Articles, Blog

TRACO 2017 – Clinical trials and Precision Medicine

January 25, 2020


TODAY AND TODAY OUR SPEAKER IS JILL SMILGT. SHE GOT HER MEDICAL DEGREE AT THE UNIVERSITY OF FLORIDA AND I’M SURE SHE’S HAPPY NOT IN GAINESVILLE, FLORIDA TODAY AFTER HURRICANE IRMA AND THEN SHE GOT A RESIDENCY AT THE UNIVERSITY OF MISSOURI. SHE THEN BECAME A PROFESSOR OF MEDICINE AT PENN STATE UNIVERSITY.FOR A FEW YEARS SHE
CAME TO NIDDK AND WAS IN CHARGE OF TRANSLATIONAL RESEARCH AND NOW SHE’S BACK AT GEORGE TOWN, UNIVERSITY, PROFESSOR OF MEDICINE AND SHE WILL TALK ABOUT TRANSLATIONAL RESEARCH, BENCH TO BEDSIDE, CLINICAL TRIALS.>>HELLO? IT IS ON. WE’RE LEAVING THAT OPEN BECAUSE THERE THERE’S SOME FRAGRANCE IN HERE THAT THEY SPRAYED THAT I’M ALLERGIC TOO. WELL, THANK YOU DR. MOODY. THANKS FOR HAVING ME. SO OF COURSE I HAVE SOME DISCLOSURES THAT I NEED TO REVEAL HERE. I’M A CO-INVENTOR NOW ON 11 PATENTS RELATED TO PANCREATIC CANCER AND I DO SOME CONSULTING CONSULTING–[INDISCERNIBLE]. OKAY. OKAY, I’M A CONSULTANT TO SOME COMPANIES. SO TODAY WE’RE GOING TO TALK ABOUT UNDERSTANDING HOW AN IDEA IS TAKEN FROM THE RESEARCH LAB TO PATIENT CARE. WE WILL LEARN ABOUT THE STEPS OF CONDUCTING CLINICAL TRIALS AND WE WILL TRY TO COMPREHEND THE OBSTACLES THERE ARE TO OVERCOME DRUG DEVELOPMENT AND I’M GOING TO GIVE YOU EXAMPLES OF MY TRANSLATIONAL PROJECTS. AND CAN YOU HEAR ME OVER THAT MACHINE OUT THERE? OKAY. SO HOW MANY OF YOU IN HERE ARE GRADUATE STUDENTS OR WORKING ON YOUR Ph.D.? NOBODY. HOW MANY OF YOU ARE M. D.s, NO? OKAY. OKAY. AND EVERYBODY ELSE IS? POST DOCS?>>POST BACKS. OKAY, OKAY. GOOD. DESIRE TO DO 1 OR THE OTHER I HOPE? OKAY. ALL RIGHT. SO 1 OF THE THINGS ABOUT RESEARCH DEVELOPMENT IS THERE’S A LOT OF DRUGS THAT ARE TESTED PRECLINICALLY. AND UNFORTUNATELY THE MAJORITY OF THOSE DO NOT MAKE IT TO THE CLINIC SO WE HAVE THIS BOTTLENECK OF DEVELOPMENT WITH DRUG DEVELOPMENT AND THAT’S A PROBLEM. OR IS THE BOTTLENECK REALLY WASHINGTON. I SAY THAT, THIS IS NOT REALLY THE BYPASS BUT PART OF THE PROBLEMS ARE THE POLITICS OF DOING RESEARCH AND THE FUNDING PROBLEMS AND WHATEVER. SO. SO IN ORDER TO DO A RESEARCH PROJECT AND ACTUALLY TO DO TRANSLATIONAL RESEARCH, YOU HAVE TO HAVE A GOOD IDEA AND IT HAS TO BE HYPOTHESIS DRIVEN RESEARCH. AND YOU KNOW YOU HAVE TO LOOK AT WHAT IS THE PROBLEM THAT’S GOING ON AND WHAT NEEDS TO BE DONE TO SOLVE THIS ISSUE AND WHAT CAN YOUR RESEARCH DO TO HELP THE PROBLEM. SO [INDISCERNIBLE]–LITTLE LOUD. OKAY. THE OTHER THING IS THAT YOU REALLY HAVE TO HAVE PASSION ABOUT WHAT YOU’RE DOING. IF YOU DON’T LIKE WHAT YOU’RE DOING, YOU HAVE TO DO SOMETHING ELSE. YOU HAVE TO LIKE YOUR RESEARCH, HAVE YOU TO BE EXCITED ABOUT YOUR FIELD. YOU HAVE TO BE EXCITED WITH EVERY LITTLE DISCOVERY THAT YOU HAVE IN YOUR DATA AND THAT’S VERY IMPORTANT. SO AS FAR AS THE PHASES OF CLINICAL TRIALS, IT’S PHASE 0 TO PHASE 4 THAT WE WILL TALK ABOUT TODAY AND PHASE 0 IS WHERE MOST PEOPLE ARE WORKING IN THE BENCH AND YOU HAVE TO IDENTIFY AN AGENT THAT ISN’T HITTING ITS TARGET, SO YOU DISCOVERED SOMETHING THAT MIGHT BE A GOOD TARGET FOR CANCER THERAPY, AND THAT YOU TESTED OF COURSE, YOU KNOW CANCER CELLS, YOU TESTED IN THE ANIMALS IN VIF O AND THEN WHEN YOU HAVE DONE THAT THEN CAN YOU TAKE IT TO THE NEXT PHASE OR PHASE 1 AND THAT’S HOW YOU FIND OUT WHAT THE DRUG RELATED TOCKS ISOTOPITY OR THE DLT OR MAXIMUM TOLERATED DOSE IS THAT YOU COULD TREAT IN HUMANS. AND THEN THE NEXT THINGS IS PHASE 2 WHICH YOU REALLY LOOKING AT THE FEASIBILITY AND SEEING IS IT REALLY BETTER THAN A PLACEBO? THEN YOU HAVE PHASE 3 WHERE YOU LOOK AT CLINICAL OUTCOMES AND THEN PHASE 4 IS POST MARKETING ONCE IT’S ALREADY APPROVED. SO THESE ARE ALSO SOME OF THE DIFFERENT TYPES OF CLINICAL TRIALS. THERE COULD BE TREATMENT TRIALS, THERE COULD BE PREVENTION TRIALS, EARLY DETECTION, SCREENING TRIALS, DIAGNOSTIC TRIALS, QUALITY OF LIFE TRIALS, GENETIC TRIALS, AND THE TRIALS CAN EITHER BE INDUSTRY SPONSORED OR INVESTIGATOR-INITIATED. AND MOST OF WHAT I’LL TALK ABOUT TODAY IS INVESTIGATOR-INITIATED BECAUSE MOST OF US ARE WORK NOTHING A RESEARCH LAB AND YOU COME UP WITH AN IDEA, YOU WOULD LIKE TO SEE YOUR IDEA GO ALL THE WAY THROUGH TO THE CLINIC TO HELP PEOPLE. THAT’S THE WHOLE REASON WHY WE’RE DOING THE RESEARCH. SO PHASE 1, USUALLY ONLY INVOLVES ABOUT 15-30 PEOPLE. THE WHOLE PURPOSE OF IT IS TO DETERMINE IF THE DOSE IS SAFE. SOMETIMES THEY DO THIS IN FORMAL CONTROLS RATHER THAN IN CANCER PATIENTS BUT VUBSLY IF YOU’RE TESTING A NEW CHEMO THERAPEUTIC DRUG, YOU DON’T WANT TO GIVE THAT TO NORMAL CEILS AND YOU WOULD TEST IT IN THE COHORT YOU’RE LOOKING AT. FOR EXAMPLE, I WILL TALK ABOUT PAN KRISTATTIC CANCER AND THEN HOW THE TREATMENT SHOULD BE GIVEN, DO YOU HAVE TO GIVE INTRA VENOUSLY, BY MOUTH, WHAT ARE THE PHARMACOKINETICS HOW LONG IS THE HALF LIFE. HOW DO THE TREATMENT IT IS EFFECT THE BODY, DOES IT CAUSE LIVER TOXICITY OR OR OTHER SORTS OF TOXICITY? AND THEN PHASE 2 IS TYPICALLY LSS THAN A HUNDRED PEOPLE AND IT HAS TO HAVE A PRIMARY END POINT. IT’S USUALLY DONE IN AN UNBIASED OR BLINDED WAY. AND SO YOU WANT TO KNOW WHAT IS THE EFFICACY. DOES THIS NEW TREATMENT ACTUALLY WORK AND IS IT MORE EFFECTIVE THAN THE PLACEBO. AND IS IT DOESN’T REALLY COMPARE
