF THIS DISEASE. AND THE DISCOVERY OF MECHANISMS FUNDAMENTAL MECHANISMS OF TECHNO -- TRAFFICKING HOW THESE TUMORS SPREAD. HOW THEY INTERACT WITH THE VASCULAR SYSTEM. AND THROUGH THE ELUCIDATION OF THOSE PATHWAYS IN THIS CANCER AS WELL AS IN OTHERS, TARGET MOLECULES FOR THERAPY HAVE DEVELOPED. AND SOME OF THEM ARE ONGOING CLINICAL TRIALS. SO OUR TWO SPEAKERS ARE VERY MUCH INVOLVED IN THIS DISEASE, AND IN ITS VARIOUS ASPECTS OF DEVELOPMENT. BARBARA CONLEY IS HER OFFICIAL TITLE IS ASSOCIATE DIRECTOR OF THE CANCER DIAGNOSIS PROGRAM AT THE DIVISION OF CANCER TREATMENT AND DIAGNOSIS AT THE NVI. SO SHE'S A PHYSICIAN, GRADUATED FROM MICHIGAN STATE UNIVERSITY, TRAINED ON COLLEGES AND INTERNISTS AT NIH. THE DIVISION OF HEMATOLOGY AND ONCOLOGY AT MICHIGAN STATE AT THE UNIVERSITY OF MARYLAND. THEN CAME HERE AND HAS BEEN VERY ACTIVE IN THE EXPERIMENTAL THERAPEUTICS ACTIVITIES OF THE NATIONAL CANCER INSTITUTE DEALING WITH THESE TUMORS. AND OUR SECOND SPEAKER IS SILVIO GUTKIND WHO RECEIVED HIS PH.D. IN PHARMACY AND BY US BIOCHEMISTRY AT THE UNIVERSITY OF BUENOS AIRES IN ARGENTINA. CAME HERE AS A POTIO POST DOC TROUBLE -- P OST DOCTORIAL. HE'S IN CRANIAL AND PHARYNGEAL RESEARCH WHEREAS THE CHIEF OF THE ORAL AND PHARYNGEAL BRANCH AND HE'S BEEN INVOLVED WITH THE PATHWAYS AND NEW DRUG DEVELOPMENTS THAT I ALLUDED TO BEFORE. NOW, IN ADDITION, WE'RE VERY FORTUNATE TO HAVE A GENTLEMAN WHO IS THE PATIENT AND WHO HAS BEEN KIND ENOUGH TO COME AND TELL US ABOUT THIS DISEASE AS HE EXPERIENCES IT. NOT AS MEDICAL TEXTBOOK OR E LERELECTOR ABOUT THE DISEASE ITSELF. BARBARA, IF YOU WOULD INTRODUCE THE PATIENT, PLEASE. >> THANK YOU. IT'S A PLEASURE TO BE HERE. I'M ACTUALLY HERE IN PLACE OF DR. CARTER VAN WAES WHICH BRINGS A THIRD INTO THE INTO THIS TRIUMPHANT WHICH IS THE NATIONAL INSTITUTED OF DEAFNESS AND COMMUNICATION DISORDERS. BETWEEN THE THREE WE DEAL WITH THE HEAD AND NECK AT NIH. BUT WE HAVE HERE MR. CANTRELL DIAGNOSED IN 2008. I'M HAPPY TO REPORT HIS DISEASE IS NOT IN EVIDENCE AT THIS TIME. I'M GOING TO LET HIM TELL YOU HOW THIS HAPPENED TO HIM. >> APPARENTLY, CAN YOU FOLKS HEAR ME? OKAY. THIS MICROPHONE IS WORKING. THEY TOLD ME I COULD SIT DOWN SO I'M GOING TO. WELL, I'M 65 YEARS HE OLD. MY NAME IS JENNINGS CANTREL. I'M A LAWYER AND I'M A SUBCONTRACTOR WITH FEMA. SO THAT OUT OF THE WAY, IN EARLY 2008, MY WIFE, I WILL DIGRESS FOR JUST A SECOND AND TELL YOU I'M WEARING THIS SHAMROCK TIE TODAY -- SINCE I DIDN'T GO ANYWHERE ON ST. PATTY'S DAY I DECIDED TO WEAR IT TODAY. THAT'S A WAY OF TELLING YOU THIS GI AND I HAVE BEEN TOGETHER A LONG TIME. IN 2008, SHE TOLD ME THAT MY BREATH HAD CHANGED BUT WE DIDN'T KNOW WHY. MAYBE IF I HAD BEEN MORE UP ON THIS ISSUE, I WOULD HAVE RECOGNIZED IT BUT I DIDN'T. AND SHE TOLD ME THAT MY BREATH HAD CHANGED AND IT WAS ORDINARILY, YOU KNOW, NORMAL BUT HAD BECOME MUSTY. AND ABOUT SIX MONTHS LATER, THAT WOULD BE IN ABOUT JULY OF 2008 I HAD A SOAR THROAT UNLIKE ANY SORE THROAT I HAD HAD AND WE DIDN'T HAVE ANY IDEA WHAT THAT WAS ABOUT. BUT IT WAS A VERY STRANGE SORE THROAT. IT HURT AND DIDN'T GO AWAY. AND IN OCTOBER, I WENT TO WORK IN LINCOLN NEBRASKA WHICH IS MY BUSINESS DOES, IT STEMS ME OUT FOR A FEW MONTHS OR MANY MARIJUANA EXPIED COME BACK. I WAS IN -- IT WAS A TOOTH ABSCESS OR SOMETHING. BUT I WENT TO A LOCAL DOCTOR THAT WAS IN ONE OF THOSE WALK-IN CLINICS. HE GAVE ME AN ANTIBIOTIC AND HE SAID IF THAT LYMPH NODE DOES NOT SUBSIDE WITHIN THE NEXT TEN DAYS, YOU NEED TO SEE A HEAD AND NECK DOCTOR. INSTEAD OF GOING TO A HEAD AND NECK DOCTOR IN TEN DAYS I WENT TO THE DENTAL CLINIC AT THE UNIVERSITY OF NEBRASKA IN LINCOLN AND THEY TOOK A LOOK AT ME AND SHUTTLED ME AROUND TO A COUPLE OF SPECIALISTS THAT MORNING. AND THEY SAID WE DON'T KNOW WHAT THIS IS I HAVE A FEELING THEY PROBABLY HAD SUSCISIONS WHAT IT MIGHT BE. BUT YOU NEED TO SEE A HEAD AND NECK DOCTOR IMMEDIATELY. SO I WENT TO SEE ONE IMMEDIATELY AND THE NEXT DAY I WAS IN THE OFFICE OF THE HEAD AND NECK DOCTOR IN LINCOLN. HE TOOK A LOOK AT ME AND HE SAID YOU NEED TO HAVE A CAT SCAN IMMEDIATELY AND I ARRANGED THAT AFTERNOON TO HAVE A CAT SCAN. THE NEXT DAY I HAD THE CAT SCAN. HE CALLED ME ON THE PHONE AND SAID YOU NEED TO COME IN AND SEE ME IMMEDIATELY. WHEN I WENT IN HE SAID YOU HAVE EITHER STAGE TWO OR STAGE THREE IN MASS ON THE BASE OF YOUR TONGUE. AND I SAID WHAT DOES THAT MEAN AND HE EXPLAINED IT WAS PROBABLY SCWAISQUAMOUS CELL CANCER. SO WITHOUT GOING THROUGH ALL THE EMOTIONAL HOOPS THAT I WENT THROUGH THE NEXT DAY I WAS ON A PLANE BACK HOME. I LIVE IN FAIR BASKET FAIRFAX I VIRGINIA. MY WEIGH HAD MADE ARRANGEMENTS FOR ME TO SEE A HEAD AND NECK DOCTOR IN FAIRFAX, A DR. PATHY PAT LEE. SHE TOOK A LOOK AT ME AND AFTER THE BIOPSY SHE TOLD ME MY WIFE I HAD A STAGE FOUR BASE OF TONGUE SQUAMOUS CELL CANCER. AND SHE MADE A COME OF TELEPHONE CALLS AND I FOUND MYSELF AT N IT H MEETING WITH DR. CARTER VAN WAES. AND HE WAS RUNNING A CLINICAL TRIAL THAT INVOLVED TREATMENT. AND HE ACCEPTED ME INTO THE TRIAL AND THEY BEGAN THE TREATMENT ON OR ABOUT NOVEMBER THE 1ST OF 2008. I RECEIVED RADIATION, I RECEIVED A CHEMO DRUG AND AN AN EXPERIMENTAL BIOLOGIC DRUG. WITHIN THE FIRST WEEK, THEY STARTED THE CHEMOTHERAPY BEFORE THEY BEGAN THE RADIATION, ABOUT A WEEK BEFORE. AND AT THE END OF THAT FIRST WEEK, BEFORE THE RADIATION HAD BECOME, HAD BEGUN, THE LYMPH NODE THAT HAD POPPED OUT HAD GOTTEN SMALL. WHEN I SAID THAT NOBODY BELIEVED ME. INCLUDING THE MEDICAL FOLK HAD TO LOOK VERY CLOSELY AND FINALLY THEY SAID YES, IT DOES LOOK A LITTLE SMALLER. SO THEY BEGAN THE RADIATION AND CONTINUED THE CHEMO AND THE BIOLOGIC DRUG. THAT WENT ON FOR THE BETTER PART OF TWO MONTHS, AND MY LAST DAY OF TREATMENT WAS JANUARY 27, 2009. AND THROUGHOUT ALL THIS TIME OF COURSE I HAD THE RADIATION BURNS ON MY NECK AND I WAS TREATED WITH VARIOUS PALLIATIVE SALVES AND CLOTHS THERAPY SOAKED IN VARIOUS TREATMENT MATERIAL. MY WIFE WOULD PUT IT ON MY NECK AT NIGHT AND I HAD TERRIBLE BURNS IN MY MOUTH AND THROAT SO THAT IT WAS IMPOSSIBLE TO EAT FOOD. THEY DID NOT GIVE ME A FEEDING TUBE. I CONTINUED TO EAT FOOD AND THE FOOD I ATE WAS ESSENTIALLY A MILK PREPARATION. IN ORDER TO GET THAT DOWN, I HAD TO TAKE A LIQUID ANESTHETIC WHICH GAVE ME A WINDOW OF ABOUT TEN MINUTES. WHEN I COULD CHUG THIS MILK SHAKE. BECAUSE IF I DID NOT HIT THAT WINDOW, IMMEDIATELY AFTER TAKING THE ANESTHETIC, THE PAIN WAS JUST TOO MUCH TO BEAR. AND I WAS SUPPOSED TO HAVE FOUR A DAYS BUT IT GOT TO THE POINT I COULDN'T MANAGE ONE OR TWO SOMETIMES. OF COURSE I, IT'S NOT THAT I DIDN'T TELL THE DOCTORS THAT I HAD GOTTEN DOWN TO ONE OR TWO BUT WHENEVER I TOLD THEM THAT THEY WERE VERY UNHAPPY WITH ME. SO I WOULD GET BACK UP TO THREE A DAY, THAT SORT OF THING. SO I CONTINUED ON AFTER THE TREATMENT STOPPED FOR MANY MONTHS WITH THIS MILK SHAKE. AND THEN IN A DYE ENHANCED CT SCAN, THEY DISCOVERED A METASTASIS TO MY LEFT LUNG. IT WAS ONE CANCEROUS NODE IN MY LEFT LUNG, AND ABOUT A MONTH AFTER THEY DISCOVERED IT, THEY DID A SURGERY ON MY LEFT LUNG WHERE THEY WENT IN AND TOOK OUT THIS CANCEROUS NODE. AND THAT WAS IN SEPTEMBER OF 2009. AND I, AFTER THAT, ALL OF THE DYE ENHANCED CT SCANS AND PET SCANS I'VE HAD, AND I'VE HAD THREE PET SCANS AND SEVERAL SETS OF DYE ENHANCED CT SCANS HAVE BEEN NEGATIVE FOR CANCER. AND I'VE, IT WAS NECESSARY, I WENT BACK UP JUST SLIGHTLY BEFORE THEY BEGAN THE TREATMENT, IT WAS NECESSARY FOR THEM TO PULL THREE TEETH BECAUSE THE DOCTORS DECIDED THAT THOSE TEETH DIDN'T LOOK LIKE THEY WERE IN PERFECT CONDITION AND THEY DIDN'T WANT TO TAKE THE CHANCE THAT SOMEHOW THERE WOULD BE A NEGATIVE RESPONSE TO THE RADIATION IF THOSE TEETH WERE LEFT IN. SO THEY WERE PULLED I GUESS TWO OR THREW WEEK THREE WEEKS BEFORE THE RADIATION BEGAN SO THEY COULD HEAL SOMEWHAT. I'VE BEEN TOLD THAT I REALLY CAN'T AFFORD TO HAVE ANY KIND OF DEPARTMENTAL PROBLEDENTAL PROBLEM THAT REQ UIRES TOOTH PULLING BECAUSE OF THE DANGER OF BONE NECROSIS. NOW I HAD A LITTLE BONE NECROSIS AFTER, FOR A FEW MONTHS AFTER THE TREATMENT ENDED. I WAS TREATED WITH A NED SIN CALLED PEN TOXIFY LIEN IN COMBINATION WITH VITAMIN E. IT WAS A 400 MILLIGRAM FAB LET AND I WAS TREATED, I TOOK IT THREE TIMES A DAY, THE COMBINATION OF THE TWO. AND I STILL TAKE PEN TOXIFY LIEN AND VITAMIN E TWICE A DAY NOW. IT'S SUPPOSED TO HELP THE BLOOD VESSELS IN MY LOWER JAW. I'VE HAD SUBSTANTIAL AMOUNT OF DIFFICULTY WITH FIBROSIS OF MY NECK, WHICH GREATLY RESTRICTS MY NECK MOVEMENT. IT'S HARD FOR ME TO WALK UP RIGHT AND HOLD MY HEAD UP BECAUSE OF THE PRESSURE OF CONSTANTLY PUSHING AGAINST THOSE MUSCLES AND IT RESTRICTS MY TED HUSHIN --HEAD TURNING FROM ONE SIDE TO THE OTHER. I'VE TRIED TO GET PACK TO A NORMAL SORT OF LIFE AND, OH, THEY USED, THE RADIATION MACHINE THAT THEY USED ON ME IS CALLED A TOTOMORROWTOMO MACHINE. I ATTRIBUTE THE FACT THAT I LOST COMPLETE USE OF THE, COMPLETE FUNCTION OF THE SALIVA DPLAND DOWGLAND --GLAND DOWN HERE IN MY MOUTH. I HAD SMALL FUNCTIONS OF THE SALIVA GLANDS ON EITHER SIDE AND I ATTRIBUTE THAT TO THE TOMO MACHINE. I'M NOT QUITE SURE WHAT ELSE TO ATTRIBUTE TO THAT, ALTHOUGH I DO BELIEVE I'VE KEPT A FAIR AMOUNT OF MY TASTE BUDS. AND SOME THING HAVE CHANGED IN THE WAY THEY TASTE BUT OTHERS HAVEN'T. I GUESS I'LL STOP THERE BECAUSE I BELIEVE THAT I'M UNDER A TIME CONSTRAINT AND IF ANYONE HAS ANY QUESTIONS, I'LL BE HAPPY TO TRY AND ANSWER THEM. THANK YOU VERY MUCH. I APPRECIATE THAT. >> ARE THERE ANY QUESTIONS? >> [INDISCERNIBLE] >> I CAN'T OPEN MY MOUTH VERY WIDE. THAT'S ABOUT AS FAR AS I CAN OPEN IT. AND I HAVE MORE DIFFICULTY CHEWING CHEWY THINGS LIKE STEAK. I GRAPH TIGHT MOR GRAVITATE MORE TO SOUP A ND CHALLENGE, THAT SORT OF THING. I STILL WORK AT MEAT A FAIR AMOUNT TO EXERCISE THE MUSCLES. I LEFT OUT THE FACT THAT WHAT FOLKS HAVE TALKED ABOUT CAUSED THIS. I SERVED IN VIETNAM AND WAS EXPOSED TO AGENT ORANGE. I HAVE NEVER SMOKED CIGARETTES. I OCCASIONALLY SMOKED A PIPE OR CIGAR. WHEN I SAY OCCASIONALLY, ABOUT THE MOST I EVER SMOKED A CIGAR WAS MAYBE ONCE A WEEK. AND I DIDN'T BEGIN SMOKING ANYTHING UNTIL I WAS 25 YEARS OLD WHICH WAS AFTER I LEFT VIETNAM. I THINK I TOOK UP PIPE THEN. I THINK THAT'S THE ONLY MAJOR THING I LEFT OUT. >> [INDISCERNIBLE] >> A TREMENDOUS AMOUNT. I WAS FAT AS A HOG WHEN THIS STARTED. I WEIGHED PROBABLY IN THE NEIGHBORHOOD OF 320 POUNDS. AND WHEN THE, MY WIFE THE THEY OWE THEORIZ ES THAT THIS WAS AN ACT OF GOD THAT I WOULD NEVER LOSE THE WEIGHT. TODAY I'M 248 MOUNDS AND I HAVE A SERIOUS INTENTION GETTING DOWN TO 220. WHICH IS ABOUT WHAT I WEIGHED WHEN I GOT MARRIED. SO I CAN TELL YOU THAT MAYBE THE REASON THEY DIDN'T PUT ME ON A FEEDING TUBE WAS THEY THOUGHT THAT I WOULD BE ABLE TO COPE WITH IT AND I DID. >> [INDISCERNIBLE] >> WELL THERE ARE TWO PARTS TO THE TONGUE. >> [INDISCERNIBLE] >> WELL, THE LINGUAL TONGUE IS ABOUT THE FRONT TWO THIRDS OF THE TONGUE AND THE BASE OF THE TONGUE IS THE BOTTOM ONE THIRD OF THE TONGUE. AND IT'S PEOPLE THINK OF IT AS THROAT BUT IT'S REALLY THE TONGUE. SO IT'S WAY DOWN HERE. >> [INDISCERNIBLE] >> THE QUESTION IS WHAT YOUR OPTIONS IN THE COMMUNITY FOR TREATMENT AND IF YOU UNDERSTOOD THE DIFFERENCE BETWEEN THAT AND THE EXPERIMENTAL [INDISCERNIBLE] >> I DID. I KNEW IT WOULD BE, THAT THERE WAS A PART OF IT THAT WOULD BE EXPERIMENTAL. I KNEW THAT RADIATION WAS STANDARD FOR EITHER SITUATION. THE EXPERIMENTAL PART WAS THE BIOLOGIC DRUG. AND MY ASSUMPTION WAS THAT MEDICINE AT N IT H WAS GOING TO BE AT GOOD AS ANYTHING I COULD FIND OUT THAT INCLUDED MD ANDERSON OR SLOAN-KETTERING OR MAYO. I KNEW A LITTLE BIT ABOUT [INDISCERNIBLE] AND I WAS NOT ANXIOUS TO HAVE THAT IF THERE WAS A WAY AROUND IT. SO, THAT'S THE DECISION I MADE. >> DURING THE COURSE OF YOUR TREATMENT, DID YOU HAVE TO HAVE A TRACHEOTOMY FOR YOUR AIRWAY? >> NO. >> WAS SURGERY EVER DISCUSSED WITH YOU AS AN ALTERNATIVE? >> WELL, IT WAS MENTIONED THAT THAT WAS THE ALTERNATIVE TO RADIATION AND DRUG TREATMENT. BUT I ALSO KNEW THAT, IF I HAD THE SURGERY, IT WOULD MEAN TREMENDOUS INTERFERENCE WITH MY ABILITY TO SPEAK. NOW, EVEN NOW WHEN I'M VERY TIRED, PEOPLE THAT KNOW ME WELL CAN TELL THAT I SLUR MY WORDS SLIGHTLY. WOULD BE WHETHEI DON'T KNOW WHETHER YOU'VE BEEN ABLE TO NOTICE IT OR NOT BUT I'VE WORKED TO TRY AND MAIAINTAIN CRISP SPEECH. I THINK LARGELY I'VE SUCCEEDED IN THAT BUT I KNOW IF I HAD HAD A SURGERY, THAT THAT WOULD HAVE BEEN, THAT WOULD HAVE BEEN OVER FOR ME. >> ONE FINAL QUESTION. >> CAN YOU DESCRIBE YOUR CHAIN CHAIN -- CHANGE OF BREATH BY YOUR WIFE. DID THAT LEAD TO ANY DIAGNOSIS. >> IT DIDN'T BUT HAD I KNOWN MORE ABOUT IT SHOULD HAVE. OF COURSE SHE HAD KNOWN ME FOR 40 YEARS AND WHEN SHE SAID IT CHANGED, I WAS CONFIDENT, I WAS SURE IT HAD CHANGED. I DIDN'T HAVE ANY IDEA WHAT CAUSED IT. AND THEN THAT PROGRESSED INTO THE SORE THROAT WHICH AGAIN WAS A VERY SORE THROAT. DIFFERENT THAN ANY I EVER HAD. BUT AGAIN, WE WOULD THEORIZED IT MIGHT BE A POLLEN ALLERGY OR SOMETHING. WE CAME UP WITH ALL SORTS OF WHAT I THINK OF AS CAULK MAY ME NOTIONS. NONE OF THEM HAD ANYTHING TO DO WITH WHAT WAS ACTUALLY HAPPENING. >> THANK YOU VERY MUCH. >> I WEUNLT A THAN.I WANT TO THANK ALL THE FOLKS AT NIH BECAUSE IF CARTER VAN WAES AND HIS TEAM HAD NOT SAVED MY LIFE, I WOULD BE DEAD TODAY. >> OKAY. CAN YOU HEAR ME? IS THAT GOOD? OKAY. SO I AM SUBSTITUTING FOR DR. VAN WAES HERE, AND BASICALLY WHAT I'LL TRY TO DO IS GIVE YOU THE VIEW FROM THE MEDICAL SIDE, AND THEN A LITTLE BIT OF BACKGROUND AND HOW WE THINK ABOUT HOW WE'RE GOING TO GO FORWARD HERE WITH HEAD AND NECK CANCER TO IMPROVE THIS TREATMENT. SO WHAT WE HAVE IS, WE HAD A 62-YEAR-OLD MAN WHO PRESENTED IN NOVEMBER OF 2008 WITH A SYMPTOMS OF WORSE BREATH AND FIVE MONTHS HISTORY OF INTERMITTENT ESTABLISHING THROAMITTENT STABBINGTHROAT P AIN AND WHAT WE CALL A SUBMANDIBULAR OR A NODE BENEATH THE JAW. OKAY. ON EXAMINATION, HE HAD A RIGHT, HE HAD A MASS, 2.1 BY 3.5 CENTIMETERS INFILTRATING THE RIGHT BASE OF TONGUE DEEP TISSUE ACROSS THE MIDLINE, BASICALLY A BIGGER MASS AND YOU COULD ACTUALLY SEE FROM THE OUTSIDE, THE CT SCAN WOULD DEMONSTRATE THE INFILTRATION BUT IT DOESN'T DEMONSTRATE EVERYTHING. IN ADDITION, HE HAD SOME LYMPH NODES ON BOTH SIDES OF THE NECK BY SCAN. SO THE PHYSICAL EXAMINATION IN THE CT SCAN ARE THE CLINICAL FINDINGS. OKAY. UNLESS YOU TAKE OUT ANY TISSUE THAT'S NOT THE PATHOLOGIC FINDING. THAT'S THE CLINICAL FINDING THAT THEY USE TO STAGE. OTHER IMAGING SHOWED THAT THERE WAS NOTHING IN THE LUNGS OR BONES THAT WOULD INDICATE METASTATIC DISEASE AT THAT TIME. SO HE ACTUALLY WAS UP STAGED. HE WAS STAGED INITIALLY AS A STAGE 4A. NOW HE WAS A STAGE 4B. T4 AND 2C. THAT MEANS THAT HE HAD A LARGE BASE OF TONGUE TEUMPLE AND HE -- LIMB TUMO R AND NOAFSDZ ONODESON BOTH SIDES OF THE NECK. HE HAD SURGERY THE TONGUE WOULD HAVE TO BE REMOVED AND THEN THE LARYNX AND HE WOULD HAVE TO HAVE RADIATION AFTER THAT, TO THE NECK AND THE LOCAL AREA. GIVEN THAT THERE IS MODEMED NO -- DENIED IMPROVEMENT OF SUR-- DEMONSTRATED IMPROVE OF SURVIVAL, WE WOULD RECOMMEND DRUG TREATMENT PLUS RADIATION. HE HAS TO GO THROUGH IT ANYWAY, HE MIGHT AS WELL NOT LOSE YOUR LARYNX AND YOUR TONGUE. OKAY. HE WAS ELIGIBLE FOR THE STUDY. SO THIS STUDY WAS BUILT ON SOME BASIC RESEARCH REGARDING THE SIGNALING PATHWAYS THAT WERE MENTIONED EARLIER. THIS REPRESENTS HERE THE SURFACE OF THE CELL. ONE OF THE BIGGEST THINGS ABOUT HEAD AND NECK CANCER IS THEY OVER EXPRESS THE EVEN DORMAL GROWTH FACTOR RECEPTOR, OKAY. BUT THEY DON'T HAVE MUTATIONS IN THEM LIKE THEY DO IN LUNG CANCER BUT THEY OVER EXPRESS IT. AND THEY ALSO MAKE FACTORS THAT BIND TO THIS RECEPTOR, STIMULATING THE DOWN STREAM SIGNALING PATHWAYS. SO ONE OF THE DOWN STREAM SIGNALING PATHWAYS GOES THROUGH HERE WHICH IS THE NF KAPPA B AND IKK PATHWAY. AND NF KAPPA B IS BASICALLY A SURVIVAL SIGNAL. IT CAN ALSO BE SEEN IN INFECTIONS BUT IT IS A SURVIVAL SIGNAL. IT'S KNOWN TO BE UP REGULATED IN CANCERS THEMSELVES AND IF YOU ALSO TREAT THE CANCERS WITH ANYTHING, LIKE CHEMOTHERAPY OR RADIATION, THIS IS UP REGULATED. AND THEN LEADS TO PROLIFERATION, MORE TUMOR SURVIVAL AND MORE BLOOD VESSEL FORMATION BY THE TUMORS. NOW THERE'S A DRUG THAT'S ACTUALLY APPROVED FOR USE IN SOME SETTINGS CALLED -- AND INHIBITS THE PROTOZOAN. IT'S THE STRUCTURE THAT GETS RID OF PROTEIN THAT THE CELLS DON'T HAVE ANYMORE. IF YOU INHIBIT THE PROTOZOAN THEN YOU HAVE MORE OF THIS INHIBITORY FACTOR AND LESS OF THIS FACTOR HERE. THIS TELLS YOU THAT THE RADIATION CAN INCREASE SOME OF THESE ISSUES HERE. IN CARTER'S LAB THEY HAD LOOKED AT THIS DRUG ALSO CALLED TS341 AND NOTICED THAT THAT IN MICE THAT -- I DON'T KNOW IF I CAN SEE THE TUMOR HERE BUT IT'S ON BOARD AND HERE IF IT'S NOT ON BOARD. SO IT INHIBITS THE DRUG, INHIBITS THE TUMORS IN MICE. THESE ARE SQUAMOUS CONNORS. -- CANNERS. THESE ARE RADIATION CURVES AND YOU CAN SEE THE DRUG CAUSES THE RADIATION TO KILL THE CELLS FASTER. WHEN WE ARE DO A PROTOCOL WE NEED A SCHEMA. THIS IS THE DRUG THAT INHIBITS THE EPIDERMAL GROWTH FACTOR RECEPTORS. THE ANTIBODY IS APPROVED FOR USE IN HEAD AND NECK CANCER, IT'S APPROVED FOR USING