TO OTHER TREATMENTS IN PHASE 2. YOU’RE JUST COMPARING IT EITHER TO SOMETIMES STANDARD OF CARE OR TO PLACEBO. AND THEN PHASE 3, IT CAN BE ANYWHERE FROM A HUNDRED TO THOUSANDS OF PATIENTS. AND THERE’S AN EQUAL CHANCE OF BEING ASSIGNED TO 1 OF THE 2 OR MORE GROUPS. AND IT DETERMINES HOW THE NEW TREATMENT COMPARES TO THE CURRENT STANDARD THERAPY AND ANNIE, OR AGAIN IT CAN COMPARE TO PLACEBO. IN THIS CATEGORY THERE CAN BE SUPERIOR OIT AND NONINFORIORITY TRIAL. SO A NONINFERIORITY TRIAL IS YOU WANT TO SHOW THAT YOUR NEW TREATMENT IS JUST AS GOOD AS THE STANDARD OF CARE. SO, MAYBE IT’LL BE APPROVED BECAUSE IT’S LESS EXPENSEIVE OR IT’S EASIER FOR PATIENTS TO TOLERATE BUT IT’S NOT ANY BETTER THAN THE STANDARD OF CARE. SO THE SUPERIORITY IS THAT IT IS BETTER THAN THE STANDARD OF CARE. AND THEN THE PHASE 4 TRIAL AND USUALLY IN HUNDREDS, TO THOUSANDS OF PEOPLE, FOR EXAMPLE, THE HEPATITIS E TIGHT US B VACCINATION WHEN IT CAME OUT THIS WAS TAKEN ACROSS THE WHOLE GLOBE. AND USUALLY IT LOOKS AT DRUG RISKS AND BENEFITS AND CALLED POST MARKETING SO AFTER IT’S ALREADY BEEN APPROVED AND IT’S OUT THERE ON THE MARKET. SO 1 OF THE THINGS WE TYPICALLY DO WHEN WE GO INTO A TRIAL IS WE HAVE NO IDEA WHAT THE SAMPLE SIZE OR HOW MANY PATIENTS WE NEED TO INCLUDE. AND SO OFTEN YOU DO WHAT WE CALL A PILOT TRIAL AND THAT MAY BE JUST A SMALL OPEN LABELED TRIAL THAT YOU ARE GOING TO TREAT A SMALL COHORT OF PATIENTS WITH YOUR STUDY DRUG AND YOU WANT TO SEE, YOU KNOW IF THERE’S ANY EFFECT AND IF YOU SEE MAYBE THERE’S A 3 OR 50% RESPONSE RATE THAT YOU WILL USE THAT INFORMATION TO HELP YOU DESEEN A BIGGER AND MORE PIVOTAL TRIAL. SO THAT WILL GIVE YOUR STATISTICIAN SOME BASIC INFORMATION ABOUT HOW EFFECTIVE THE DRUG MIGHT BE WHEN IT GOES AGAINST A PLACEBO. SO THIS WILL HELP YOU CALCULATE THE SAMPLE SIZE, AS YOU MOVE INTO THE PHASE 2. SO WHEN YOU’RE DOING A RANDOMIZED CLINICAL TRIAL, THERE’S SUPPOSED TO BE AN EQUAL CHANCE OF BEING RANDOMIZED OF 1 OR 2 OF THE TREATMENT GROUPS. AND 1 GROUP USUALLY GETS THE MOST WIDELY ACCEPTED TREATMENT OR STANDARD OF CARE AND THE OTHER GETS THE PLACEBO AND IT IS IMPORTANT THAT THEY TRY TO BE BALANCED. SO WHEN YOU’RE RANDOMIZING YOUR PATIENTS, YOU WOULD LIKE TO MAKE SURE THAT IF YOU’RE OUTCOME IS GOING TO BE SAY, QUALITY OF LIFE, YOU WANT TO MAKE SURE THAT WHEN YOU RANDOMIZE THE PATIENTS AT THE ONSET THAT THE ALL THE PATIENTS WITH THE WORST QUALITY OF LIFE DON’T END UP IN 1 TREATMENT ARM VERSUS THE OTHER. SO YOU YOU WANT TO MAKE SURE THEY’RE BALANCED. MOST PEOPLE BALANCE FOR AGE, FOR GENDER AND MAYBE IF THERE IS SOME EFFICACY POINT THAT YOU’RE LOOKING AT, LIKE RESPONSE RATE, LIKE RESIST CRITERIA ON CAT SCAN, YOU WANT TO MAKE SURE THAT EVERYBODY WHO IS IN TREATMENT A-IS NOT STAGE 3 CANCER AND EVERYBODY IN TREATMENT B IS STAGE 4. SO THEY SHOULD BE BALANCED AT THE ONSET. WHENEVER YOU’RE DOING CLINICAL TRIALS, IT’S VERY IMPORTANT THAT PATIENTS RIGHTS ARE PROTECTED AND THERE ARE ETHICAL AND LEGAL CODES THAT GOVERN THE MEDICAL TRACTIS IN CLINICAL TRIALS. ALL PATIENTS HAVE TO SIGN AND UNDERSTAND AN INFORMED CONSENT. THERE ARE REVIEW BOARDS. MOST INSTITUTIONS WILL HAVE THEIR INSTITUTIONAL REVIEW BOARD AND THERE ARE, BEFORE THAT, THERE’S OTHER SCIENTIFIC REVIEWS. FOR EXAMPLE FIT GOES THROUGH A REVIEW WHEN YOU’RE SUBMITTING PROTOCOL TO BE FUNDED BY THE NIH, THERE’S PEER REVIEW IN SCIENTIFIC REVIEW TAKEN–THEY REVIEWS THAT PROTOCOL. THERE ARE ALSO IN OTHER MEDICAL CENTERS LIKE IN GEORGE TOWN WE HAVE LOMBARDI CANCER CENTER AND WE HAVE OUR OWN CANCER SCIENTIFIC REVIEW AND THEY WILL REVIEW IT AND MAKE SURE EVERYTHING IS ETHICAL BEFORE IT MOVES ON TO THE IRB. AND THEN AFTER THAT THERE’S ALSO A DATA AND SAFETY MONITORING BOARDS SO THAT WHEN THE STUDY IS GOING YOU WANT TO MAKE SURE THAT SOMEBODY IS MONITORING HOW IT’S DOING AND ESPECIALLY IF IT’S DONE IN A BLINDED FASHION BECAUSE IF EVERYBODY WHO’S GETTING THE TREATMENT IS LIVING MUCH LONGER AND EVERYONE ON THE PLACEBO IS DYING, THEY MAY UNBLIND IT AND END UP TREATING EVERYONE. SO THERE MAY BE EARLY STOPPING RULES THAT YOUR DATA SAFETY MONITORING BOARD WILL GO BY TO DETERMINE IF THE DRUG IS A BENEFIT OR IF IT’S DETRIMENTAL. IF THEY FIND THAT EVERYONE ON THE TREATMENT ARM IS ENDING UP WITH LIVER TOXICITY, THEY MAY TERMINATE THE STUDY PREMATURELY. AND OF COURSE, MOST RECENTLY, THERE’S–IF GENETIC TESTING IS GOING TO BE DONE, THAT HAS TO BE ADDED TO THE CONSENT. AND TODAY WE STORE A LOT OF BLOOD SAMPLES AND PEOPLE WILL GO BACK TO THEM, LATER IN TIME AND DO SOME GWAS STUDIES OR RNASEQ, AND THEY’RE LOOKING FOR SOME GENETIC ALTERATION. IF BLOOD SAMPLES OR TISSUE SAMPLES WILL BE STORED THERE HAS TO BE IBT–INTEGRATE INCLUDED IN THE CONSENT FORM, A PARAGRAPH ABOUT THE RISKS AND BENEFITS OF THAT BECAUSE IF YOU DISCOVER THAT THIS PATIENT HAS A HEREDITARY YOU KNOW SNP THAT MAY WORSEN THEIR LONG-TERM SURVIVAL AND IF INSURANCE COMPANIES FIND OUT ABOUT THAT THEY COULD LOSE INSURANCE. SO ALL THOSE NEED TO BE STATED UP FRONT IN THE CONCEPT FORM SO PAICIALTS ARE AWARE AND THEY CAN ELECT TO HAVE THEIR SAMPLES REMOVED AND NOT KEPT IN STORAGE WITH THE NEW GENETIC CODES. SO HOW DO YOU DO IT? WHAT ARE THE NUTS AND BOLTS? I WILL GIVE YOU EXAMPLES FROM MY EXPERIENCE AND SOME STUDIES THAT I’VE DONE. FIRST OF ALL IT TAKES A WHOLE RESEARCH TEAM AND THAT’S VERY IMPORTANT. NO MAN IS AN ISLAND ANYMORE. THERE CAN BE–THE PRINCIPAL INVESTIGATOR, CO INVESTIGATORS, THERE ARE OTHER VERY, VERY IMPORTANT KEY PLAYERS THAT WILL HELP A STUDY BE SUCCESSFUL. ONE OF THOSE IS THE NURSE OR STUDY COORDINATOR WHO WILL MAKE SURE THAT ALL THE DOCUMENTS AND THE PATIENTS ARE TAKEN CARE OF PROPERLY. HAVING A STATISTICIAN IS EXTREMELY IMPORTANT BECAUSE THEY TELL YOU YOUR SAMPLE SIZE AND THEN THEY’LL CRUNCH YOUR DATA WHEN YOU’RE DONE. HI1 STUDY THAT HAD OVER A HUNDRED PATIENTS IN IT AND I JUST HANDED THE XL FILE WITH THE DATA IN IT OVER TO THE STATISTICIAN AND THEY DID ALL THE ATHAT WILL SIS. AND IT’S ACTUALLY BETTER THAT WAY BECAUSE YOU DON’T WANT THE PERSON WHO’S IN CHARGE OF THE STUDY DOING THE ANALYSIS, THAT WAY IT IS YOU KNOW NOT BIASED TO 1 GROUP VERSUS THE OTHER AND THE STATISTICIANS USUALLY DON’T KNOW WHICH IS THE TREATMENT GROUP, THEY JUST KNOW GROUP A AND GROUP B. SO THAT MAKE ITS A MUCH MORE RIEJ EDUCATIONAL STUDY. YOU SHOULD HAVE A DATA MANAGER, AND WHENEVER THEY’RE ENTERING THE DATA, THE DATA MANAGER MAY NOT KNOW WHAT THE NORMAL RANGE IS FOR SAY AN ALT AND THE LIVER ENZYMES, SO USUALLY WE HAVE A PLACE IN OUR XL FILE FIST THEY ARE ENTERING SOMETHING AND IT FALLS OUTSIDE THE RANGE OR THEY’RE ENTERING A NUMBER BY MISTAKE, IT WILL POP UP RED, THERE ARE A LOT OF WAYS TO FOOL PROOF THIS SO THEY DON’T END UP WITH DATA IN ERROR. AND THEN OF COURSE WE TALKED ABOUT THE DATA SAFETY MONITORING BOARD AND YOU HAVE TO HAVE AN