HEAD AND NECK CANCER FOR VALIDATE INFORMATION AT THIS TIME. I DON'T KNOW -- RADIATION AT THIS TIME. I DON'T KNOW IF IT WAS 2008 BUT AROUND THAT TIME THEY GOT IT APPROVED. THE EXPERIMENTAL DRUG WAS THE BORTEZOMIB. THAT IS THE STANDARD TREATMENT AND THE NEW DRUG IS DOSE ESCALATED GRADUALLY BECAUSE YOU DON'T KNOW WHAT THE SIDE EFFECTS ARE GOING TO BE. AND THEN HERE, THIS IS INTENSITY MODULATED RADIATION THERAPY. THAT'S A WAY OF TARGETING THE THERAPY MORE CLOSELY TO THE TUMOR. IT'S USED A LOT IN HEAD AND NECK CANCER. TO AVOID AS MUCH TOXICITY AS POSSIBLE TO THE NORMAL STRUCTURES. THIS NORMALLY GOES FIVE DAYS A WEEK FOR SEVEN WEEKS. THE HE CAN ENDS ARE LEFT FOR RECOVERY. SOMETIMES YOU ALSO DOUBLE UP AT THE END OF THIS TREATMENT IS ANOTHER WAY OF DOING THAT. IN THIS PROTOCOL THERE WAS SOME SERUM THAT WAS LOOKED AT FOR INFLAMMATORY FACTORS THAT CARTER WAS STUDYING TUMOR BIOPSIS IF IT WAS OPTIONAL AND SAFE TO DO SO. OF COURSE THE STAGING AND THE IMAGING WHICH IS PRETTY STANDARD JUST TO SEE ON SCAN HOW IS THE TUMOR DOING. NOW NORMALLY, OF COURSE, MR. CANTREL MENTIONED PET SCANNING. WE DON'T DO THAT DURING TREATMENT. YOU HAVE TO WAIT ABOUT THREE MONTHS AFTER TREATMENT BEFORE THE PET SCAN TELLS YOU ANYTHING USEFUL. OKAY. SO AFTER TREATMENT IN THE SPRING OF 09, THE TREATMENT TOOK A VERY LONG TIME. AND THEN RECOVERY TOOK A LONG TIME. BUT THEY DID LOOK DOWN THERE AND THE RIGHT BASE OF TONGUE WAS NORMAL. JUST SHOWING SOME INFLAMMATION CONSISTENT WITH RADIATION INJURY. BUT AGAIN IN SEPTEMBER, IMAGING DID SHOW A LEFT UPPER LOBE NODULE THAT WAS SURGICALLY RESPECTED. THIS WOULD BE STANDARD, SURGICALLY RESECT THAT AND IT SHOWED A POORLY DIFFERENTIATED CANCER THAT WAS POSITIVE FOR P16. NOW, P16 IS A FACTOR THAT'S IF IT'S POSITIVE IT'S GOOD FOR YOU, OKAY. NOW, IT'S ALSO ASSOCIATED WITH HUMAN PAPILLOMA VIRUS. WHICH HAS BEEN SHOWN TO CORRELATE WITH THE INCIDENCE OF ORAL PHARYNX CANCER LATELY. HOWEVER THE STUDY AS A WHOLE DID NOT TURN OUT WELL. IT ACTUALLY HAD TO BE STOPPED EARLY. WHAT WE WOULD NORMALLY EXPECT, NOW THIS WASN'T ONLY ORAL PHARYNX CANCERS BUT IT WOULD NORMALLY EXPECT IS THAT MOST PATIENTS WOULD HAVE A COMPLETE RESPONSE. OKAY. NOW HALF OF THOSE HAVE BEEN RELAPSED AFTERWARDS. BUT IN THE FIRST SEVEN PATIENTS, THEY WERE SEEING A LOT MORE PROGRESSIVE DISEASE THAN THEY WERE COMPLETE RESPONSE, AND SO THEY ACTUALLY STOPPED THIS TRIAL AND WHAT THEY THEN NOTICED THAT ON OTHER, YOU REMEMBER THOSE STUDIES WITH THE BIOPSIS AND ALL THAT KIND OF THING. BASICALLY THOSE TWO DRUGS TOGETHER INCREASE THE EGFR SIGNALING. WE DON'T KNOW WHY YET THAT HAPPENED BUT IT JUST SHOWS YOU THAT EVEN THOUGH YOU HAVE PRECLINICAL DATA, IT DOESN'T ALWAYS TURN OUT LIKE IT'S SUPPOSED TO. SO A LITTLE BIT ABOUT HEAD AND NECK CANCER. WE ARE TALKING MOSTLY TODAY ABOUT SQUAMOUS CANCER OF THE HEAD AND NECK. THERE ARE OTHER TYPES OF CANCER THAT OCCUR IN THE HEAD AND NECK. HEAD AND NECK MEANS UPPER DIGESTIVE TRACT, NOT BRAIN, OKAY. NOT SKIN. JUST THE ARROW DIGESTIVE TRACK. THERE ARE ABOUT 42,000 CASES IN THE U.S. ABOUT 500,000 WORLDWIDE. IT ARISES FROM THE ORAL AND THE PHARYNX AND THE LARYNGEAL WAY MUST MUCOSA, THE LINING OF THE ORAL PHARYNGEAL TRACT. AND OF COURSE IT DOES AFFECT MAJOR THINGS THAT YOU NEED TO LIVE, HOW YOU COMMUNICATE, HOW YOU EAT, HOW YOU INTERACT WITH PEOPLE. AND 50% WILL DIE WITHIN FIVE YEARS. NOW OF COURSE DETAILS ARE IMPORTANT. I DID MENTION THAT THERE ARE OTHER TYPES OF CANCERS IN THE HEAD AND NECK, THE NASAL PHARYNX CANCER THAT'S A LITTLE DEEPER CAN PRESENT WITH LIMB FAD KNOW THEY LIKE OUR PATIENT DID AND PRINTS WITH STUFFINESS IN THE AREA BACK HERE. BUT THERE ARE OTHER HISTOLOGIES THAT MAY OCCUR IN THE HEAD AND NECK AS WELL. AND YOU HAVE TO DIFFERENTIATE WHAT'S UP HERE. WHAT BRINGS IT ON IN TOBACCO AND ALCOHOL ARE THE TRADITIONAL FACTORS. OUR PATIENT IS VERY LIGHT USER OF TOBACCO AND ALCOHOL. BUT OTHER CARCINOGENS CAN ALSO DO THIS. TWO RIGHT RHESUS NOW DEFINE THE HUMAN -- RIGHT RHESUS NOW DEFINE THE HUMAN -- ASSOCIATED THE EVEN STEEP BAR VIRUS, HUMAN PAPILLOMA WHICH IS THE AREA OF THE BASE AND TONGUE. GENETIC FACTORS PARTICULARLY THOSE THAT IMPACT DNA REPAIRS SUCH AS -- ANEMIA, CONGENERALITA. -- IS THIS GOING ON WITH THE AGENT ORANGE, WE'RE NOT QUITE SURE ABOUT THAT. BACTERIAL, PERIODONTAL DISEASE MAY BE, ESPECIALLY ORALLY CAN CAUSE SOME OF THESE PRIMA LEG INFORMANT OR EXPOSURE TO RADIATION AS WELL. DR. SAYS HE DOESN'T KNOW WHAT ALCOHOL HAS TO DO WITH IT AND ACTUALLY THAT'S THE CASE. IF YOU JUST HAVE ALCOHOL YOUR RISK IS NOT ELEVATED THAT MUCH. BUT IF YOU ADD SMOKING AND ALCOHOL YOU HAVE UP TO 40 TIMES THE RISK. NOW YOU HAVE TO BE VERY DEDICATED SMOKER, YOU KNOW. YOU REALLY CAN'T, I MEAN UNLESS YOU HAVE ONE OF THESE UNDERLYING DNA REPAIR PROBLEMS, YOU HAVE TO BE PRETTY DEDICATED SMOKER AND DRINKER. SOME POL POLYMORPHISMS. OCCUPATIONAL EXPOSURES ARE ASSOCIATED WITH HEAD AND NECK CANCERS AND THE VIRAL ISSUES. NOW, THINGS HAVE BEEN CHANGING IN THE LAST FEW YEARS, OKAY. HERE YOU SEE LARYNX CANCER STEADY AS A ROCK FROM 75 TO 2003. OKAY. BUT LOOK WHAT'S HAPPENING WITH ORAL PHARYNX. IT USED TO BE A VERY BAD ACTOR, ONLY 50% SURVIVAL. THIS IS SURVIVAL. BUT THE SURVIVAL HAS BEEN IMPROVING OVER THE LAST 20 YEARS. WE ATTRIBUTE THAT TO THE HPV-RELATED CONNORS WHICH TEND TO OCCUR A LITTLE YOUNGER AND TEND TO BE IN THOSE PATIENTS WHO DON'T HAVE A LOT OF SMOKING AND DRINKING. THE RISK FACTORS SEEM TO BE SEXUAL PRACTICES, ORAL SIX, THAT KIND OF THING. MULTIPLE PARTNERS. BUT A LOT OF PEOPLE HAVE HPB JUST LIVING IN THEM. WHAT TRIGGERS SOMEBODY TO GET A CANCER AND SOMEBODY NOT. I WOULD CAUTION YOU THAT THESE ARE EPIDEMIOLOGICAL STUDIES AND IT DOESN'T MEAN ANYTHING FOR A GIVEN PATIENT ONE WAY OR ANOTHER. FUNCTIONAL EFFECTS, WE HEARD SOME OF THAT. VOICE AND SPEECH FOLLOWING DENTITION, THE HANDLING OF SECRETIONS. TASTE IS A BIG DEAL. IF YOU LOST YOUR TASTE YOU WOULD NOT REALLY ENJOY YOUR LIFE THAT MUCH. HALITOSIS IS BAD BREATH AND OF COURSE THE COSMETIC DEFORMITY. WE HEARD ABOUT THE NECK FI BROATIONZ KIN --FIBROSIS KIND OF THING. HENCE WE NEED MORE TREATMENTS THAT ARE BETTER. SO IF YOU HAVE AN EARLY STAGE TUMOR, YOU CAN BE CURED WITH SURGERY OR RADIATION SINGLE MODALITY, ARE OKAY. FIVE YEARS DISEASE FREE SURVIVAL IS 80 OR 90%MENT HOWEVER WHEN YOU GET TO STAGE THREE, 4A AND 4B WHICH IS LOCAL REGIONALLY ADVANCED, THEN YOUR FIVE YEAR DISEASE-FREE SURVIVAL IS DROPPING EXCEPT IF YOU HAVE ORAL PHARYNX THAT MIGHT BE ASSOCIATED WITH HBV. THOSE PEOPLE TEND TO DO A LOT BETTER. MORE SURVIVAL LIKE THIS HERE. STAGE 4C IS METASTATIC AND RIGHT NOW IF SOMEONE PRESENTS METASTATIC OR BECOMES METASTATIC NOT IN THIS CASE WITH A SINGLE NODULE BUT MORE DISEASE THEY'RE NOT CURABLE. TREATMENT IS PALLIATIVE AT THIS POINT. SURVIVAL HAS BEEN ABOUT SIX MONTHS. HOWEVER, IT'S NOW EXTENDED MORE CLOSER TO A YEAR WITH THE MODERN TREATMENTS. AND SO WHEN SOMEONE HEARS YOU HAVE STAGE 4 CANCER, IF YOU HEARD THAT AND YOU HAD BREAST CANCER YOU WOULD SAY OH MY GOD, YOU KNOW, IT'S METASTATIC, IT'S NOT GOING TO BE CURED. BUT NOT SO WITH HEAD AND NECK CANCER. EVERYTHING UP TO THIS STAGE WE CONSIDER CURABLE. NOW WHAT'S THE DIFFERENCE? PRIOR TO 1980, TREATMENT REALLY DEPENDED ON SURGERY IN THE SIGHT OF THEIR DISEASE. AND THE PATIENT'S CONDITION OF COURSE. AND WHEN THE CO-MORBIDITIES THAT THEY HAD. IT WAS SURGERY FOLLOWED BY RADIATION OR RADIO THERAPY ALONE. USUALLY THE RADIO THERAPY ALONE WOULD BE FOR PEOPLE WHO COULDN'T TOLERATE SURGERY. SO THEY HAD LOW CONTROL RATES IN THE LOCAL REGIONAL AREA. FIVE YEAR SURVIEFLGZ WER SURVIESTLESZ SURV IVALS WERE PRETTY LOW. THERE WERE -- BLOW OUTS -- HOWEVER SOME GROOM IN THE 80'S DECIDED WELL WE'RE NOT DOING GREAT WITH SURGERY, LET'S SEE WHAT WE CAN DO WITHOUT SURGERY. LET'S TRY AND PRESERVE THE VOICE AND SEE WHAT HAPPENS. SO THIS WAS AN EXPERIMENTAL TRIAL. EITHER THEY WOULD GET CHEMOTHERAPY UP FRONT FOLLOWED BY RADIATION OR SURGERY FOLLOWED BY RADIATION. WHAT THEY FOUND WAS THAT SURVIVAL IS EXACTLY THE SAME IN BOTH GROUPS. HOWEVER TWO THIRDS OF THOSE PATIENTS STILL HAD THEIR VOICE. THEREFORE, AND A THIRD OF THEM YOU COULD SALVAGE THEM IF YOU FOLLOWED THEM CLOSELY. SO ORGAN PRESERVATION IS NOW THE ORDER OF THE DAY EXCEPT WITH SARYGZ. WITH -- SURGEONS WHO HAVE A 30EU7 POINT BUT IT'S A SUBTLE ONE. SO THIS IS THE TRIAL THAT FOLLOWED THAT ONE BECAUSE THEY SAID WELL YOU DID NOT DO RADIATION ALONE, MAYBE YOU DON'T NEED THE CHEMOTHERAPY SO THEY DID THE THREE ARMS HERE AND EACH OF THESE TRIALS TAKE ABOUT TEN YEARS TO DO, ARE OKAY. SO WHAT THEY FOUND OUT WAS THAT RADIATION WITH CONCURRENT -- THAT OUR PATIENT WANTED TO AVOID WAS, THIS IS LARYNX NOW, HAD THE BEST LARYNX GEA LARYNGEAL PRESERVATION RAT E AND THE BEST LOCAL REGIONAL CONTROL. BUT TO DATE THE SURVIVAL IS NOT REALLY DIFFERENT. AND HERE YOU SEE NO SIGNIFICANT DIFFERENCE IN SURVIVAL. THIS IS A VERY SMALL STUDY THAT SHOWED SOME IN FAVOR OF SURGERY BUT BASICALLY SURVIVAL'S ABOUT THE SAME. SO NOW THEN THE QUESTION WAS, WELL IF YOU HAVE ORAL PHARYNX, THE BAD ACTORS BEFORE WE HAD HPV AS AN ETIOLOGY, CAN WE DO RADIATION ALONE OR SHOULD WE DO RADIATION WITH CHEMO. SEVERAL TRIALS PROVED THAT ACTUALLY IT'S BETTER IF YOU DO RADIATION WITH CHEMO. SURVIVAL IS QUITE A BIT BETTER IF YOU DO RADIATION WITH CHEMO. AND THESE ARE BASICALLY SOME STUDIES THAT SHOW THIS. SOME OF THEM WERE MORE SIGNIFICANT THAN OTHERS. SOME OF THEM USE RADIATION TWICE A DAY, A LITTLE BIT DIFFERENT IN THE CHEMO, BUT BOTH OF THEM WERE PLATINUM WITH OR WITHOUT ANOTHER AGENT. OKAY. SO THEN THE QUESTION IS, WELL, WHAT IF YOU GIVE CHEMO BIG, TRIPLE CHEMO BEFORE, SO PEOPLE COULD TOLERATE IT AND THEN DO RADIATION WITH A LITTLE CHEMO. SO THEY DID THIS STUDY WITH TRIPLE VERSUS THE DOUBLE. AND RADIATION WITH CHEMO LIGHT, BASICALLY. AND WHAT THEY FOUND BASICALLY WAS THAT IN THE UNRESECTABLE PATIENTS, THESE WERE BOTH RESECRETARIABLE. THE UNRESECTABLE PATIENT THAT HAD THE BETTER SURVIVAL AND POTENTIALLY ALSO THE ORGAN PRESERVATION THAT WAS SECTABLE BUT THEY WANTED TO PRESERVE THE ORGAN. HOWEVER THE IMPORTANT THING IS LOOK AT THE DIFFERENT METASTASIS. THEORETICALLY YOU WANTED TO GIVE CHEMO BECAUSE IT GOES EVERYWHERE AND GETS RID OF YOUR METASTASIS. DID IT? I DON'T KNOW, YOU'RE STILL IN SINGLE DIGITS SO IT MIGHT NOT HAVE WORKED THIS WAS BEFORE WE KNEW ABOUT THE HPB AND BETTER PROGNOSIS. WE TOOK THOSE THAT HAD HBV POSITIVE DISEASE. WHAT YOU CAN SEE IS THAT THE SURVIVAL, THIS IS THE HPB POSITIVE DISEASE HERE. COMPARED TO EVERYBODY ELSE. IT'S PRETTY IMPRESSIVE. THIS IS ONLY ON THE ORAL PHARYNX SIGHT, OKAY. THIS IS REALLY CAUSED EVERYBODY TO JUMP UP AND DOWN, REALLY. IT'S GREAT. SO WHETHER YOUR TREATMENT OPTIONS RIGHT NOW STAGE ONE AND TWO, SURGERY OR RADIATION, DEPENDING ON OTHER FACTORS MOSTLY. STAGE THREE AND 4A CURABLE, CAN USE ANYTHING YOU WANT. VARIOUS PEOPLE HAVE VARIOUS WAYS OF PARSING THIS OUT AS TO HOW THEY'LL TREAT PATIENTS. NOW THE OTHER THING THAT I DIDN'T TALK ABOUT WAS THE -- PLUS RADIATION IS ALSO SHOWN TO HAVE A SURVIVAL ADVANTAGE, JUST THE U.S.-RUSSIA. ANTHE -- [INDISCERNIBLE] 4B YOU MAY STILL WANT TO DO RADIATION AND CHEMO BECAUSE OF THE LOCAL PROBLEM BUT BASICALLY YOU'RE LOOKING AT NON-CURABLE SITUATION. NOT 4B, 4C. 4B, 4B THEY TEND, THIS IS BOTH SIDES OF THE NECK, THEY TEND TO DO MORE INDUCTION CHEMO THAN CONDOMINANCONCOMITANT BUT IT'S NOT A CERTAIN THINKING. SO CONCALL OPPORTUNIT CONCOMITANT WITH CHE MO IS BETTER THAN RADIATION ALONE IN GENERAL. HOWEVER THERE ARE SOME INCREASED TOXICITIES YOU HAVE TO PAY FOR THAT. YOU MAY NEED A BREAK DURING RADIATION BECAUSE PATIENTS CAN'T TOLERATE IT. GENERALLY IF THE PATIENTS TEND TO LOSE MORE THAN 10% OF THEIR BODY WEIGHT, YOU HAVE TO CONTEMPLATE STOPPING AND HOLDING OFF SO THEY DON'T DIE OF STARVATION. LATE RELAPSE REMAINS A PROBLEM. AND WE'RE STILL WORKING ON WHETHER OR NOT WE'RE GOING TO DO UP FRONT CHEMO. THE OTHER THING THAT HAS DEVELOPED IN THE LAST FEW YEARS IS THAT AFTER SURGERY, THERE ARE RISK FACTORS THAT TELL YOU WHETHER OR NOT YOU NEED RADIATION WITH CHEMO OR RADIATION BY ITSELF. AND THAT'S AN IMPERFECT ART AT PRESENT BUT IT DOES LOOK LIKE THAT IF YOU DON'T HAVE A POSITIVE MARGIN OR EXTRA CAP HER SPREAD, NOT A TUMOR SPREAD OUTSIDE YOUR LYMPH NODES, YOU MAY OR I MAY NOT HAVE A SURVIVAL DIFFERENCE. PATIENTS WITH POSITIVE MARGINS OR EXTRACAPSULAR EXTENSION DO HAVE A BENEFIT FROM RADIATION WITH CHEMO, AND THIS IS SUSPLATEN. WHAT'S THE PROGRESS, CONCURRENT RADIATION WITH CHEMO IS STANDARD. AND YOU CAN GET PATIENTS THROUGH IT. YOU CAN USE CHEMOTHERAPY UP FRONT FOLLOWED BY CONCURRENT RADIATION AND CHEMO OR CHEMO ALONE IN SOME PEOPLE. RADIATION THERAPIST A HUGE ADVANCE AS FAR AS PATIENTS COMFORT. HPV RELATED OR OWE PHARYNX TUMORS HOPEFULLY TREATED DIFFERENTLY. SURGEONS HAVE NOT BEEN IDLE. THEY HAVE FIGURED OUT SOME WAYS TO PRESERVE THE ORGAN BUT STILL DO SURGERY. AND THEN SUPPORTIVE CARE, I CANNOT LEAVE THIS OUT BECAUSE IT'S VERY IMPORTANT. SPEECH AND SWALLOWING THERAPY. TEN YEARS AGO PEOPLE WOULD HAVE GOT A FEEDING TUBE RIGHT THEIR THROUGH STOMACH AND THEY WOULD HAVE BEEN FED THROUGH RADIATION AND CHEMO. BUT IT TURNS OUT THAT IF YOU KEEP SWALLOWING, IF YOU PRACTICE AT IT YOU MAY HAVE A BETTER OUTCOME. HEMOPOIETIC FACTORS, GCSF THING THAT BOOST YOUR WHITE COUNT, BIG DIFFERENCE. AND CONTROL OF EMESIS, CONTROL OF VOMITING. CISPLATIN IS ONE OF THE -- DRUGS THAT THERE ARE AND WE CAN GET PATIENTS THROUGH WITH NO VOMITING NOW. ALTHOUGH WITH FATIGUE. A LITTLE BIT OF EXOME SEQUENCING JUST FOR SILVIO'S SAKE. THE LANGUAGE OF THE DAY IS SEQUENCE IT. YOU'LL FIND THE ANSWER AND THEN YOU CAN FIX THE WHOLE THING, JUST INVENT THE DRUG AND THAT'S IT. UNFORTUNATELY, IT'S NOT GOING TO BE THAT SIMPLE. WE FOUND THAT NOT SURPRISINGLY, THERE'S A LOT OF MUTATIONS, YOUR TUMOR. THERE'S FEWER HPV THAN NON-HPV. I THINK YOU HAVE A EXPECTED THAT. P53 MUTATIONS DON'T OCCUR IN THE HPV TUMORS BUT THEY DO OCCUR IN ANYTHING THAT'S NON-HPV. HOWEVER MOST OF THE AFFECTED MUTATIONS ARE TUMOR SUPPRESSERS AND WE DON'T KNOW WHAT TO DO THAT. YOU CAN'T, IT'S NOT THAT DRUGGABLE. SO THIS IS THE GENETIC LANDSCAPE WE KNOW OF RIGHT NOW. SILVIO'S DEFINING SOME MORE FOR US, OKAY. BASICALLY YOU HAVE TP53 MUTATIONS. NOTCH ONE. THAT MAY BE A STEM CELL KIND OF MARKER SO LIKE ALL OTHER TUMORS, STEM CELLS MIGHT BE IMPORTANT. CELL CYCLE MARKERS, SURVIVAL MARKERS, INTERACTION WITH OTHER CELLS AND A LITTLE BIT OF HRAK NOT KRAS. SO THE MUTATED GENES INTERESTINGLY ENOUGH OFTEN THOSE THAT ARE AFFECTED BY ANOTHER PROBLEM LIKE LOSS OF HETERO ZYGOSITY, DELETIONS OR AM PLICATIONS. REMEMBER YOU HAVE TO GET FROM YOUR PARENT, ONE FROM ANOTHER PARENT. IF ONE IS MUTATED YOU SHOULD HAVE A NORMAL GENE LEFT. SOMETHING HAS TO HAPPEN TO THAT NORMAL GENE IN ORDER TO EVIDENCE THE ABNORMAL LANDSCAPE. SO NOTCH ONE AGAIN, INTERESTINGLY IF YOU NOTCH OUT OF MICE THEY TEND TO DEVELOP EPITHELIAL TUMORS. IS IT A DRIVER YET TO BE DETERMINED. GENE SIGNATURES HAVE BEEN LOOKED AT SO THESE ARE, YOU KNOW, BASICALLY WHAT ARE THE GENES TELLING YOU. HOW ARE THEY EXPRESSING THEMSELVES HERE. THERE HAVE BEEN SOME THAT ARE PRAGUE TOSS ANYTHING EPITHELIAL TO MESENCHYME, USUALLY YOU GET UNDIFFERENCE SHAITD WHEN YOU -- DIFFERENTI ATED AND NUCLEAR FACTOR KAPPA B. CARTER'S ON THE RIGHT TRACK HERE. THIS SIGNATURE HAS COME OUT AS A POOR PROGNOSTIC FACTOR. THERE WAS A RECENT REPORT FOR GENE EXPRESSION PROFILING AND THEY ACTUALLY DID A SUPERVISED ANALYSIS WAY OF LOOKING AT THINGS. AND THEY LOOKED AT RESPONDERS VERSUS NON-RESPONDERS, SO THEY FIGURED IF YOU COULD FIND A SIGNATURE THAT DIFFERENTIATED THOSE TWO, THAT MIGHT BE A USEFUL SIGNATURE. AND SORRY FOR THE MISSPELLING. THEY FOUND 12 YANKEES THAT HAD 70% SPECIFICITY SENSITIVITY AND 91 SPECIFICITY. THAT WAS THE DATA SET WHEN IT WAS ARRIVED. THIS IS A NO-NO. DO NOT DO THAT. SO THEY KNEW THAT AND SO THEY ACTUALLY SPLIT THEIR SAMPLES BUT THEN AGAIN I'M NOT SURE THEY WERE DIFFERENT ONES. AND THEY COULDN'T FIND ANYTHING. THEN THEY WENT TO THE LITERATURE WHICH IS PRETTY TYPICAL, FIND IT AND SEE IF IT WORKS. THE 42 GENE SIGNATURE MIGHT BE SHOWING SOMETHING. BUT THIS IS AN AREA THAT'S JUST NOT DOING MUCH HERE. SO WHAT TARGETED THERAPIS THERAPY DO WE HAVE, EPIDERMAL GROWTH FACTOR, BASICALLY -- RADIATION IS APPROVED BY THE FDA FOR TREATMENT FOR TOUR FOR HEAD AND NECK CANCER. IT'S SUPPOSED TO BE A LITTLE LESS TOXIC. CAN'T PROVE IT BY ME. I THINK THE IMRT IS THE BIGGER ISSUE THAN JUST THE SAW TALK MA'AM. THE PROTEASOME INHIBITORS WE WENT THROUGH THAT PHASE ONE TRIALS. I LOOKS LIKE THERE MIGHT BE SOME ANTAGONISM AND SILVIO GUTKIND IS GOING TO TALK ABOUT MTOR INHIBITORS DOWN THE ROAD. WHEN YOU LOOK AT WHAT KIND OF DRUGS ARE IN CLINICAL TRIALS AND WHAT MIGHT BE USEFUL IN HEAD AND NECK CANCER YOU HAVE A REASONABLE LIST. THIS IS GREAT. THIS IS ONE WE HAD TEN YEARS AGO. SO SARK INHIBITORS. VACCINE, AURORA KINASE, GOSSYPOL, HDAC INHIBITORS LOOKING AT EVEN GENETIC MODIFICATION. HSP90 INHIBITORS THAT GETS MANY TARGETS OF ONE DRUG. AND HEDGE HOG INHIBITORS LOOKING MORE AT THE STEM CELL CHARACTERISTICS. AND LAST BUT