INVESTIGATION PHARMACIST BECAUSE WHEN THIS IS DONE IN A BLINDED FASHION, THE ONLY 1 WHO REALLY KNOW WHAT IS THE PATIENT IS GETTING IS THE PHARMACIST. AND IF THERE’S A PROBLEM AND YOU HAVE TO UNBLIND THE STUDY, IT’S THE PHARMACIST WHO KNOW WHAT IS THEY’RE TAKING. SO BEFORE YOU START THE TRIAL, THERE’S SEVERAL THINGS YOU NEED TO DO. FIRST OF ALL YOU CAN’T DO A CLINICAL TRIAL WITH A DRUG OR A DEVICE IN HUMANS WITHOUT APPROVAL FROM THE FOOD AND DRUG ADMINISTRATION. SO YOU HAVE TO APPLY FOR AN I, AND D OR INVESTIGATIONAL NEW DRUG NUMBER AND I SHOW YOU AN EXAMPLE OF THE 1571 FORM I HAVE HERE. THEN YOU ALSO HAVE TO WRITE A PROTOCOL AND THAT’S THE STUDY DESIGN AND WHAT YOU PLAN TO DO AND WHAT THE OUTCOMES ARE. YOU HAVE TO HAVE A CONSENT FORM THAT THE PATIENTS WILL BE SIGNING AND THIS HAS TO BE APPROVED. YOU HAVE TO GET APPROVAL BY THE INSTITUTIONAL REVIEW BOARD AND THEN THE HARD PART IS FINDING A SPONSOR, GETTING FUNDING AND GETTING MONEY TO DO YOUR STUDY. AND THEN THERE’S A LOT OF RESPONSIBILITIES THAT THE PRINCIPLE INVESTIGATION OVERALL THE PRINCIPLE INVESTIGATION IS RESPONSIBLE FOR EVERYTHING, EVERYTHING FROM SUBMITTING THE INFORMATION TO THE FDA, TO THE IRB, TO OVERSEEING THE NURSE COORDINATORS AND THE PATIENT CARE. AND THEN, YOU HAVE TO REGISTER EVERYTHING ON THE CLINICALTRIALS.GOV WEBSITE. THIS IS REQUIRED IF YOU WANT TO PUBLISH YOUR RESULTS. AND IT HAS TO BE REGISTERED BEFORE PATIENT NUMBER 1 SIGNS THE CONSENT FORM. IF THE PATIENT SIGNS THE CONSENT FORM AND YOU HAVE NOT YET COMPLETED AND FINALIZED THE REGISTRATION, YOU ARE NOT ALLOWED TO PUBLISH YOUR DATA. SO KEEP THAT IN MIND. SO THIS IS AN EXAMPLE OF A 1571 FORM. ONE OF THE 1S THAT I FILLED OUT AND YOU HAVE TO PUT IN THIS 1, EVERY TIME YOU SEND IT IN, YOU HAVE TO PUT YOUR I& D NUMBER IN THE LITTLE BOX AND THEN THERE’S ANOTHER LITTLE BOX FOR THE SERIALL NUMBER, SO THE FIRST TIME YOU SUBMIT YOUR APPLICATION AND YOUR PROTOCOL AND YOU’RE GETTING APPROVE ALGORITHMS, IT’S SERIAL NUMBER 00000. AND THEN THE NEXT 1 YOU SEND IN, IF YOU’RE SENDING A REPORT SAYING I’M CHANGING THE PROTOCOL TO THIS PARAGRAPH TO THE NEXT PARAGRAPH, YOU HAVE TO SUBMIT THE CHANGES AND YOU APPROXIMATE UTR IN WHAT YOU’RE SUBMITTING INTO THE REPORT DOWN AT THE BOTTOM AND THEN THE NEXT CEREAL NUMBER WILL BE 001 AND THEN 002, ET CETERA. SO, YOU HAVE TO SEND THEM IN IN SEQUENCE SO THIS IS ALL DONE ELECTRONICALLY THROUGH THE FDA AND YOU HAVE TO DO THIS FOR EVERY TIME YOU SUBMIT SOMETHING TO THE FDA AND COMMUNICATE WITH THEM. THE OTHER THING THAT’S REALLY IMPORTANT WITH YOUR RESEARCH, BEFORE YOU TAKE IT TO A CLINICAL TRIAL OR EVEN BEFORE YOU GO OUT AND PRESENT A POSTER AT A MEETING, YOU HAVE TO MAKE SURE THAT YOU’VE SECURED INTELLECTUAL PROPERTY. SO YOU MAY NOT HAVE THE PATENT YET, BUT IF YOU HAVE FILED A PROVISIONAL PATENT WHICH IS VERY INEXPENSIVE, IT’S ONLY A COUPLE HUNDRED DOLLARS AND THE INSTITUTIONS WILL DO THAT FOR YOU, IT PROTECTS YOU AND SO YOU SHOULD DO THAT BEFORE YOU GO OUT AND PRESENT ANYTHING PUBLICLY, EVEN AT A POSTER SESSION. SO THE OTHER THING IS THAT THE PATENT BELONGS TO WHOEVER YOU ARE WORKING FOR. SO FOR ME, YOU KNOW IF I’M WORKING FOR GEORGE TOWN AND I HAVE A GREAT DISCOVERY THERE, THEY ARE THE OWNERS OF THE PATENT BECAUSE THEY PAY MY CHECK. SO,–BUT THAT’S IMPORTANT AND IF FOR SOME REASON, THE UNIVERSITY OR THE IN TIH OR WHATEVER CHOOSES NOT TO PURSUE YOUR PATENT, THEY DON’T THINK THAT IT’S GOING TO GO ANYWHERE, THE INVENTORS HAVE THE RIGHT TO GET THAT INVENTION BACK AND FILE IT THEMSELVES. AND I DID THAT WITH 1 OF MY PATENTS WHICH IS NOW LICENSED AND IS BEING APPROVED BY THE FDA TO TREAT CHRON’S DISEASE. SO IT’S IMPORTANT THAT YOU STAY ON TOP OF THINGS. FINDING A COMPANY, THERE’S A LOT OF BIOTECH COMPANIES OUT THERE, AND THEY’RE PROBABLY EASIER TO DEAL WITH THAN THE BIG PHARMA BECAUSE BIG PHARMA LIKES THEIR OWN IDEAS RATHER THAN DEALING WITH UNIVERSITIES. THAT’S JUST MY OPINION. BUT THEN, YOU WANT WHEN THE PATENT COMES OUT AND ISSUES, YOU WANT TO LANGUAGES IT TO A COMPANY BECAUSE YOU CAN’T DO–YOU KNOW ONCE YOU’RE AN INVESTIGATOR, YOU HAVE TO TURN IT OVER IT A COMPANY SO THAT THEY WILL DEVELOP IT. THEY HAVE THE RESOURCES AND THEY CAN DO THE MULTICENTERRED TRIALS SO THAT’S IMPORTANT BUT THE VERY IMPORTANT THING ABOUT WHEN YOU LICENSE YOUR PATENTS, YOU SHOULD HAVE MILESTONES IN THERE FOR WHATEVER COMPANY YOU’RE DEALING WITH AND IF THE COMPANY DOES NOT REACH THEIR MILESTONE AND THEY DON’T DEVELOP YOUR DRUG OR YOUR IDEA, IN THE TIME FRAME THAT THEY’RE SUPPOSED TO, THERE SHOULD BE A CLAUSE THAT YOU GET IT BACK. BECAUSE THERE ARE COMPANIES THAT ARE OUT THERE THAT WILL TAKE PEOPLE’S IDEAS AND JUST SET IT ON THE SHELF TO KILL THE IDEA SO THEY CAN COME UP WITH A COMPETITOR. SO THAT’S VERY IMPORTANT. THIS IS JUST 1 OF THE PATENTS. THIS IS WHAT A PATENT LOOKS LIKE AND THIS IS JUST 1 OF MY PATENTS THAT ISSUED IN 2014. SO THE NEXT THING YOU NEED DO IS WRITE YOUR PROTOCOL AND THERE’S AN OUTLINE IN HOW YOU HAVE TO DO YOUR PROTOCOL. EVERYTHING FROM THE TITLE PAGE TO THE SUMMARY, USUALLY YOU DO AN OVERVIEW SUMMARY OF THE WHOLE PROJECT, AND THEN THAT’S FOULED BY THE HUNDRED AND SOMETHING PAGE DOCUMENT OF THE ENTIRE PROTOCOL. AND THIS IS JUST 1 OF MY PROTOCOLS. I’M JUST SHOWING YOU EXAMPLES OF THINGS THAT WREER–WE’RE WORKING ON. I DON’T KNOW IF THE POINTER IS WORKING. YOU PUT THE PROTOCOL NUMBER THERE, YOU PUT THE TITLE OF YOUR PROTOCOL. IF IT HAS A NUMBER, YOU WANT TO SAY WHAT CLINICAL STAGE IT IS THIS, IS STAGE 1 AND 2, HOW HOW LONG IT’S GOING TO BE, WHAT’S THE INVESTIGATIONAL DRUGS THAT YOU’RE USING. WHAT’S YOUR RESEARCH HYPOTHESIS, AND THEN YOU JUST SPELL OUT WHAT’S YOUR PRIMARY, SECONDARY OBJECTIVES, WHAT WILL YOU DO BY THIS STUDY. SO IN THIS STUDY, WE ARE DOING A PHASE 1 AND WE WILL TRY TO FIND OUT WHAT RECOMMENDED PHASE 2 DOSE IS BY DOING THE PHASE 1 AND THEN WE WILL MOVE INTO THE PHASE 2 PART OF THE STUDY. AND THEN OF COURSE, YOU WANT TO SAY HOW MANY CENTERS ARE INCLUDED, HOW MANY PATIENTS YOU WILL TREAT, INCLUSION, EXCLUSION, CRITERIA, ET CETERA, ET CETERA. SO THAT’S THE OUTLINE FOR YOUR PROTOCOL AND WHAT YOUR DRUGS ARE AND WHAT THE DOSAGE, JUST KIND OF A SUMMARY AND THEN YOU GO INTO DETAIL IN THE FULL PROTOCOL . SO THE AIMS OF A PHASE 1 TRIAL AND FIRST IN HUMAN TRIAL IS REALLY JUST TO LOOK AT THE SAFETY AND TOXICITY, DETERMINE MAXIMUM TOLERATED DOSE, LOOK AT ANY PHARMACOKINETICS AND I DID WORK WITH A DRUG CALLED ON, GF, OPILOT PROJECT ODE GROWTH FACTOR AND YOU WANT TO STUDY THE ROUTE OF ADMINISTRATION BUT WHEN WE DID THIS STUDY, WE USED THE TYPICAL DOSE ESCALATION STUDY, CLASSICICALLY BY 3 DESIGN WHERE YOU ENROLL 3 PEOPLE AT 1 DOSE. AND THE DOSE YOU CHOOSE SHOULD BE, YOU START OFF ABOUT A HUNDRED TO A THOUSAND FOLD LOWER THAN THE DOSE THAT YOU MAYBE USE IN ANIMALS. SO WHEN I DID THIS STUDY, THE VERY FIRST TIME I KNEW THAT I HAD USED A CERTAIN DOSE IN MY MICE, SO WE USED THE LOWER DOSE AND THE VERY FIRST PATIEN I GAVE IT TO, ENDED UP IN THE HOSPITAL IN THE EMERGENCY ROOM THAT WEEKEND AND I HAD TO MAKE A DECISION, YOU KNOW WAS IT MY DRUG THAT MADE HER GET SICK OR WAS IT BECAUSE SHE HAD METASTATIC PANCREATIC CANCER AND SO I WENT AHEAD AND I ENROLLED THE NEXT 2 PATIENTS AND THEY DID JUST FINE. SO WE ESCALATED AND WE ACTUALLY ENDED UP GOING FROM THE 50, FROM THE 25 DOSE ALL THE WAY UP TO 250. SO THE PATIENT ACTUALLY HAD JUST GOTTEN SICK BECAUSE OF HER CANCER. SO I’M GOING TO TELL YOU ABOUT SOME OF THE RESEARCH I DO WITH PANCREATIC CANCER AND CLINICAL TRIALS WE’RE WORKING ON AND HOW YOU CAN TAKE AN IDEA FROM THE BENCH TO THE BEDSIDE. ANYBODY HERE WORKING ON PANCREATIC CANCER? NOBODY. AH, OKAY. WELL. COME ON, I NEED SOME COMPETITION WELL IT’S THE THIRD LEADING CAUSE OF CANCER RELATED DEATHS IN THE UNITED STATES. ABOUT 53,000 PEOPLE A YEAR, AND THE MEDIAN SURVIVAL UNFORTUNATELY IS ONLY 3-6 MONTHS AND ONLY ABOUT 6% SURVIVE 5 YEARS. THIS SURVERIFIAL RATE HAS NOT CHANGED IN THE PAST 50 YEARS IN SPITE OF ALL OF OUR TECHNOLOGY, ALL OF OUR PET SCANS, DIAGNOSTICS, TREATMENTS, NOTHING HAS BEEN EFFECTIVE. SO THE DEATH RATE FROM PANCREATIC CANCER IS ACTUALLY INCREASING. AND YOU CAN SEE OVER HERE THAT IT IS GOING TO–IT’S ALREADY SURPASSED COLO RECTAL CANCER AND IT’S SURPASSING BREAST CANCER AND IT’S GOING TO BE SOON–IF I CAN GET THAL TO WORK–SECOND TO LUNG CANCER BY 2020. SO THESE ARE OUR CURRENT TREATMENTS FOR BREAST CANCER WITH CHEMO THERAPY AND THE 1 ON THE LEFT IS FOLFIRINOX, AND THEY GOT ABOUT 11 MONTHS BUT AS YOU GET DOWN TO THE NUMBERS TOWARDS THE END THERE ARE VERY FEW PATIENTS STILL ALIVE. THOSE ARE THE NUMBER OF PATIENTS. AND THEN OUR OTHER STANDARD TREATMENT IS GEMOCIIT, ABIXINE, AND THAT INCREASED SURVIVAL FROM 6 MONTHS UP TO ABOUT 8 MONTHS. SO NEITHER 1 OF THOSE GOT–THAT WEIGH OUR STANDARD. THAT’S THE BEST WE’RE DOING TODAY. NEITHER OF 1 OF THEM IS EVEN AT 1 YEAR. SO WHY, WHY IS THE PROGNOSIS SO POOR WITH PANCREATIC CANCER. WELL 1 OF THE PROBLEM SYSTEM THAT 90% OF THE PEOPLE WHO ARE DIAGNOSED WITH PANCREATIC CANCER IT’S ALREADY SPREAD BEYOND THE PANCREAS. IT’S VERY METASTATIC AND BECAUSE OF THAT THEY’RE NOT AMENABLE TO SURGERY. BUT WE DON’T HAVE ANY SCREENING TESTS FOR PATIENT WHO IS MIGHT BE AT HIGH RISK. WE DON’T HAVE, LIKE BREAST CANCER, YOU CAN SCREEN WITH MEDICARE AND MEDICAIDING MAMMOGRAPHY, WE CAN’T SCREEN COLONOSCOPYS LIKE WE CAN FOR COLO RECTAL CANCER AND THERE’S NO SCREENING TEST AND THE CURRENT SCAT SCANS AND MRIs ARE NOT SENSITIVE ENOUGH TO PICK IT UP IN THE EARLY STAGES. AND IT’S ALSO RESISTANT TO CHEMO HER ACTIVITIES AND THERAPY AND
IMMUNOTHERA
PY. EVERYTHING WE TRIED TO TREAT PANCREATIC CANCER WITH HAS FAILED. SO MY RESEARCH AND DR. MOODY IS AN EXPERT IN THIS FIELD. THERE ARE 3 RECEPTORS, A, B, C. AWAS DISCOVERED IN THE ALIMENTORSHIP SKILLARY TRACT AND B-WAS IN THE BRAIN AND C-WAS A SPLICE VARIANT THAT’S ONLY FOUND IN PANCREATIC CANCER. SO THE CCK RECEPTORS ARE CLASSIC G-PROTEIN RECEPTORS THAT HAVE A 7 TRANSMEMORY RESPONSE BREAN DOMAIN AND THE CCK AND GHAST RIN ARE THE MAJOR LIGANDS FOR THE RECEPTOR AND THEY HAVE THE SAME TERMINAL TYPE OF PEP TIDE AND THAT’S HOW THEY COMBINE TO THE SAME RECEPTOR WITH DEFINITE AFFINITY. SO, WHAT IS ALCOHOL O CYSTIC KINEIN, TO REFRESH YOU WITH YOUR PHYSIOLOGY, THIS IS A LIVER, THAT’S A PANCREAS, THAT’S A GALLBLADDER, SO WHENEVER YOU EAT AND ESPECIALLY WHENEVER YOU EAT SOMETHING HIGH IN FAT, PREFATTY ACIDS AND CERTAIN AMINO ACIDS GET INTO THE SECOND PORTION OF THE DUDE NUM, AND THAT I SIMULATE THE RELEASE OF THE ICELLS IN THE DUODENUM, AND CCK IS A CLASSIC HORMONE SO IT GETS INTO THE BLOOD STREAM AND CIRCULATES TO THE RECEPTORS AND PANCREAS AND IT CAUSES THE PANCREAS TO SECRETE THE ENZYMES TO HELP YOU DIGEST YOUR FOOD. IT ALSO CAUSES CONTRACTION OF THE GALLBLADDER SO THAT IT WILL HELP YOU EMULSIFY YOUR FAT AND GIVING–YOU JEST YOUR FAT AND CAUSES RELAXATION OF THE SNINKTER OF ODI, SO GHAST RIN IS THE OTHER PEP TIDE THAT BINDS TO CCK RECEPTORS AND GHAST RIN IS MADE IN THE GCELLS IN THE AN THRUM OF THE STOMACH, SO THE STOMACH IS DIVIDED IN HALF, YOU HAVE THE ENDOKRIN AND THE EXOKRIN, THEY RELEASE THE GAS CELLS, GET IN THE BLOOD STREAM AND ACTOT CHROMATIN CELLS WHICH ALSO SECRETE HISTAMINE IF ANY OF YOU ARE FAMILIAR WITH PEP SID AC OR SWRAN TACK THOSE ARE HISTAMINE BLOCKERS, H2 BLOCKERS AND THEY BLOCK ACID BY BLOCKING OF THE HIOF THEA–HIOFHISTAMINE. SO REGARDLESS OF WHATEVER IS SIMULATING THE PARIETAL CELL TO SECRETE ACID WHETHER IT’S THE HISTAMINE, ASIT O CHOLINE OR GHAST RIN, THE END RESULT IS THE PROTON PUMP WHICH SECRETES THE ACID. AND SO, IF YOU DON’T SECRETE–IF YOU BLOCK THIS WITH A PROTON PUMP INHIBITOR, NECKSIUM, LITTLE PURPLE PILL THAT EVERYBODY IS SO GOOD FOR THEIR HEART BURN, THE PROBLEM S&P THAT IT BLOCKS THE NORMAL FEEDBACK SO GATTRIN IS BEING–IF THE PROTON INHIBITORS ARE BLOCKED HERE, GASTRIN WILL GO UP BECAUSE YOU’RE NOT MAKING ENOUGH ACID. AND WHEN THAT GOES UP, 1 THINK THIS I SEE WHEN I SCOPE THESE PATIENTS IS YOU GET ALL THESE POLYPS IN THE STOMACH AND THESE POLARIZED ITCHS ARE BECAUSE THE