NOT LEAST, THEY'VE DONE SOMETHING WITH THE HPV-RELATED ISSUES. SO THIS IS A NEW TRIAL THAT JUST STARTED UP, NATIONAL TRIAL, PHASE THREE USING RADIATION WITH CISPLATIC OR RADIATION WITH -- WITH HPV ASSOCIATED ORAL PHARYNX CANCER. THEY WILL BE LOOKING AT MOLECULAR PROFILES AND SERUM BIO MARKERS SO HOPEFULLY IN THE NEXT TEN YEARS WE MAY HAVE AN ANSWER AS TO WHICH ONE SHOULD BE USED. SO THE QUESTION, THOUGH, THAT BOTHERS MANY PEOPLE IS CAN WE BACK OFF TREATMENT WITH HPV POSITIVE CANCERS. AND NOT TREAT PEOPLE -- THE ETHICAL ISSUE IS IF YOU HAVE A TREATMENT WORKING FOR THE PATIENTS, WHY DO YOU WANT TO BACK OFF WITH THE RISKS THAT IT WON'T WORK THAT WELL. SO THOSE ARE THE THINGS TO REALLY BE CAREFUL ABOUT. WE'LL GIVE IT TO SILVIO NOW, UNLESS YOU WANT TO ASK ME ANY QUESTIONS OR YOU WANT TO WAIT UNTIL THE END FOR QUESTIONS? >> [INDISCERNIBLE] >> SO THE QUESTION IS ARE THE EFFECTS OF -- MILDER ON THE SKIN THAN TUSKMA'AM ALONE. WE HAD SOME HINTS IN THE EARLY TRIED THAT IT MIGHT HAVE BEEN BUT THERE ARE SO FEW PATIENTS THAT I'M NOT GOING TO GO OUT ON THAT LIMB. ANY OTHER QUESTIONS? >> OKAY. SO THANK YOU FOR THE KIND INTRODUCTION. I'M SILVIO, OKAY. BARBARA, THANK YOU SO MUCH FOR YOUR PRESENTATION. SO I GUESS THIS IS REFRESHING. WHAT I WILL TRY TO CONNECT -- WHICH ONE DO YOU LOOK INTO, ANY PERSON. LET'S GO TO THIS ONE. PROBABLY IF THERE'S A SINGLE MESSAGE THAT WE WOULD LIKE FOR YOU TO TAKE FROM THIS AND I CERTAINLY AM TAKING MYSELF, THERE'S A HUGE GAP. I MEAN THIS IS NOT OUR WORK, THIS WAS PRESENTED, REPORTED AND YOU HAVE SEEN THIS PROBABLY MANY TIMES. IT WAS IN 2008. THERE'S A BIG GAP OR WHAT'S CALLED A VALLEY OF DEATH BETWEEN WHAT WE DO AND MANY OF YOU, DOING RIGHT NOW IN I DON'T REMEMBER LAB, MAYBE EVEN IN YOUR CLINIC. THE PATIENTS THEY NEED THE MOST ARE FINDINGS. SO THIS IS SOMETHING THAT IT WOULD BE PERHAPS THE MOST IMPORTANT MESSAGE THAT WE ALL CAN AND SHOULD CONTRIBUTE TO CLOSE THIS GAP AND TO WORK IN WHATEVER WE DO, NO MATTER WHICH SUBJECT HOPEFULLY WITH HAVING THE CANCER WE CAN BRING THIS TO THE PATIENTS. SOMETIMES IT DOESN'T WORK BUT AT LEAST WE NEED TO TRY TO DO THAT. SO SOME OF THE INFORMATION THAT BARBARA WAS PROVIDING WHERE CANCER -- IN MY CASE I WOULD CALL IT ORAL CANCER, HEAD AND NECK CANCER, SQUAMOUS CARCINOMA OF THE HEAD AND NECK. WE'LL GOING TO ONE OR THE OTHER AND THE MORE SPECIFIC WOULD BE SQUAMOUS CARCINOMA OF THE HEAD AND NECK OR A SUBSET OF THEM. THERE ARE 500,000 NEW CASES IN THE WORLD AND CUTS A QUARTER MINUTE DEATHS. AWE APPROXIMATELY 45,000 NEW CASES, 9,000 DEATHS. THE RISK FACTORS WE ALREADY WENT THROUGH THIS. BUT AN IMPORTANT ISSUE, MOST OF THE CANCERS OCCUR IN INDIA, IN SOUTHEAST ASIA. THIS IS DUE TO THE USE OF A BEETLENUT USUALLY COMBINED WITH TOBACCO. CERTAINLY HERE TOBACCO AND ALCOHOL MAY ACCOUNT FOR 75% OF ALL OF THE ORAL CANCER. CERTAINLY THERE'S, BARBARA WAS MENTIONING, RIGHT NOW 10 TO 20% OF THE HEAD AND NECK CANCERS ARE DUE TO HPV. THE HPV NUMBER OF CASES KEEP RAISING. SO WE'VE SEEN MANY MORE THAN BEFORE. IMPORTANT ISSUES DISPROPORTIONATE IMPACT AND MINORITY GROUPS IN TERMS OF IMPACT IN PERCENTAGES AND SURVIVAL. ONLY THEY MOVE THE HPV PATIENTS. ONE DAY SOMEONE ASKED ME THEY NEED HPV TO PROTECT YOU FROM DEATH. NO, NO, NO THAT'S NOT THE WAY IT WORKS. THE HPV PATIENTS DO BETTER WHEN YOU DO THE URINE ANALYSIS, IT WAS SKILLED REALLY TO REPRESENT. THOSE THAT DON'T HAVE HPV SURVIVAL. IF YOU REMOVE HPV, HPV DOES NOT PROTECT YOU. 50% SURVIVAL HAS IMPROVED MARGINALLY OVER THE LAST FEW DECADES. CERTAINLY MOST CASES UNFORTUNATELY AT THE ADVANCE STAGES WE REALLY NEED TO WORK IN EARLY DETECTION WHICH IS SOMETHING-- INTO THAT. AND THE MECHANISMS NO MATTER HOW MUCH WE KEEP SEQUENCING ARE NOT FULLY UNDERSTOOD. SO THEY'RE NOT EMERGING OR NOW THERE ARE FEW EMERGING THERAPIES THAT WE CAN USE FOR THIS DISEASE. AS ANY OTHER CANCER TYPE, ORAL CANS FROM AN UNBALANCED SITUATION BETWEEN ONCOGENES TO SUPPRESSOR GENES COMBINED WITH GENOMIC STABILITY. IN THIS CASE, ACTIVATION CAN COME FROM GENETIC CHANGES AND MUTATIONS AND SO FORTH. GENERALLY THE TO BE CARCINOGENS OR -- USE A NUMBER OF GENETIC ALTERATIONS COMBINED WITH GENETIC DISABILITY LEAVES A -- ORAL MUCOSA TO GAIN SOME OF THESE LIKE THE -- IN THE HPV NEGATIVE CASES, IT'S BEEN LOST, AND EPI GENETIC -- THIS WILL EVOLVE EVENTUALLY INTO METASTATIC DISEASE. SO, MANY YEARS AGO, WE WERE GIVEN THE OPPORTUNITY. I WOULD LOVE BY THE WAY WE WORK ON SIGNALING. SO WE ARE THE NALLING LAB. WHAT DOES IT MEAN. WE'RE WORKING, TRYING TO UNDERSTAND HOW MOLECULES TALK TO EACH OTHER, HOW THEY ORGANIZE AND TRANSMITTING SIGNALS FROM THE MEMBRANE TO THE NUCLEUS, HOW THEY INDUCE PROLIFERATION AND HOW WE EVEN TALK TO EACH OTHER. SO THAT WOULD BE BASICALLY WHAT IS THE SIGNALING LAB. WE'RE GIVEN AN OPPORTUNITY WORKING AT THE DENTAL INSTITUTE IN CLOSE ASSOCIATION TOGETHER WITH THE NCI -- TO START DEVELOPING THE -- SO OUR INITIAL WORK WAS DONE IN COLLABORATION WITH OUR COLLEAGUES. WE START WORKING ON THIS WORK -- BASICALLY USING LASER CAPTURE MICRO DISSECTION, ARE WE WERE ABLE TO DO, ARE IF YOU WILL, YOU CAN CALL IT HIGH END TECHNOLOGY THAT WAS DEVELOPED HERE AT THE NH AND ISOLATED TISSUES FROZEN TISSUES COLLECT ONLY THE TUMOR CELLS AND THEN EXTRACT RNIA, DNA. THAT WAS THE EARLY STAGES OF THE GENE DISCOVERY HAVING THE CANCER WE CALLED HAVING THE CANCER GENOME ANATOMY PROJECT IN EARLY 2000. THEN OF COURSE PROFILE IT, GENE ARRAYS WORKING WITH -- ALSO DEVELOPING NANO SENSORS FROM SOME OF THESE BIOMARKERS HOPEFULLY BARBARA, WE CAN TALK AFTERWARDS WITH SOME INTERESTING STUFF. AND YOU HAVE HEARD, SO THE ORAL CANCER ONCOGENOME DONE AFTER DEEP SEQUENCING USING TOTAL FEURMS. WTOTAL -- TUMORS -- SO YOU USE THESE APPROACHES TO GAIN SOME KNOWLEDGE OF WHAT IS DEREGULATED IN THESE TUMOR TYPES. BUT IN THE END OF THE DAY YOU GO INTO BASICS WHICH IN OUR LAB IS WATCHING THE -- SEAS BARBARA WAS MENTIONING, IT'S TYPICAL IN CANCER, THERE'S A LARGE OVER EXPRESSION OF EGF RECEPTOR. THERE ARE FACTORS OF THIS RECEPTOR PLUS THE MEMBRANE, THEY WILL SEND SIGNALS GIVING THE CELLS TO PROLIFERATE. THESE RECEPTORS ARE EXPRESSED 80 TO 90% WERE OVER EXPRESSED. BUT THERE ARE FEW MUTATIONS IN THESE RECEPTORS NOT TYPICAL LIKE FOR EXAMPLE IN LUNG CANCER OR OTHER CANCERS UNDE CANCER THERE ARE MUTATIONS. THE OVER ACTIVITY IS NOT REALLY NOT EVERY TIME IS IT EXACT SO YOU CAN SAY AROUND 20 TO 50%. YEARS AGO IN THE 2002 WHEN EVERYBODY WAS WORKING WITH EACH RECEPTOR, IF YOU WANT TO FIND SOMETHING NEW, THERE ARE DIFFERENT APPROACHES, OKAY. ONE, YOU CAN BE LUCKY. YOU START DIGGING INTO THIS, YOU FIND SOMETHING INTERESTING. ONE POSSIBILITY. YOU CAN BE SMART AND YOU CAN FIND SOMETHING WOULD I THINKING. YOU CAN BE SYSTEMATIC, IT NEVER FAILS. SO AT LEAST, WE WORK IN -- MANY OF THESE SIGNALING MOLECULES WITH A VERY SYSTEMATIC APPROACH TRYING TO UNDERSTAND WHAT WAS DEREGULATED IN THIS CANCER. FOR ANYONE THAT WAS WORKING FAT -- MASTER OF THE UNIVERSE MUCH EVERYBODY INDUCE MAP KINASE. SO HOWEVER HAVING THE CANCER VERY FEW HAD CANCER WHO HAD -- ALTERATION. WHAT WE FOUND IS IN OTHER CALLED AKT WAS ALMOST ALWAYS ACTIVE. THE INITIAL STUDY WAS PUBLISHED IN 2002, BUT WE SHOW USING OLD FASHION APPROACHES, NOT IN THE TISSUES FROM CHEMICALLY INDUCED CANCERS IN THE BACK OF THE MICE. SO YOU USE A CARCINOGEN IN MICE. YOU PAINT THEM WITH TPA, ALMOST EVERY OTHER DAY OR THREE DAYS, THREE TIMES A WEEK AND THEN YOU GET TUMORS. WE SHOW AN ACTIVATION USING KINASE -- SO YOU HAVE TO ISOLATE, USE HOT ATP AND DIFFERENT SUBSTRATES. MAYBE EVEN EARLIER, EVEN AT THE STAGE OF PAPILLOMA WE CAN SEE ACTIVATION. SO BOTTOM LINE, IT'S ACTIVE IN THIS PARTICULAR CASE, IN USING KINASE -- IN MICE THAT DEVELOP TUMORS. THE KINASE IS A FORCEFUL LEADER -- FOR EXAMPLE OR IN THIS CASE PROTEIN. SO IT'S A PROTEIN KINASE. AND IT'S ACTIVATED BY A PHOSPHORYLATION CALLED -- IT ACCUMULATES IN THE MEMBRANE AND THERE'S ANOTHER KINASE CALLED TPK ONE THAT WILL PHOSPHATE IN A POSITION AND THERE'S OUGHT PHOSPHORYLATION. THE BOTTOM LINE IS THE KINASE IS ACTIVATED BY A LIPID IN OTHER KINASE. WHAT WE FOUND IN 2004, NOW USING HUMAN TISSUES THAT 90% OF HUMANS HAVING CONNORS HAVE ACT VALUATIONS IN ATK. HOW YOU DO THAT. SO WELL, SORRY, FIRST, WHY AKT ACTIVATED. WE DON'T KNOW, WE CANNOT ACCOUNT FOR EVERY SINGLE CASE, OKAY. BUT ROUGHLY. SO 20% OR 30% WOULD BE DUE TO HFR. AS BARBARA WAS MENTIONING, 5% OF THE CANCERS HAVE MUTATIONS IN RATS. IT IS BELIEVED IN ASIA, MAYBE MORE ALTHOUGH THAT IS QUESTIONABLE, I WILL KEEP THESE FACTORS -- WILL INDUCE ACTIVATION OF AKT