CHROMATIN CELLS ARE STIMULATED AND GASTRIN IS A TERRIFIC HORMONE AND IT STIMULATES GROWTH. SO IT STIMULATES GROWTH IN ANIMAL MODELS AND CAN CAUSE GASTRINNOIDS IN CANCER. SO PEEZ WE FOUND THE CCK B-RECEPTORS ARE OVER EXPRESS INDEED PAN KRETATTIC CANCER COMPARED TO NORMAL CANCER AND WE FOUND IF YOU TREATED CANCER CELLS WITH GASTRIN OR CCK THAT IT STIMULATES THE GROWTH IN CELL CULTURE AND THAT’SOT FAR RIGHT. AND WHAT WE FOUND, WHAT WE LOOKED AT WHAT TYPE OF RECEPTOR WAS ON THE CANCER CELLS WE FOUND IF WE TREATED THE CANCER CELLS WITH GHAST RIN WE COULD STIMULATE THE GROWTH BUT IF WE ADDED IT WITH THE CCK ANTAGONIST, IT DID NOTHING BUT WE COULD BLOCK THE EFFECT WITH THE CCK B RECEPTORRAN TAGANIST. SO THAT LET US KNOW IF THE CANCER CELLS HAVE BOTH STAY WITH AAND B RECEPTOR THAT’S RESPONSIBLE FOR THE GROWTH. AND THEN WE SHOWED ALSO AN IN ANIMAL MODELS IF YOU TREAT THE ANIMALS WITH GHAST RIN, CAN YOU STIMULATE THE GROWTH OF THEIR PANCREATIC CANCER AND CAN YOU BLOCK THE EFFECT WITH AN ANTAGONIST WITH THE GASTRIN OR B-RECEPTOR. WE FOUND THAT THE GASTRIN AND CCK B RECEPTOR ARE TURNED ON EARLY IN THESE PRECURSOR LEGIONS CALLED PAN AND LESIONS IN THE PANCREAS AND THE PANDA LESION IS THE SAME THING TO PANCREATIC CANCER AS A POLYP IS TO COLON CANCER, IT’S A PRECANCEROUS LESION AND THEY GET TURNED ON VERY EARLY AND IT CAUSE ITS TO PROGRESS. SO WE STAINED–WE HAD TRANSGENIC KRASE MODEL MUTANT MICE THAT GET THESE PANIN LESIONS AND WE SHOWED IF WE STAIN IT FOR CCK B RECEPTORS THAT THEY’RE MARKETEDLY OVEREXPRESSED IN THE MOUSE PANCREAS WHICH IS REALLY SURPRISING BECAUSE THE MOUSE PANCREAS HAS THE A-RECEPTORS BUT UNDER THE INFLUENCE OF KRASE MODEL, THEY MAKE BRECEPTORS. SO WE TOOK OUR TRANSGENIC KRAS MICE AND PUT THEM IN THEIR DRINKING WATER A CCK ANTAGONIST TO BLOCK THE RECEPTOR AND THEN AFTER SEVERAL MONTHS WE TOOK THE AGED-MATCHED MICE AND ON THE TOP YOU CAN SEE A CONTROL MICE THAT THEIR PANCREAS WAS COMPLETELY REPLACED WITH THESE PRECANCEROUS LESIONS AND EARLY CARCINOMA WHEREAS THE MOUSE THAT WAS ON THE CCK RECEPTOR ANTAGONIST THERAPY THE SAME AGE, HAD VERY FEW IF ANY OF THESE LESIONS. AND WE HAD WAITED ACTUALLY TILL THE MICE WERE 3 OR 4 MONTHS OLD WHEN WE STARTED THE TREATMENT BECAUSE WE WANTED TO MAKE SURE THAT THEY ALL HAD SOME HAMMONDS. THIS WAS AN EYELET SELL IN THE PANCREAS. SO WITH PANCREATIC CANCER, WE TALK ABOUT TANNINS WHICH WERE THE PRECANCEROUS LESIONS BUT IF YOU CUT OUT THE CANCER THEY ONLY MAKE UP ABOUT 20% OF THE WHOLE TUMOR AND THE REST OF THE TUMOR IS MADE UP OF TROAMA OR FIBROSIS. AND THERE’S A LOT OF THINGS THAT PLAY A ROLE IN CONTROLLING THE GROWTH OF PANCREATIC CANCER INCLUDING THAT THERE’S A LACK OF TUMOR INFILTRATING CELLS AND THERE’S INHIBITORY TREGULATORY CELLS THAT SUPPRESS THE NORMAL IMMUNE SYSTEM FROM FIGHTING THE PANCREATIC CANCER. SO THERE’S A LACK OF THE CD8 CELLS AND AN INCREASE IN THE T-REGULATORY CELLS. AND THEN THIS FIBROSIS, IT’S THOUGHT THAT THAT MAY PREVENT OUR CHEMO THERAPY FROM GETTING INTO THE CANCER AND THERE’S BEEN STUDIES THAT SHOW THAT THE MORE FIBROSIS THAT’S THERE, THE LESS PEOPLE WILL RESPOND TO THE CHEMO THERAPY. SO, THIS IS A–THIS IS A STUDY DONE BY BERNA, THAT THERE ARE CCK RECEPTORS ACTUALLY ON THE PANCREATIC STELLATE CELLS AND THESE ARE THE 1 BLASTS THAT CALL ALL THAT FIBROSIS OF THE MICRO ENVIRONMENT. AND THIS WAS A PICTURE WE STAINED THEM FOR THE CCK B-RECEPTOR AND THEY WERE POSITIVE. SO WE DID A SIMILAR STUDY ON OUR MICE AND IF WE PUT THEM ON THE CCK ANTAGONIST, CAN WE BLOCK THE FIBROSIS TOO? SO INDEED WE DID. SO THE BLUE STAIN IS A MASON’S TRI KROAB STAIN AND YOU CAN SEE THE AGE-MATCHED MICE THERE’S MUCH LESS FIBROSIS BECAUSE THE CCK RECEPTOR ANTAGONIST BLOCKED THE FIBROSIS. AND THEN THE THIRD CELL THAT CCK RECEPTORS ARE FOUND ON ARE THE IMMUNE CELLS. AND THE IMMUNE CELLS, MEANING THE LYMPHOCYTES HAVE BOTH CCK A AND B RECEPTORS. AND THAT’S IMPORTANT BECAUSE AS THE CANCER PROGRESSES FROM NORMAL TO CANCER ON THE FAR RIGHT THERE, THE T-CELLS, THE T-REGULATORY CELLS INCREASE AND THEY SUPPRESS OUR OWN HOST AND IMMUNE SYSTEM FROM FIGHTING OFF THE CANCER AND THE CD8 CELLS OR THE TKILLER CELLS DECREASE. SO WE DID SOME STUDIES AND A LOT OF RESEARCH IS CHANGING. WE USED TO DO HUMAN CANCER STUDIES IN NUDE MICE BUT THE PROBLEM IS THEY NUDE MICE DON’T SO IF YOU’RE INTERESTED IN LOOKING AT THE IMMUNITY OR WHAT’S GOING ON IN THE MICRO ENVIRONMENT, YOU HAVE TO USE A MOUSE WITH A NORMAL IMMUNE SYSTEM. AND WITH ALL OF OUR NEW IMMUNE CHECK POINT ANTIBODIES YOU HAVE TO USE AN ANIMAL MODEL THAT HAS AN IMMUNE SYSTEM. SO, THEY’VE BEEN DEVELOPING MORE AND MORE ANIMAL MODELS THAT ARE MORE SIMILAR TO HUMANS THAN HAVE AN INTACT IMMUNE SYSTEM. SO IN OUR STUDIES WE USE C57 BLACK 6 MICE OR TRANSGENIC MICE THAT HAVE AN INTANKT IMMUNE SYSTEM SO CAN YOU STUDY IMMUNE CHECK POINT ANTIBODIES. SOPHISTICATEDY WE DISCOVER THAT 1 OF THE PROBLEMS WITH PANCREATIC CANCER IS THAT IT DOESN’T TYPICALLY RESPOND TO IMMUNE THERAPY AND THE REASON IT DOESN’T RESPOND IS BECAUSE THERE’S NO CD8 CELLS IN THE TUMOR OR TO ATTACK THE TUMOR AND THEN ALSO YOU HAVE THIS FIBROSIS, AND THE T-REGULATORY CELLS IN THE MICRO ENVIRONMENT THAT PRESENT IT FROM THIS–THE IMMUNE CHECK POINT ANTIBODIES FROM WORKING. SO WE CAME UP WITH A HYPOTHESIS THAT IF WE TREATED PANCREATIC CANCER, WITH CCK RECEPTOR BLOCKADE, WE COULD DECREASE THE FIBROSIS, AND WE COULD ALTER THE IMMUNE SIGNATURE OF THE MICROENVIRONMENT AND MAKE IT MORE SUSCEPTIBLE TO IMMUNE CHECK POINT ANTIBODIES. AND ACTUALLY THAT’S WHAT WE FOUND. SO THESE ARE ANIMALS WHO WERE GETTING TBS OR THE IMMUNE CHECK POINTS OR THE ANTAG NIFULT BY ITSELF, BUT WHEN WE ADDED THEM UP TOGETHER IN THE COMBINATION, THE TUMORS DID NOT GROW. AND THE REASON THEY DIDN’T GROW, WE LOOKED AT THE INSIDE OF THE TUMORS IMMUNE O CHEMICALLY AND WE FOUND THAT THE CD8 CELLS GO UP WHEN WE GIVE A COMBINATION AT THE IMMUNE CHECK POINT, ANTIBODIES ALONG WITH OUR CCK ANTAGONIST AND THE TREGULATORY CELLS GO DOWN. WE ALSO SHOW THAT THIS IMPROVED SURVIVAL