THROUGH BINDING A LIPID KINASE. THE KINASE ITSELF IS MUTATED 10% OF THE CANCERS BUT FURTHERMORE IT'S AMPLIFIED, AMPLIFICATION ONE COPY, SEVEN, 10, 20 COPIES OF KINASE ALPHA -- THIS IS AMPLIFICATION OF KINASE, MUTATIONS ABOUT 10%. THERE ARE ALSO THE PHOSPHATASE WHICH IS A MOLECULE THAT WILL SHUT OFF THIS SYSTEM WHICH IS P10. IT DEPHOSPHORYLATES -- ROUGHLY 5% OF THE HEAD AND NECK CANCERS AND YET DECREASED EXPRESSION PRIMARILY BY PROMOTER HYPER METHYLATION, YOU RUN 30%. SO IF YOU MAKE ALL OF THIS IS NOT A HUNDRED% BUT BETWEEN HF4 AND MUTATIONS AMPLIFICATIONS -- OR DOWN REGULATION, YOU ACTIVATE AKT. SO FURTHERMORE AS BARBARA WAS PRESENTING TO BEAUTIFUL STUDIES, DEFINING THE BLUE PRINT OF THE ORAL CANCER ONCOGENOME, THEY WERE IDENTIFIED TAKING FROM ONE OF THE STUDY STUDIES. THE MUTATIONS FOUND WERE PRIMARILY IN TUMOR SUPPRESSOR GENES. AND YET, IF YOU TAKE ALL OF THE POTENTIAL DRIVER ONCOGENES, MAOATIONS THAMUTATIONS, THEY ARE PATHWAYS. AGAIN PK10 AND -- THE MUTATIONS HAVE BEEN SO FAR IDENTIFIED ONE WAY OR ANOTHER LEAD TO ACTIVATION OVERACTIVITY. SO BASICALLY, THE ANALYSIS OF THE CANCER ONCOGENOME PROVIDES IF YOU WILL LENDS MORE SUPPORT TO THE IDEA THAT AKT PATHWAY IS ONE OF THE DRIVERS MOST LIKELY HAVE CANCER. SO HOW YOU DO, EXPLORE THIS RIGHT NOW YOU DON'T NEED TO DO MORE KINASE. IT'S VERY SIMPLE. THERE ARE ANTIBODIES THAT WILL RECOGNIZE ONLY THE PHOSPHORYLATED ACTIVE -- SO THIS IS FOR EXAMPLE WILL BE THE BEST. BUT IT WORKS BETTER. IF YOU LOOK INTO NORMAL TISSUES WHO WERE INITIALLY DONE IN COLLABORATION OF THE UNIVERSITY OF MARYLAND. YOU DON'T SEE ANY -- THAT WOULD BE THIS BROWN REACTION. YOU CAN SEE DIS PLASIA WHICH ARE NORMAL AND EVEN CANCERS WELL -- AND SO FORTH. YOU CAN SEE VERY NICE ACTIVATION FOR THIS BROWN STAINING SUGGEST -- IN THESE TUMORS. SO SOMETHING VERY IMPORTANT IS REPRODUCIBLE. IT'S NOT ONLY IN OUR LIFE. IT'S QUITE IMPORTANT EVERYWHERE. SO OTHER LABS TO PERFECTLY REPRODUCE THIS BUT THE ACTIVATION WITH ADVERSE OUTCOME. IN THE TONGUE FOR EXAMPLE OR PHARYNGEAL CANCERS. SO THIS IS A VERY REPRODUCIBLE FINDING. IT IS ACTIVATED AND INITIALLY LEADS TO FULL PROGNOSIS. SO CAN WE TARGET THAT. AND THIS IS WHEN WE ARE INTERACTING WITH BARBARA WHEN SHE WAS HERE AT THE NCI THE FIRST TIME. SO AT NCI, THEY DEVELOPED A DRUG CALLED -- PHASE ONES WERE CONDUCTED IN NIH. THESE HAVE MANY KINASES INCLUDING PKT1. IT IS VERY SENSITIVE -- SO WE SEE UCN01 IS IN ANIMAL MODELS, TUMOR MODELS AND WERE ABLE TO PREVENT TUMOR PROGRESSION. HOWEVER IT HAS MANY TOXICITIES, VERY BIG PROBLEMS WITH A DISTRIBUTION, ETCETERA ETCETERA. IT WAS NOT THE BEST CANDIDATE TO DEVELOP THE DRUG FOR HEAD AND NECK. SO THEN WHAT YOU DO WHEN YOU SEE A SATISFACTION PERSON YOU START LOOKING WHAT IS DOWN STREAM. WE LOVE TO HAVE A LOT OF ARROWS. THE MORE ARROWS WE HAVE THE MORE HEART WE LOOK. THIS IS A GENERAL ISSUE SO JUST ONLY WHAT IS SUBSET OF MOLECULES THAT WERE -- A PROTEIN CALLED BAD WHICH IS REALLY BAD AND CONTROLS SURVIVAL -- CONTROLLING 53 AND -- CONTROLS -- FOR EXAMPLE WHICH IS USUALLY ACTIVE OR OVER ACTIVE IN FOR EXAMPLE COLON CANCER. SO THERE ARE MANY EXCELLENT CANDIDATES THAT MADE IMMEDIATE PROTUMOR GENIC ACTIVITIES OF AKT. THERE WAS ONE, IF YOU WILL, WITH THE MOST BORING OF ALL OF THEM CALLED M4. IN THIS ONE CONTROL -- TRANSLATION -- AT THAT TIME. SO DUE TO THIS EXPERIMENT, WE DECIDE TO FOCUS ALMOST EXCLUSIVELY ON MTOR. THE MAIN REASON FOR THAT IS BECAUSE SOME OF MOLECULES, SOME OF THE PROTEINS, THE TRANSLATION IS CONTROLLED BY MTOR INCLUDES CYCLING IS WHICH IS OVER EXPRESSING HEAD AND NECK CANCER -- OVER EXPRESSING -- AND CONTROLS THE RELEASE OF PROJEANNIE FACTORS -- SO WE REALLY DECIDE TO FOCUS ON THESE. THERE ARE OTHER FOCUS ON MTOR HERE. THERE WILL BE NO TEST, DON'T WORRY. OKAY. SO IT REGULATES MTOR BY PHOSPHORYLATING PC1 AND TC2 THAT INHIBITS TC2. TC2 IS A REGULATOR OF ANOTHER PROTEIN SMALL GTP IS CALLED REP AND ACTIVATION OF MTOR. WHEN YOU ACTIVATE KT, IT WORKS LESS, THEREFORE IT BECOMES MORE ACTIVE AND MTOR BECOMES ACTIVATED. MTOR IS AN EXTREMELY BIG KINASE, I WILL MENTION A BIT MORE AT THE END. AND CONTROLS MANY PATHWAYS. SO YOU WILL FIND MANY. THE IMPORTANT ONE FOR THIS, THE PURPOSE OF THIS PRESENTATION WILL BE P76 KINASE AND A PROTEIN 6 AND THEN -- WHICH IS NEGATIVE REGULATOR OF THE INITIATION FACTOR 4E. THE IMPORTANT IF YOU WILL FROM ALL OF THESE IS SIX, IT'S A WONDERFUL ANTIBODY THAT WHEN 6 IS PHOSPHORYLATED YOU CAN RECOGNIZE IT AND AGAIN IN NORMAL TISSUES YOU DON'T SEE ALMOST IF ANY, LOOK VERY IMPORTANT IT'S ONLY THE UPPER LAYERS THAT DO NOT PROLIFERATE. THEY DON'T HAVE ANY FAUST FORE-- COLLECT ROUGHLY 1,000 TUMORS FROM ALL OVER THE WORLD. MANY COUNTRIES, ARGENTINA, JAPAN, MEXICO, SOUTH AFRICA, THAILAND AND MANY LABS IN THE U.S. THEY SEND US SOME OF THE TISSUES AND PATHOLOGY IN THE BLANCH --WHAT THEY DID IS THEY PREPARE SPAGHETTI. SO YOU HAVE THE TISSUE BLOCK AND THEN YOU USE THE PUNCH AND THEN YOU TAKE A PIECE OF THAT TISSUE AND THEN YOU COLLECT THESE CYLINDERS THAT LOOK LIKE A BUNDLE OF SPAGHETTI. YOU CAN SLICE THEM AND THEN IN A SINGLE SLIDE YOU WILL BE ABLE TO HAVE AROUND 300-400 OF THESE TISSUES. THEN YOU CAN INTAI INTERROGATE NOT ONE TISSUE AT THE TIME. THE BIG PICTURE OF WHAT IS GOING ON AND WHAT IS THE RELATIONSHIP AMONG THAT. SO YOU CAN DO FOR EXAMPLE -- THIS WILL BE THE STAINING, THE ISSUES -- FOR EXAMPLE. THIS IS -- INFLAMMATION AND SO ON AND SO FORTH. AND THEN YOU CAN USE AM GRITTALS OR COMPUTER -- ALGORITHMS FOR EXAMPLE AND THEN YOU CAN CLUSTER ANALYSIS AND LET THEM CLUSTER BY THEMSELVES. SO HERE ARE 327 TISSUES. WHEN YOU'VE BEEN ALLOWED INTO THE CLASS BY THEMSELVES, ALL OF THE NORMAL TISSUES CLUSTER TOGETHER. AND THEN YOU CAN SEE ALSO THERE ARE THESE MARKERS, IF YOU WILL OR ACTIVATED EXPRESSION OR MARKER ACTIVATION CLUSTER AGAIN BY THEMSELVES, YOU CAN SEE AKT AND FAUST FORELACE 6 ARE CLOSE TO EACH OTHER. THEY ARE CLOSE TO SOMETHING BUT THEY'RE NOT THAT CLOSE TO -- INFLAMMATION HAVE NOTHING TO DO WITH PTC3 -- SOME TISSUES ARE PCT POSITIVE IN RED AND GREEN IS NEGATIVE. NOT REALLY A LOT OF RELATIONSHIP -- SO NOW IT'S IN PATIENTS THEY HAVE THE -- THEY'RE NOT REALLY LIKELY TO BE WHAT DRIVES THE ACTIVATION -- WHICH CAN EXPLAIN WHY IT'S NOT ALWAYS RIGHT. SO NOT ONLY TO MAKE -- PATHWAY, BECAUSE THERE'S AN EXQUIZ IT INHIBITOR OF MTOR. THE FIRST ONE IS REP MYOSIN AND NOW THERE ARE MANY DERIVATIVES -- COMPANY PRODUCING -- OR RELATED. RARAPAMYCIN WAS INITIALLY IDENTIFIED OR ISOLATED FROM MICRO ORGANISMS IN THE EASTER ISLAND THAT IS IN CHILE. AND THIS IS CALLED THE ISLAND'S CALLED -- WHY RAPAMYCIN IN ITS NAME. SO RAPAMYCIN HAS BEEN APPROVED BY FDA IN 1999 AND HAS BEEN USED ALREADY FOR 13 YEARS. PRIMELY THPRIME PRIMARILY THE PRESSENT WHEN IT'S USED -- NOT ALONE. THAT'S REALLY IMPORTANT. WHEN COMBINED WITH OTHER DRUGS, CAN LEAD THE SUPPRESSANT, HAVE BEEN USED FOR EXAMPLE CHEMO TRANSPLANTATION AND IT'S USED FOR -- I MEAN THIS IS USED IN THE BOTTOM LINE. SO THERE ARE THE RAPAMYCIN, CALLED RAP LOCKS -- BOTH OF WHICH HAS BEEN APPROVED TWO YEARS AGO MORALS FO AWE MORE OR AGO MORE O R LESS FOR -- CARCINOMA. THERE'S TOO MUCH ACTIVITY BY THE WAY OF -- XENO GRAPH I WILL SHOW YOU IN A MINUTE. SO YOU TREATED MICE WITH RAPAMYCIN, THIS IS A DIFFERENT DAY SO IT WILL BE CONTROLLED. RAPAMYCIN, YOU TAKE THE TISSUES. FIRST YOU DO -- CHEMISTRY, BEAUTIFUL DECREASE. THE STAINING CAME FROM RAPAMYCIN, YOU BLOCK -- WE TRUST AND VERIFY THESE FINDINGS OF COURSE, THE OLD FASHION WESTERN BLOCK AND WE CAN SEE -- IT'S GONE AS WELL. SO RAPAMYCIN WORKS HITTING ITS TARGET INTO THE TUMORS. WE SEE THE DECREASE IN PROLIFERATION JUDGED BY DECREASE -- THE DIE -- WITH WE SEEN LESS A ANGIOGENESIS JOY MORE IMPORTANT THIS IS NOT THE BEST. THIS IS THE EXAMPLE OF I WOULD SAY ALMOST ALWAYS HAPPEN. SO THESE TUMORS IN THE MODEL, IF YOU TAKE RAPAMYCIN VERY QUICKLY THE TUMOR DISAPPEARS. DECREASES AND DISAPPEARS. OF THESE ONE OF THE MODELS WITH SEVERAL EFFECTS. THAT WAS 2005. WHAT WE DO WITH THIS INFORMATION. WE ATTEMPT TO HAVE A CLINICAL TRIAL, OKAY. HOW MANY TRIALS HAVE BEEN CONDUCTED WITH DRUGS THAT WORKED EXCELLENT IN MODELS THAT DON'T WORK IN THE CLINIC. TOO MANY. TOO MANY EVEN TO FOLLOW THEM. SO WE DECIDED TO MAKE A REAL -- AND REALLY TRY TO USE MUCH MORE COMPLEX ANIMAL MODELS TO REALLY CHALLENGE RAPAMYCIN OR HOW THE INHIBITORS WORK. SO FIRST WE STARTED TO USE GENETICALLY MODELS THAT PLAWKS THE ACTIVATION. IF YOU REMOVE P10 FOR MOUSE, IN THIS CASE WE USE A P10 FLUX. -- IF YOU REMOVE IT THEN YOU HAVE LESS AND ATP BECOME MORE ACTIVE. WHAT