OF OUR MICE IN THAT ONLY THE MICE GET THE COMBINATION THERAPY WERE A LIVE AT THE END OF THE STUDY. THE OTHER IMPORTANT FINDING WAS THAT WE SAW THAT ONLY THE, CK ANTAGONIST REVERSED THE FIBROSIS, NOT THE IMMUNE CHECK POINT ANTIBODY. SO THE EMUNE CHECK POINT ANTIBODIES BY THEMSELVES WERE NOT EFFECTIVE. SO WHAT WE’VE DONE DO YOU SENSE WE COMPLETED THAT IN ANIMALS, WE DESIGNED A CLINICAL TRIAL TO DO THE PHASE 1, PHASE 2 TRIAL AND WE WILL USE OUR CCK RECEPTOR ANTAGONIST ALONG WITH IMMUNE CHECK POINT ANTIBODY AND WE ARE GOING TO DO A PILOT TRIAL IN ATIENTS, WE ARE GOING TO FIGURE OUT WHAT THE MAXIMUM TOLERATED DOSE IS OF OUR CCK ANTAGONIST AND WE WILL WORK WITH A COMPANY THAT HAS ALREADY APPROVED OUR PROTOCOL AND WE WILL TREAT PATIENTS WHO HAVE PANCREATIC CANCER. SO WHERE WE ARE RIGHT NOW, WE SECURED INTELLECTUAL PROPERTY, WE’RE GETTING THE IND NUMBER, WE HAVE A SOURCE FOR OUR ANTAGONIST, I HAVE AN INDUSTRY PARTNER OF AND OF COURSE I’M WAITING FOR THE FUNDING AND HOPEFULLY THAT WILL COME THROUGH. SO NOW THE OTHER PROBLEM I MENTIONED WITH PANCREATIC CANCER IS THAT THERE’S NO BIOMARKERS, THERE’S NO WAY TO SCREEN PATIENTS THAT MIGHT BE AT HIGH RISK, CAT SCANS, PET SCANS, MRIs ARE NOT SENSITIVE ENOUGH. SO WHAT ARE WE GOING TO DO? AND ARE THERE ANY BLOOD TESTS OR ANYTHING THAT WE CAN DO TO EVALUATE PATIENTS? SO MANY YEARS AGO WHEN I WAS DOING JUST A REGULAR PC R TRYING TO FIGURE OUT WHAT TYPE OF RECEPTORS PANCREATIC CANCER HAD, I FOUND THAT COMPARED TO NORMAL PANCREAS, THERE WAS THIS BIGGER PC R PRODUCT IN SOME OF OUR PANCREATIC CANCER PATIENTS AND YOU GUYS DON’T DO A SOUTHERN ANYWHERE BUT THAT’S A SOUTHERN BLOT BELOW THAT BUT THERE’S ABOUT A 200 BASE PAIR DIFFERENCE BETWEEN PANCREATIC CANCER AND THE CCK RECEPTOR NORMAL PANCREAS AND ACTUALLY WHAT WE FOUND OUT WAS THAT IN UP TO 35 TO 40% OF PATIENTS WHO HAD PANCREATIC CANCER, THEY HAD A SINGLE NUCLEOTIDE POLYMORPHISM THAT CAUSED THIS SLICING OF THE CCK B RECEPTOR GENE. WHEN THIS OCCURS, THE FOURTH INTRON IS SPLICED OUT AND TRANSLATED INTO PROTEIN. SO THIS CORRELATES WITH THE SNP THAT WE FOUND AND THE REASON WHY WE COULDN’T DO THIS IN MICE AND IT NEVER WOULD HAVE BEEN FOUND IF WE WERE JUST WORKING WITH MICE RATHER THAN HUMAN PLOOD AND TISSUE SAMPLES IS BECAUSE IN HUMANS THE FOURTH INTRON HAS AN OPEN READING FRAME BUT IN MICE OR RATS THERE’S A TOP CO DON. SO WE COULD LOOK ALL WE WANTED IN OUR ANIMAL MODEL BUT WE FOUND THIS DISPLACED VARIANT BUT WE DID FIND THERE IS A SNP. AND THE SNP IS VERY IMPORTANT BECAUSE IT MAY PREDICT WHO MIGHT BE AT RISK OF GETTING PANCREATIC CANCER. SIMILAR TO THE BRACKET TUBE WITH BREAST CANCER, BRACCA 1 WITH OVARIAN CANCER. THE OTHER IMPORTANT THING IS WHERE THIS OCCURS IS IN THE THIRD INTRA CELLULAR LOOP AND WHAT IT DOES, THAT’S THE PART OF THE CCK RECEPTOR THAT STIMUMENTS GROWTH. AND SO, HYPOTHESIZED, WELL IF THEY HAVE THIS EXTRA PIECE BECAUSE THE FOURTH INTRON IS TRANSLATED INTO PROTEIN, MAYBE PEOPLE WHO HAVE THIS SNP–THEIR CANCERS GROW MUCH FASTER AND THAT HAVE ACCELERATED GROWTH. WE DID MAKE AN ANTIBODY TO OUR SNP PROTEIN, BUT DISTINGUISHES IT FROM THE REGULAR CCK B RECEPTOR AND YOU CAN IMAGE THE CANCER SELLS THAT HAVE THIS GENO TYPE FOR THE SNP AND THEY EXPRESS THE SPLICE VARIANT OR WE CALL THE CCK C RECEPTOR. SO WE DID A PAY LOT TRIAL, AND WE TOOK 110 PATIENTS AND WE TOOK BLOOD SAMPLES FROM THEM AND WE CONFIRMED IT–WE ALSO DID TISSUE SAMPLES AND THEN WE SAW THAT THEIR SURVIVAL WAS EFFECTED WITH WHETHER THEY HAD THE SNP OR NOT AND THEN WE DID A LARGER TRIAL IN ALMOST PATIENTS TO CONFIRM OUR RESULTS AND THAT’S ANOTHER TYPE OF CLINICAL TRIAL ONCE YOU DO YOUR PILOT TRIAL AND WE DID SHOW THERE FTION A DIFFERENT IN SURVIVAL WITH THE SNP, SO THEY’RE HOPING AND NOW WE IDENTIFY THIS SNP IF IN CANCER BY EASILY DOING A BLOOD SAMPLE OR A BUCKLE MUCOSEIS SWAP, WE MIGHT BE ABLE TO IDENTIFY PEOPLE AT HIGH RISK OF GETTING PANCREATIC CANCER. SO THE THIRD PROBLEM IS THAT CHEMO THERAPY IS TOXIC AND IT DOESN’T SPECIFICALLY TARGET PANCREATIC CANCER. A LOT OF CANCER, YOU KNOW IF YOU CAN IDENTIFY A RECEPTOR, THE SURFACE OR WHETHER IT’S ON THE CANCER OR 2 NEW ORLEANS, AND THEN CAN YOU ACTUALLY TARGET YOUR THERAPY. SO THERE ARE NO TARGETS SO FAR FOR PANCREATIC CANCER AND THERE’S NO IMAGING TESTS THAT HAVE BEEN EFFECTIVE IN DETERMINING IT EARLY. SO WE DECIDED WE WOULD TARGET A NANO PARTICLE, IT’S A THERAPEUTIC AND A DIAGNOSTIC COMPOUND. SO WHAT’S A NANO PARTICLE? AND THIS KINDS OF PUT IT IN PERSPECTIVE, NANO MEANS BETWEEN 10 AND HUNDRED NANO METERS IN SIZE. AND JUST TO SUMMARIZE WHY WE USE THE CKK RECEPTOR AS A TARGET, IF YOU LOOK ON THE LEFT, IN THE NORMAL PANCREAS, THERE ARE SOME CCK RECEPTORS ON THE CELL SURFACE, AND CCK OR GASTRIN CAN BIND TO THE RECEPTOR AND WHEN THEY DO THAT THEY SECRETE YOUR DIGESTIVE ENZYMES SO IN PANCREATIC CANCER, CANCERRARY NOT INTERESTED IN DIGESTING YOUR FOOD AND CANCERS INTERESTED IN PROLIFERATING SO WHEN THE RECEPTOR IS STIMULATED, THE CANCER CELLS GROW. AND THEN, WHAT HAPPENS IS, SOMETHING TURNS ON GASTRIN AND THE GASTRIN STARTS BEING PRODUCED BY THE PANCREATIC CANCER CELLS SO IT STIMULATES GROWTH BY AN AUTOCRINE MECHANISM AND THE LITTLE LOOP HERE IS THE SPLICE VARIANT WITH THE CCK RECEPTOR WHICH IS PRESENT IN ABOUT 40% OF PATIENTS. DIFFERENT TYPES OF NANO PARTICLES. ONE OF THEM IS A NANO LIPO STUDIES OF MULTIPLE ENDOCRINE, 1 IS A CALCIUM PHOSPHATE NANO PARTICLE. AND WE CAN DESEEN THEM SO THEY CAN–DESIGN THEM SO THEY CAN CARRY SIRNA AND THEY CAN KNOCK DOWN GASTRIN ON THE CANCER AND WE PUT IT OUTSIDE SO IT CAN BIND SPECIFICALLY TO THE CKK B RECEPTOR AND THEN WE CAN LOAD THESE PARTICLES WITH EITHER A FLUOROFLOR OR MAG NONAPOPTOTIC TIGHT SO WE CAN E DENTIFY IT FOR IMAGING OR WITH MRI. SO WE’VE ALSO DESIGNED A SPECIAL WAY WE CAN FIND A DNA APTAMER BY DEVELOPING THE SELEX METHOD AND THIS BINDS SELECTIVELY TO THE CKK B RECEPTOR AND DOES NOT STIMULATE GROWTH. SO WE HAVE TAKEN THIS AND CO VALENTINEDENTLY PUT ON THE NANO PARTICLES SO THE NANO PARMS WILL DELIVER WHATEVER