HAPPENS TO THE MICE, THEY QUICKLY THEY DEVELOP THESE TUMORS WHICH RESEMBLES -- THE PATIENTS HAVE THESE DEFICIENCIES, BY THE WAY. WHAT HAPPENED WITH THE RAPAMYCIN THEY LOOK BETTER. THIS IS THE THING MOUSE, THEY LOOK MUCH BETTER. WE ASKED THE MICE HOW THEY FEEL AND THEY COULDN'T TELL US BY THE WAY. SO YOU CANNOT DOCUMENT VERY NICELY HOW REALLY, ONLY BY HISTOLOGY. SO WE DID SOMETHING EVEN WORSE, IF YOU WILL. WE RUN THE MICE AFTER EXCESS OF P10 BUT BEFORE THEY DEVELOPMENT ANY LESIONS. AND WE KEPT THE MICE FOR ONE YEAR IN THE LOW DOSE OF RAPAMYCIN. THE RESPONSE WAS AMAZING. SO THE MICE REALLY SURVIVED. THE MAJORITY DID NOT. THESE WILL BE THE CONTROLLED MICE AND THIS IS THE RAPAMYCIN LOW DOSE OF RAPAMYCIN. SO THIS IS EXCELLENT -- SO WHAT WE DO WAS USE TO COMBINATION OF APPROACHES AGAIN TO EXCISE A STOP SIGNAL AND EXPRESS THIS ONCOGENE THAT WAS DESCRIBED BEFORE USING TAMOXIFEN SO THE BOTTOM LINE IS WHEN YOU GIVE THE MICE TAMOXIFEN IN THE -- THEY WILL EXPRESS THESE VAST ONCOGENE AND WHAT HAPPENED TO THE MICE. THEY DEVELOP LEATIOND LESIONS BASICALLY. AT THE SAME TIME YOU REMOVE PCT3 AND DEVELOP TWO MOST VERY QUICKLY IN THE CASE OF RATS ARE BENIGN TUMORS IN THE CASE OF -- THIS WILL BE THE TONGUE OF A MOUSE, OKAY. RAPAMYCIN IS EFFECTIVE IN BLOCKING AND IT'S EQUALLY EFFECTIVE IN BLOCKING -- INDUCED. I WILL NOT TELL YOU ABOUT ALL OF THE DETAILS IN THE ANALYSIS ONLY THAT RAPAMYCIN WAS EXCELLENT IN TWO MOS INDUCED BY GENETIC -- SO ON AND SO FORTH. FURTHER WORK ON GOING WE ALSO WORK ON -- MANY OTHERS BUT YOU CAN ALSO ASK THE QUESTION HOW MANY MEASURES WE HAVE ONE OR TWO MUTATIONS, OKAY. WE HEARD BEFORE AND AGAIN SO THERE ARE FOUR, FIVE SIX, MANY MUTATIONS. SO THIS IS VERY CLEAN, TOO CLEAN TO BE TRUE. SO WE'VE HAD TO, IF YOU WILL, CALLED OLD FASHION OR BACK TO THE FUTURE AND WE DECIDE LET'S USE CHEMICALLY INDUCED MODEL OF CANCER BECAUSE THE CHEMICAL -- MUTATIONS MOST LIKELY RESEMBLE MUCH BETTER THE CLINICAL SITUATION THAN JUST A COUPLE OF ONCOGENES. SO THERE WERE NO ANIMAL MODELS FOR CANCER CHEMICALLY INDUCED. WE TRIED TO PERSUADE OUR MICE TO SMOKE. THEY DIDN'T WANT TO. THEY ARE MICE, THEY KNOW WHAT THEY'RE DOING. NO ONE WANTED TO SMOKE. SO WE DECIDE TO USE IT, TOBACCO MEDIC, A CHEMICAL CALLED -- IT'S JUST A DRUG, IF YOU WILL. HAD BEEN USED FOR BRUSHING IN THE RATS, TONGUE OF THE RATS. VERY LIMITED USE IN MICE BECAUSE THEY INDUCE CO -- CANCERS. THEY CANNOT EAT. SO THE PERSON ACTUALLY NORMAL PERSON FROM ISRAEL JOINED THE LAB AND SHE SAYS THIS IS GOING TO WORK. SO SHE STARTED BRUSHING. I MEAN YOU HAVE TO SEE A PERSON BRUSHING THE TONGUE OF THE MICE, OKAY ON A DAILY BASIS. DOWN FROM THE RATS INTO THE MICE. UNFORTUNATELY I DIDN'T TAKE A MOVIE OF THAT. THAT WOULD HAVE BEEN WONDERFUL. ANYWAY, IT WAS BEAUTIFUL, OKAY. SO THEN WE REALIZE THE MICE DON'T DRINK THE WAY WE DRINK, OKAY. THEY LICK. SO ALL WE HAVE TO DO IS TO PUT INTO THE WATER IN A LOW DOSE OF THIS DRUG IN THE WATER BECAUSE THE WAY THEY LEAK, CONCENTRATED IN THE TONGUE. SO THE BOTTOM LINE IS THAT WE GAVE, WE HAVE TO ADJUST THE RESPONSE CURVE, KEEP THE MICE DRINKING THIS, VERY SENSITIVE USING 57 MICE IF ANYONE REALLY WANTS TO KNOW, TYPICAL MICE THAT WE ALL USE IN THE LAB. AND THEN WE STARTED GIVING THIS DRUG AND JUST REPLACED BY WATER. THIS HAPPENED TO THE MICE. THEY ALL DEVELOPED ONLY LESIONS IN THE TONGUE AND VERY FEW IN OTHER PLACES BUT ONLY IN THE ORAL CAVITY. ALL OF THE MICE IS TUMOR FREE SURVIVAL AND THIS WILL BE. SO YOU STOP GIVING THE DRUG AND THE TUMORS GOING UP AND UP. THE NUMBER IN THE SIZE OF THE TUMOR. THEY'VE ALL HAVE VERY AGGRESSIVE SQUAMOUS CARCINOMA AS WELL AS DYSPLASIA. SO WE HAVE PRIMA LEGGANT LESIONS, HIGH GRADE DISPLAYERS AND LOW GRADE AND SO FORTH THAT WILL RESEMBLE SQUAMOUS CARCINOMA. SO THIS SQUAMOUS CARCINOMA, THEY HAVE MODERATE PROLIFERATION SO IT WILL BE THE CONTROLS -- INFLAMMATION COX 2 NO YOU SEE THIS -- LOOK INTO THE NORMAL -- BUT IN THE CANCER IT'S EVERYWHERE. THE SAME THING FOR NICOTINE. SO IF YOU HAVE RAPAMYCIN YOU CAN SEE -- WE'LL GO INTO THAT IN A SECOND. THE MOST IMPORTANT YOU CAN PREVENT SO THE NUMBER OF SQUAMOUS CARCINOMA DECREASED DRAMATICALLY. THE TUMOR AREA DECREASED DRAMATICALLY. THIS IS A TYPICAL EXAMPLE. ONE EXPERIMENT IS ALL THE TONGUES FROM THE GROUP WITH RAPAMYCIN AND CONTROLS AND HERE IS JUST A GRAPHICAL REPRESENTATION OF ALL OF THESE LESIONS. SO WE REALLY PERSUADED IT REALLY WORKS AT LEAST IN ANIMAL MODELS. JUST GOING INTO THE ISSUE OF HPV, DOES IT REALLY WORK FOR HPV OR WE NEED TO WHEN WE DO A CLINICAL TRIAL REMOVE HPV. GOING BACK INTO OUR TISSUE IT WAS PUBLISHED TWO WEEKS AGO. SO P16 IS AN EXCELLENT MARKER FOR THE PRESENCE OF HPV. SO IT WOULD BE ALL OF THE HPV POSITIVE. IN ALL OF THEM, THE MAJORITY OF THEM SIMILAR TO KNOW HPV -- VALIDATED THAT WITH A GROUP OF VALIDATED HPV LESIONS IN COLLABORATION WITH OUR COLLEAGUES IN CHICAGO. IF WE LOOKED INTO THE DISTRIBUTION OF THE POSITIVE 316, POSITIVE HPV CASES ROUGHLY 20% OF ALL OF OUR HAVE CANCER HPV POSITIVE. AND WE HAVE SOME IN SOUTH AFRICA, MAYBE MORE IN THE U.S. IS AROUND 20%. CHINA IS A BIT LOWER DEPENDING ON WHERE YOU'RE COMING FROM SO ON AND SO FORTH. SO THIS IS REALLY AFFECTS THE ENTIRE WORLD. IT'S NOT ONLY FEW CASES. SO YOU CAN GET THE PICTURE ROUGHLY 20% OF OUR RANDOMLY ACQUIRED, IF YOU WILL TISSUES, ALL OF THEM, ROUGHLY 20% OF HPV POSITIVE. IN THIS CASE, WE USE A SEE NO SEE SEE NO GRAPH MODEL AGAIN. USING THIS JUST IN A SIMILAR MODELS WE SHOW THAT THIS HPV POSITIVE ARE VERY SENSITIVE TO RAPAMYCIN AND ANOTHER DRUG CALLED -- 1 WHICH IS RELATED TO RAPAMYCIN. BOTH OF THEM ARE EFFECTIVE. WHAT CAN YOU USE THIS RAPAMYCIN FOR TYPICAL ISSUE IN A CANCER VERY OFTEN MA TALS SIZE TO THE CERVICAL LYMPH NODES. METASTASIS, EXPRESSED TO THE SURGICAL LYMPH NODE IS ONE -- IMPORTANT PROGNOSIS FACTOR. SO THERE IS THIS DISSEMINATION IN THE LYMPH NODES, THE SURVIVAL DECREASES TO ALMOST 50%. SOMETHING I NEED TO MENTION, THERE ARE ROUGHLY 800 LYMPH NODES IN THE HUMAN BODY, 200 OF THEM ARE ALL LOCALIZED IN CLOSE TO THE ORAL CAVITY. SO IT'S VERY VERY, DESSEMINATION IS VERY OFTEN TO THE LYMPH NODES. SO WE WANTED TO ASK WHETHER IT MIGHT HAVE BEEN METASTASIS. SO USUALLY WHAT WE TOOK SOME MICE AND INJECTING INTO THE TONGUE. FOR EXAMPLE YOU CAN SEE THE INDIA INK WILL GO SPECIFICALLY TO CERTAIN LYMPH NODES THAT WERE SPECIFICALLY TO DRAIN THE LYMPH NODES. THEN WE CAN INJECT THE TUMOR CELLS NOW WITH GREEN FLUORESCENT PROTEIN INTO THE TONGUE. WE CAN SEE THEM VERY NICELY ENTER THE LYMPHATIC VESSELS. SO THESE TUMORS ARE EXTREMELY LYMPHOGENIC SO WE USE THE PROLIFERATION OF THE LYMPHATIC VESSELS. THE -- VERY TYPICAL IN THIS CANCER TYPE SO THIS IS A LYMPHATIC VESSELS, THESE ARE THE TUMOR CELLS ENTERING INTO THE LYMPHATIC VESSELS. EVEN BETTER, YOU CAN DISSECT IN THIS CASE THE NECK AND IDENTIFY THE LYMPH NODES THAT WERE INVADED IN COLLABORATION WITH -- AND HIS GROUP WE'RE NOW DOING PHOTO MY CROP SK MICROSCOPY. THESE ARE THE RED BLOOD CELLS WITH THE DIE. SOME ARE TRYING TO GET INTO THE BLOOD. THESE ARE THE-LYMPH NODES FOR EXAMPLE. YOU NEED TO SEE NOT ONLY WHAT THE TUMOR CELLS DO HOW THEY BEHAVE OR MISBEHAVE WITH RAPAMYCIN IN THESE TUMORS FOR EXAMPLE. SO WITH RAPAMYCIN, WE BLOCK -- IT'S MUCH LESS I'M NOT -- REPORTED AS WELL. MUCH LESS LYMPHOANGIOGENERAL -- AND THE SURVIVAL OF THE MICE NEEDS TO BE EXTENDED AND WE NEED TO TERMINATE THEM BECAUSE THEY ARE TAKING UP SPACE [INDISCERNIBLE] HOW DOES IT WORK. WE ARE NOT SURE. WE DON'T KNOW. I CAN TELL YOU WHAT WE THINK. SO THIS IS WHAT I DESCRIBED WITH THE KINASE -- PATHWAY NOW A LITTLE BIT MORE COMPLEX. MTOR HAS TWO COMPLEXES. TOR1 AND TOR2. THE ONE I WAS REFERRING TO -- IS THE COMPLEX TOR1. SO WHAT WE FOUND IN TISSUES AND -- SO ON AND SO FORTH, RAPAMYCIN VERY QUICKLY IF ONE GOES DOWN IT CONTROLLS THE -- INDUCE THE FEEDING OF THE CELLS BY BLOOD SUPPLY. IN PARALLEL, IT A ALSO CONTROLS GLUCOSE METABOLISM. AND TOR CONTROLS -- VERY QUICKLY AFTER THE USE OF RAPAMYCIN WE SEE DECREASE IN ANGIOGENESIS AND DRAMATIC CHANGES IN GLUCOSE METABOLISM IN THESE TISSUES. NOW THE ISSUE IS YOU CANNOT WHY IN THESE TUMOR WORKS -- ONE OF THE REASON WE THINK IT'S BECAUSE THIS OTHER TOR2 PHOSPHORYLATE -- SPECIFICALLY IS NOT THIS PATHWAY. THIS IS ONLY -- IT'S USUALLY NOT A TARGET FOR TOR1 -- DOESN'T BLOCK. IT'S VERY NICE DECREASING. DOESN'T HAVE THE FACT TO DO WITH THE FACT THAT PROLONGED RAPAMYCIN IN SOME CASES MAY DECREASE ACTIVITY OF THE TOR2 AND THIS IS WHAT WE OFTEN SEE IN THIS TUMOR TYPE. WE CAN ALWAYS DOCUMENT, IN THE MAJORITY OF THE CASES GOING DOWN TO CHECK THIS COMPLEX IS ALSO -- SO THE IDEA IS BOTH OF THESE -- WILL BE TOR1 INDIRECTLY TOR2 AND ALL OF THEM MACON TRIBUTE T MAY CONTRIBUTE . IT WAS SHOWN THAT YOU BLOCK -- AND SOME OTHER TUMORS, IF YOU BLOCK TOR1 WITH RAPAMYCIN THEN THEY SAID NEGATIVE FEEDBACK LOOP LEADING TO INCREASE CONDUCTIVITY OF NICOTINE -- PRIMARILY THROUGH THE -- RECEPTORS. SO YOU PREVENT MTOR ACTIVATION AND THEN YOU HAVE NEGATIVE -- THAT IT'S EVEN MORE -- KINASE NICOTINE. THIS WAS SHOWN IN BLASTOMA DOES NOT HAPPEN IN CANCER. AS I MENTIONED TO YOU PRIMARILY -- ACTIVATION -- SO THE ABSENCE OF THESE -- THAT WILL PREVENT ACTIVITY OF THESE, MAYBE ONE OF THE REASONS WHY THE TUMOR MAY RESPOND. ANOTHER ONE MUCH MORE CONVOLUTED IF YOU WILL BUT WE FEEL IT'S VERY IMPORTANT. YOU COMPLETE THIS LINE OF RESEARCH, WHAT WE FOUND IS THAT THE -- HAPPENED SO WHEN WE OVER ACTIVATE MTOR IN THE EPITHELIAL STEM CELLS, WHAT HAPPENS THE CELLS VERY QUICKLY WILL UNDERGO SAW NIECES. IN THE NORMAL TISSUES YOU NEVER SEE IN THE BASAL LAYER ACTIVATION OF MTOR -- BECAUSE THEY DON'T TOLERATE. AS SOON AS YOU TURN ON -- MTOR THEY UNDERGO VERY QUICKLY SENESCENCE OR YOU CAN CALL IT DIFFERENTIATION. IN TOR -- DIFFERENTIATION MAY PREVENT THE CELLS MAYBE ONE MECHANISM TO PREVENT CANCER PROLIFERATION. THEREFORE THE IDEA OF SURVIVING CELLS CAN TOLERATE HAVING MTOR ACTIVE CAN BY PASS THE SENESCENCE MAYBE THE ONES THAT CAN PROLIFERATE BACK TO THE TUMOR, IN OUR IDEA THAT MAY BE ONE OF THE REASONS IT BECOMES ADDICTED TO MTOR. ANOTHER ISSUE I WANT TO MENTION, THIS IS ONLY BECAUSE WE JUST -- COMING IN THE NEXT TO YOU DAYS. SO NOT ONLY YOU CAN USE RAPAMYCIN TO BLOCK MTOR WHICH MAY BE THE IDEA I'LL SHOW IN A SECOND FOR HOPEFULLY SOON WE WILL KNOW FOR THE PATIENTS -- THERE IS A WAY TO BLOCK MTOR NOT AS STRONG A RAPAMYCIN -- THAT WE MAY PREVENT THE DEVELOPMENT OF THE CANCER ITSELF. I'LL SHOW YOU THAT EVEN LESIONS HAVE ACT VALUATIONS OF MTOR YOU MAY NOT BE ABLE TO USE RA RAPAMYCIN THAT SMALL LESIONS BUT MAYBE SOMETHING SAFER THERE IS A POSSIBILITY. IN THAT REGARD THERE IS A DUG USED FOR TYPE 2 DIABETES. APPROXIMATELY ONE MILLION AMERICANS RIGHT NOW ARE TAKING -- FOR TYPE TWO DIABETES. THIS DRUG IS RELATIVELY SAFE, EXTENSIVELY USED. BLOCK ONE OF THE FUNCTIONS IS BLOCK COMPLEX ONE IN MITOCHONDRIA PARTIALLY. THAT DECREASES THE LEVEL OF ATP, INCREASE AMP, PRODUCTIVE KINASE CALLED A AND P KINASE. ACTIVATION OF ANP KINASE MANY MECHANISMS WILL BLOCK ACTIVATION. SO THE BOTTOM LINE WHEN YOU USE -- DOSES THAT WILL BE COMPARABLE TO THOSE USES -- IN A STUDY THAT'S COMING IN THE NEXT WEEK OR SO. WE FOUND THAT WE CANNOT BE USED TO TREAT CANCER PATIENTS. WE KNOW IT'S USED TO TREAT CANCER SO -- BUT THE MICE HAVE PRE CONDITIONS USING -- YOU CAN PREVENT THE EVOLUTION INTO CANCER. SO THE CONCLUSIONS -- THERE IS A HIGH INTERFERENCE OF CANCER -- INCLUDING U.S. HOWEVER IT IS CALLED MOLECULAR REVOLUTION -- IN CANCER AND OTHER CANCERS -- HUMAN GENOME SEQUENCING. SO WE HAVE AN UNPRESS DEBTD LEVEL OF -- CANCER EVEN AT INDIVIDUAL LEVELS. SO ONLY 0 OF THIS MUTATION ANALYSIS CAN BE DONE WITH A SINGLE PATIENT -- SO THE IDEA IS THIS OPPORTUNITY TO DEVELOP DETECTION MARKERS. THERE'S I WILL MENTION IN OUR WORK IN CONFIRMED BY MANY OTHERS IS WIDE SPREAD ACTIVATION OF ATP -- CANCER AND THE POSSIBILITY, THE POSSIBILITY THAT HAVING THE CANCER MAY ARISE FROM -- STEM CELLS MAY HAVE 1K5EU7ESCAPED FROM MTOR DEPENDENT DIFFERENTIATION. THE OVERALL IDEA OF HAVING CANCER IN THE POTENTIAL CANCER STEM CELLS MAY BE ADDICTED TO AND THAT'S DEPENDENT ON NICOTINE FOR SURVIVAL IN THE TUMOR ENVIRONMENT. IF THIS IS ALL OKAY IT MAY BE POSSIBLE TO USE -- MOLECULAR TARGET PREVENTIVE STRATEGY OR FOR TREATMENT OF HEAD AND NECK CANCER. THIS IS WHAT WE ARE TESTING. THANKS TO OUR COLLABORATORS AT NCI AND N -- BASED ON THIS YAWTION WE'RE ABLE TO PUT TOGETHER A CLINICAL TRIAL PHASE ONE -- RAPAMYCIN TREATMENT. THE PATIENTS DEVELOP NEWLY DIAGNOSED, VERY IMPORTANT NEWLY DIAGNOSED PATIENTS HAVING THE CANCERS. STAGE THREE OR STAGE 4A WAS DESCRIBED BY BARBARA. THESE PATIENTS RECEIVE DURING 21 DAYS ORAL RA RAPAMYCIN -- TO BE VERY SPECIFIC. AND THEN BIOPSIES BEFORE AND AFTER WITH CLINICAL END POINTS. AND THEN WE HAVE TO UNDERGO SURGERY WHEN RAPAMYCIN LEVELS ARE ALREADY LOW ENOUGH TO PREVENT ANY SIDE EFFECT. SO THIS CLINICAL TRIALS VARY SO WE HAVE OUTLINED ALL OF THE OBJECTIVES, CLINICAL OBJECTIVES AS WELL AS BIOCHEMICAL OBJECTIVES, INCLUDING THE ABILITY TO DETECT UP CO-GENESIS AND SO FORTH CYTOKINES. WE THINK THAT TWO PATIENTS ALREADY UNDERWENT TREATMENT, IT WAS THE FIRST -- TISSUES COME FROM THE FIRST PATIENT. BY THE WAY BOTH OF THEM DID EXCELLENT. I CAN SAY NO MORE THAN THAT. BOTH OF THEM HAVE INTERESTING RESPONSES. BOTH PATIENTS WERE TREATED IN SOUTH CAROLINA IN THE U.S. WHERE THE OTHER TYPE FOR THIS TRIAL. THE IDEA IS THIS TYPE OF ANALYSIS WHICH IS ONLY 21 DAYS HOPEFULLY POSITIVE RESPONSE CAN HELP BRIDGE OUR ACTIVITIES HERE IN THE LAB AND AGAIN THE PATIENTS THEY NEED THESE FINDINGS. HOPEFULLY -- THE VALUE OF HEALTH. THAT SAID THE SECOND MESSAGE YOU NEED TO FAKE. ONE IS YES WE CAN DO IT. THE SECOND THE FIGHT AGAINST ANY CANCER IS A TEAM EFFORT. SO THIS IS NOT OUR LAB, YOUR LAB, IT'S REALLY A TEAM EFFORT TO PICK A FEW OF THE MANY PEOPLE INVOLVED OUR CURRENT MEMBERS IN OUR GROUP AT THE NDCR, OUR COLLABORATORS AS WELL, PAST MEMBERS OF OUR LAB, MANY PEOPLE AT NCI, OUR GROUPS, THE GROUP OF -- PARTICULARLY FOR THIS -- OUR COLLEAGUES IN SOUTH CAROLINA. AGAIN, THIS IS JUST SHORT LIST OF THE PEOPLE WE'RE COLLABORATING WITH AND THIS IS THE METHOD, THIS IS SOMETHING WE NEED TO DO TOGETHER AND HOPEFULLY WE'LL KEEP TRYING. [APPLAUSE] >> WOW, THAT'S FANTASTIC I THAT'S ONE OF THE MOST EXCITING PRESENTATIONS I EVER HEARD. TRALT -- >AT ANY RATE -->> I'M JUST THE SPEAKER. >> THAT WAS REALLY BEAUTIFUL. ANY QUESTIONS? >> [INDISCERNIBLE] DID YOU TRY -- THERAPY LIKE -- FOR EXAMPLE [INDISCERNIBLE] >> THE QUESTION IS CAN YOU COMBINE IT. THE ANSWER TO THAT IS WHY NOT. SO THE ANSWER IS ALSO THE ANSWER WE OBTAIN IS VERY CONFUSING. SO THE RADIATION I'M NOT SO SURE IS THE BEST. THE ANSWER TO THIS, WE WOULD HAVE ONGOING IN COMBINATION TO LEGAL TRIALS IN HOPKINS IN PITTSBURGH BEGINNING TO ADDRESS IN PHASE ONE TRIALS, NUMBER ONE. IN THE LAB -- WHAT IS BEAUTIFUL EMERGING IS THE RESPONSES OF -- SO WE HAVE MODELED THE RESPONSE BEAUTIFUL TO -- SOME OF THEM YOU HAVE OCCURRENCE. AFTER -- WE PUT RAPAMYCIN, THEY DON'T HAVE RECURRENCE. SO THAT MAY BE THE REAL USE. I'M NOT SO SURE THE PATIENCE RESPONSE TO -- PATIENT DID NOT RESPOND I'M NOT SO SURE WHETHER BECAUSE WE DON'T HAVE ANY MODELS YET. BUT THOSE THAT DO RESPOND TO PREVENT RELAPSE WHICH IS USUALLY WHAT WILL HAPPEN WITH PATIENTS UNDER TREATMENT, THAT WILL BE TOTALLY A GOOD CHOICE. REGARDING HIS PLATEN IN MANY OTHER COMBINATIONS WE'RE DOING THOSE EXPERIMENTS IN COLLABORATION WITH OTHER GROUPS. AND I CAN TELL YOU SOME CASES WE DO SEE SOME -- BUT AGAIN THE PROBLEM WITH THE COMBINATION THERAPY IS THE BENEFIT OF ONE VERSUS THE OTHER REQUIRES A HUGE NUMBER OF EXPERIMENTS AND SOMETIMES OTHER GROUPS MAY BE BETTER PREPARED TO ADDRESS THAT. >> [INDISCERNIBLE] KINASE EXPRESSION IN THE ANIMAL MODELS IS VERY UP REGULATED IN THE PRIMA LEPREPRIMAPREMALIGNANT CELLS -- IS T HERE ANY EXPLANATION FOR THAT. >> -- IN PATIENTS WE SEE -- OKAY, WE ALWAYS SEE PRE MALIGNANT -- THE DEFINITION OF A PRE MALIGNANT LESION IS A LESION WE COME INTO CANCER. FROM THE MOMENT YOU HAVE THIS SO-CALLED POTENTIAL PRE MALIGNANT LESION AND YOU CAN DIAGNOSE WAS A REAL PRE MA LEG NUNS WILL BE FIVE TO TEN YEARS -- THAT WILL BE NUMBER ONE. SO IF YOU'RE GOING TO -- IN SOME OF THESE POTENTIAL PRE MALIGNANT LESIONS, 10% OR 20% AT THE MOST WE SEE ACTIVATION OVER MTOR WAS IN THE BASAL LAYERS. ALL THE OTHERS WE DON'T. SO WE THINK IT'S MORE ACTIVITY WHICH IS USUALLY VERY LIMITED, IF ANY, IN THE NORMAL TISSUES IS THAT LACK OF COMPARTMENTIZATION OF THE ACTIVATION OF FAUST FORE6 THAT WILL BE IN THE BASAL LAYER. SO IN MOST, BY THE WAY, IN ORAL TISSUES AND EVEN IN THE SKIN, THE ONLY CELLS THAT PROLIFERATE ARE IN THE BASAL LAYER. SO THAT WILL BE THE AN IS MOST LIKELY IF NOT ONLY THE AMOUNT OF WRITS ACTIVATING IN THE NORMAL TISSUES -- WHICH ONE OF THEM WILL EVOLVE INTO CANCER BUT WE THINK THAT MAY BE A GOOD WAY TO IDENTIFY THOSE -- REQUIRES MORE WORK. >> ANY OTHER QUESTIONS? LISTEN, THANK YOU VERY VERY MUCH. THANKS BOTH OF YOU FOR SPENDING AFTERNOON SHARING YOUR EXPERIENCE WITH US. NEXT WEEK WE GO TO EXPRESS INFLAMMATORY BOWEL DISEASE. THANK YOU VERY MUCH.