WE WANT THEM TO DIRECTLY TO CANCER AND THEY WILL BIND TO THE CANCER–TO THE CKK RECEPTOR. THIS IS JUST A PICTURE OF A COUPLE OF MICE HERE ON THE LEFT. THESE WERE INJECTED WITH NANO PARTICLES THAT HAD INDOCIDE IN GREEN IN THEM FOR FLUORESCENCE AND THEY WERE NOT TARGETED TO THE CCK RECEPTOR AND AT 7 HOURS AND 24 HOURS, THERE’S NOTHING LEFT. HOWEVER IN THE MOUSE THAT HAS AN ORTHOTOPIC PANCREATIC CANCER GROWING IN ITS PANCREAS, WHEN THEY WERE INJECTED WITH THE NANO PARTICLES WITH THE TARGETED NANO PARTICLES CARRYING THE CHLOR O FLOR, YOU CAN SEE IT’S 7 HOURS AND THEN 24 HOURS LATER, THE STILL CONCENTRATE INDEED THE TUMOR IN THE PAN REAS, SO WE’VE NOW DEVELOPED A TARGET THAT WILL SELECTIVELY TARGET PANCREATIC CANCER AND IT CAN CARRY FLUOROCHLORS SO WE MIGHT BE ABLE TO USE HAD THIS FOR DIAGNOSIS AND IMAGING FOR PEOPLE WHO HAVE SMALL AND EARLY CANCERS. ANOTHER WOB OF THE NANO PARMS WE DECIDED IS CALLED A COMPLEX MICE CELL AND IT ACTUALLY IS MADE UP WITH POLYLISINE TAIL WHICH IS POSITIVELY CHARGED AND WHEN WE ADD IT TO THE SIRNA, IT FORMS A MY SELL AND WE HAVE THE APTAMER MEROT OUTSIDE HERE SO IT’LL BIND TO THE RECEPTOR, THE SIRNA IS ON INSIDE SO IT’S PROTECTED FROM THE BLOOD AND DOES NOT DEGRADE AND WE HAVE POLYETHYLENE GLYCOL SO IT DOESN’T CONGLAMERATE IN THE BLOOD AND THE BLOOD CELLS DON’T TAKE IT UP AND WE’VE ALREADY DONE STUDIES IN MICE WHERE WE SHOW THAT IF WE CAN GET THIS NANO PARTICLE INSIDE OUR CANCER CELLS, WE CAN ACTUALLY–WE DELIVERED SIRNA TO GHAST RIN TO SEE IF WE COULD KNOCK DOWN GASTRIN, AND WE COULD KNOCK IT DOWN BY QRTPC R AND WE SHOWED IT WAS KNOCKED DOWN BY PEP TIDE AND THEN WHEN WE TREAT OUR ANIMALS, ONLY THE ANIMALS THAT GOT THE NANO PARTICLES THAT WERE SELECTED FOR THE CCK RECEPTOR AND CARRY THE GASTRIN, SIRNA HAD DECREASED GROWTH. SO THERE’S GREAT POTENTIAL FOR THIS PLATFORM THAT WE COULD TARGET WHATEVER YOUR RECEPTOR OF CHOICE IS. IT CAN CARRY WHATEVER SIRNA YOU WANT, IF YOU WANT TO KNOCK DOWN SOMETHING, THIS CAN DO IT. ALSO THERE ARE CCK RECEPTORS AND OTHER CANCERS LIKE GHASTIC CANCER, COLON CANCER, MEDULARY CANCER AND LUNG CANCERS. SO,–SO WE HAVE A–WE HAVE A TEAM OF SCIENTISTS AND WE’RE HOPING WE APPLIED TO BE 1 OF THE AACR DREAM TEAM STAND UP TO CANCER AND AGAIN, TO TAKE SOMETHING LIKE THIS WITH OUR NANO PARTICLES AND TAKE IT TO THE CLINIC, IT’S GOING TO TAKE A WHOLE TEAM OF SCIENTISTS. I MEAN I’M A CLINICIAN SCIENTIST. WE HAVE AN ONCOLOGIST WORKING WITH ME, WE HAVE SOMEBODY WHO’S A MATERIAL SCIENCE ENGINEER WHO HELPED DESIGN THIS, I HAVE AN IMAGINGLY ENGINEER, PHARMACOLOGIST, TOXICOLOGIST, PROJECT MANAGER AND WE HAVE PATIENT ADVOCATES TO MAKE SURE THAT WE ARE DOING THE RIGHT THINGS AND SPENDING MONEY WISELY. SO THAT’S TAKING AN IDEA, YOU FIND OUT THERE’S A PROBLEM, NO WAY TO DIAGNOSE PANCREATIC CANCER IN THE EARLY STAGE. SO WOE FOUND A RECEPTOR AND WE CAN TARGET IT. SO WHAT ARE THE OBSTACLES WITH TRANSLATIONAL RESEARCH TODAY, WELL OF COURSE, THE BIGGEST OBSTACLE IS MONEY. IT COSTS MONEY TO TAKE ANY PROG OCT FROM THE BENCH TO THE BODY BODY–BEDSIDE, AND IS THERE A LACK OF FUNDS? MISUSE OF FUNDS? DISPARITY OF FUNDS? WHATEVER, IT TAKES A LOT OF MONEY TO DEVELOP THESE IDEAS. OOM A–I’M A CLINICIAN SCIENTIST SO I CAN SAY CLINICIANS DON’T GET PROTECTED TIME TO DO TRANSLATIONAL RESEARCH. THEY WOULD RATHER HAVE ME IN THE CLINIC DOING COLONOSCOPYS BECAUSE THEY THINK IT MAKES MORE MONEY AND HELPS MORE PEOPLE, BUT YOU KNOW IN THE LONG RUN, YOU KNOW COMING UP WITH A CURE OR DISCOVERY FOR A CANCER IS I THINK MUCH MORE IMPORTANT. BUT IT’S GETTING THERE THAT DOESN’T PAY AS MUCH AS FAST. THERE IS THIS BIG DIVISION BETWEEN INDUSTRY, I THINK AND THE NIH AND ACADEMIA. YOU KNOW INDUSTRY LIKES TO COME UP WITH THEIR OWN IDEAS BECAUSE THEY WANT TO HAVE THE PATENT RIGHTS AND EVERYTHING, IF YOU COME UP WITH AN IDEA, YOU HAVE TO LICENSE IT TO THE COMPANY AND THEY HAVE TO PAY YOU. SO THEY WOULD RATHER COME UP WITH THEIR OWN AND THAT OF COURSE, INDUSTRY ALWAYS COMES UP WITH WHAT I CALL THE ME TOO DRUGS, AS SOON AS 1 GETS A DRUG, THERE’S A ME TOO DRUG AND THEY’RE ALL THE SAME BUT THEY MODIFIED IT A LITTLE BIT. THEN THERE’S PROBLEMS GETTING PATIENTS TO GO INTO RESEARCH STUDIES AND IF I CAN TALK TO CONGRESS, I COULD TELL THEM WHEN THEY’RE COMING UP WITH A HEALTHCARE BILL, THEY SHOULD TELL PEOPLE IF THEY ENROLL IN A RESEARCH STUDY THAT THEY WILL GIVE THEM A DISCOUNT BECAUSE THAT WILL GET MORE PEOPLE INTO RESEARCH STUDIES AND HELP KEEP OUR COST DOWN FOR HEALTHCARE. BECAUSE THEN IT WILL BE COVERED BY THE RESEARCH STUDY: AND OF COURSE, THERE’S NO MORE 1 MAN BAND. YOU NEED A WHOLE TEAM OF SCIENTISTS TO DO A PROJECT. AND THE PROGRAM LINE IS, DOES THE RESEARCH REALLY HAVE ANY CLINICAL RELEVANCE? THESE ARE A COUPLE OF MY PATIENTS WHO WITH THEIR PERMISSION LET ME SHOW THEIR PICTURES. THEY HAD FAILED STANDARD CHEMO THERAPY FOR PANCREATIC CANCER AND THEY ENROLL INDEED MY RESEARCH STUDIES AND THEY’RE HAPPY TO TALK ABOUT PARTICIPATING IN RESEARCH. AND WE NEED MORE PATIENT ADVOCATES LIKE THIS THAT WILL SUPPORT RESEARCH. AND THEN, WHAT ABOUT OUR CCK ANTAGONIST? WHAT’S THE POTENTIAL SIDE EFFECT? WELL IT MIGHT BE DECREASE HEART BURN. I THINK THAT WOULD BE A BENEFICIAL SIDE EFFECT, THERE ARE CCK RECEPTOR AS WE TALK ABOUT IN THE STOMACH BUT IF WE DELIVERAUR GASTRIN RNA TO THE STOMACH THOSE DON’T MAKE GASTRIN SO THERE WON’T BE HARM BUT OUR ANTAGONIST IF WE BLOCK THE RECEPTOR WE WILL PROBABLY HAVE LESS ACID. THESE DRUGS WERE ACTUALLY DEVELOPED 20 YEARS OR MORE AGO TO TREAT PEPTIDE OIC ULCER THE PROTON PUMP INHIBITORS THEY HAVE FALLERN OFF THE WAY SIDE, THEY’RE NO LONGER UNDER PATENT AND PEOPLE HAVE LOST INTEREST IN THEM BECAUSE THE PROTON PUMP INHIBITORS ARE A BILLION DOLLAR BUSINESS. AND SO, PEOPLE HAVE FORGOTTEN ABOUT THESE DRUGS BUT THEY MIGHT HAVE ANOTHER USE. SO YOU NEED TO THINK ABOUT THAT WHEN YOU’RE DOING RESEARCH TOO, IS ABOUT REPURPOSING OLD DRUGS. THEY MAY BE BENEFICIAL FOR ANOTHER CAUSE. I JUST WANT TO THANK MY COLLABORATORS THAT HELPED ME WITH RESEARCH AND OF COURSE ALL OF MY ANIMAL VOLUNTEERS. SO I’M HAPPY TO TAKE ANY QUESTIONS. [ APPLAUSE ] YES?>>[INDISCERNIBLE].>>THAT’S AN EXCELLENT QUESTION AND THERE’S A POSSIBLE HYPOTHESIS. ONE, IS THE OBESITY AND THE METABOLIC SYNDROME. HIGH FAT DIETS IT’S WELL KNOWN IT COUNTRIES THAT CONSUME HIGH FAT DIETS THE INCIDENCE OF PANCREATIC CANCER IS SKITTOMA ROCKETING, WE KNOW HIGH FAT STIMUMENTS CKK, IT BINDS TO THE CKK RECEPTOR ASK THEY MAY STIMULATE THE GROWTH OF PANCREATIC CANCER. THE OTHER POSSIBILITY AND YOU KNOW, I’LL GO ALTHOUGH THE INDUSTRY DOESN’T WANT TO HEAR ME SAY THIS IS THAT FOR THE PAST 20 YEARS WHEN THE INCIDENTS OF PANCREATIC CANCER HAS NEARLY QUADRUPLES, ALSO HAS THE USE OF PROTON PUMP INHIBITORS. PROTON PUMP INHIBITORS RAISE YOUR GHAST RIN LEVEL AND WE SHOWED IN OUR STUDY THAT THOSE PRECANCEROUS LESIONS IN THE PAN KRE TINS ASWHICH EVERYBODY HAS SOME OF THOSE KIND OF LIKE PEOPLE HAVE POLYPS IN THEIR COLON WE DON’T KNOW WHAT TRIGGERS THEM TO GO ON TO BECOME CARCINOMA INUE IN CANCER AND WE SHOWED WE COULD PREVENT THAT EFFECT IF WE USE THE CCK ANTAGONIST WHICH PLOKINGS THE GHAST RIN. SO IT’S POSSIBLE THAT THE PROTON PUMP INHIBITORS THAT HAVE BEEN OVERLY USED AND ABUSE INDEED THE PAST 20 YEARS ARE RELATED TO THE INCREASED INCIDENCE OF PANCREATIC CANCER. THAT’S MY THOUGHT. SO, OTHER QUESTIONS?>>CLINICAL TRIAL ARE YOU GOING TO SCREEN THE PATIENT FIRST TO MAKE SURE THEY HAVE [INDISCERNIBLE]?>>YES WE ARE. YES WE ARE. SO PATIENTS WILL HAVE BIOPSIES BEFORE THEY START IN THE STUDY AND ALSO ABOUT 4 WEEKS INTO THE STUDY BECAUSE WE’RE INTERESTED NOT ONLY IN THE RECEPTOR DENSITY, AND HOW WELL THEY RESPOND BASED UPON THEIR CCK RECEPTOR NUMBER AND ALSO WE WANT TO LOOK AT THE MICROENVIRONMENT, TOO, TO SEE IF OUR THERAPY WILL BE INCREASING THE INFLUX OF CD8 POSITIVE CELLS AND MAYBE DECREASING FIBROSIS. SO WE’LL BE DOING A SECOND BI APSEY IN OUR CLINICAL TRIAL AND THAT LEADS TO BELTER UNDERSTANDING OF WHAT HAPPENS IN HUMANS, WE KNOW WHAT HAPPENS IN MICE, BUT WE WANT TO KNOW IF THE SAME THING HAPPENS IN HUMANS. YES?>>[INDISCERNIBLE].>>SO A TRANSFECTED CELL WITH CCK LINE RECEPTORS?>>[INDISCERNIBLE].>>SO ALL PANCREATIC CANCER CELL LINES WE HAVE SCREENED IN ALL PANCREATIC CANCERS FROM THE OPERATING ROOM THAT WE HAVE SCREENED, ALL HAVE CCK RECEPTORS. SO WE DID NOT HAVE TO OVEREXPRESS IT AT ALL IN OUR CANCER CELLS. IN THE ANIMAL THAT I SHOWED UP THERE THAT WE DID THE BINDING, IT ACTUALLY WAS BSTC3 WHICH ACTUALLY DOESN’T HAVE AS MANY RECEPTORS AS BANK 1 WHICH IS ANOTHER PANCREATIC CANCER CELL LINE FROM ATCC THAT EVERYBODY USES. WE DO, NOW THAT WE’RE DOING SIN BEGIN AIC MODELS IN AN IMMUNE CONFIDENT MICE, WE’RE USING CELL LINES, THEY’RE CALLED MP3, MPCELL LEANS, THEY WERE RERIEF FRIDAY ORGANOIDS FROM DAVID’S LAB AT COLD STREAM HARBOR AND HE TOOK THE CELLS FROM THESE CANNONS PANINS AND THE CANCERS THAT DEVELOPED FROM THE KRASE MODEL MOUSE AND DEVELOPED THEM AS ORGANOIDS AND DEVELOPED CELL CULTURES AND YOU CAN PUT THEM BACK INTO THE MICE AND THEY RESEMBLE THE HUMAN CANCER VERY WELL BECAUSE THEY HAVE MUTANT KRASE MODEL AND THEY ALSO OVEREXPRESS CCK B-RECEPTORS AND THEY MAKE GASTRIN WHICH OTHERS MAY NOT. SO THEY’RE A GOOD MODEL TO USE WHEN YOU ARE DOING IMMUNE COMPETENT MICE. YES?>>[INDISCERNIBLE].>>SO THE LONGER TERM SURVIVORS AS FAR AS THE PEOPLE WHO HAD THE SNP ALL DIED RAPIDLY. SO THE PANCREATIC CANCER WHETHER YOU HAVE THE SNP OR DON’T HAVE THE SNP IS STILL A POOR PROGNOSIS. THERE ARE SOME LONGER TERM SURVIVAL PATIENTS AND AT LEAST IN OUR STUDY, THE 1S THAT SURVIVE LONGER HAD THE WILD TYPE GENE O TYPE. THE CC-GENOTYPE RATHER THAN THE HETEROGENEOUS ROW ZYGOTE CC, OR THE AA, WHICH IS THE SNP. SO IT MAY BE RELATED TO IT AND WHEN WE DID OUR STUDY THE STATISTICIAN, WHY IT’S IMPORTANT TO HAVE A STATISTICIAN IN YOUR TEAM HE EVALUATED ALL THE DATA AND MADE SURE WE CORRECTED FOR STAGE OF DISEASE SO WE’RE SURE THAT THE SURVIVAL WAS NOT INFLUENCED BY SOMEBODY WHO LIVED LONGER BECAUSE THEY WERE EARLY STAGE DISEASE. SO THEY CORRECTED FOR ALL OF THOSE FACTORS. SO IT MAY BE RELATED TO THAT. YES?>>THANK YOU VERY MUCH.>>[ APPLAUSE ]>>OKAY, IN TERMS OF ANNOUNCEMENTS, NEXT WEEK WE DON’T HAVE CLASS. OUR NEXT CLASS WILL BE 2 WEEKS FROM TODAY. AND LET’S SEE, FILE AND CLOSE. NOW THERE’S KURT’S. OKAY OUR NEXT SPEAKER IS KURT HARRIS, HE GOT HIS M. D. DEGREE FROM THE UNIVERSITY OF KANSAS AND DID A RESIDENCY AT UCLA. HE GOT [INDISCERNIBLE] FOREVER AND HE’S WON NUMEROUS AWARDS. I SAW HIM WITH THE AACR [INDISCERNIBLE] AWARD WHERE HE SPOKE BEFORE THOUSANDS OF PEOPLE AND GAVE AN EXCELLENT TALK. AND HE’S PUBLISHED OVER 500 JOURNAL ARTICLES, HIS CLAIM TO FAME IS HE IS EDITOR IN CHIEF OF THE JOURNAL CAR SIN O GENESIS SO HE WILL TALK TO US ABOUT LUNG CANCER, PRECISION MEDICINE STRATEGY. KURT?>>OKAY. SO I THINK JILL GAVE YOU A VERY NICE PRESENTATION ABOUT PANCREATIC CANCER AND HOW DOJ CLINICAL TRIALS AND I I WILL TALKING TO YOU ABOUT PRECISION MEDICINE AND THEN I’LL USE SOME EXAMPLES OF LUNG CANCER TO ILLUSTRATE THE CURRENT STRATEGIES OF PRECISION MEDICINE INCLUDING THE NCI PRECISION CONSER INITIATIVE. SO–YEP–WE ALL NEED HELP. FANTASTIC. ALL RIGHT. SO, WHEN I WAS GOING THROUGH MEDICAL SCHOOL AND LEARNING MEDICINE, THIS IS WHAT I LEARNED THIS, IS TRADITIONAL MEDICINE, LIFESTYLE, MEDICAL HISTORY, SCIENCE, AND SYMPTOMS, WE ACTUALLY PUT OUR HANDS ON PATIENTS AND DID PHYSICAL EXAMS, AND VARIOUS SIMPLE LABORATORY TESTS AND CHEST X-RAY AND THINGS LIKE THAT. SO PRECISION MEDICINE IS DIFFERENT. IT’S MULTILAYERED, IT’S INDIVIDUAL CENTRIC AND INTERCONNECTED THAT USES INFORMATION, COMMENTS IN THESE VARIOUS OMICs WHICH I WILL BE TALKING ABOUT. SO THE IDEA OF PRECISION MEDICINE FOLLOWS VARIOUS STRATEGIES SUCH AS THOSE CALLED PERSONALIZED MEDICINE AND B-FORM MEDICINE AND SO ON AND SO FORTH, BUT THIS WAS FROM A NIA–NCI–EXCUSE ME, A NATIONAL ACADEMY OF SCIENCE REPORT IN WHICH THERE WAS INFORMATION COMMONS THAT UTILIZES VARIOUS OMICS THAT’SOT FOUNDATION OF CLINICAL INFORMATION AND EPIDEMIOLOGICAL INFORMTION. THIS LEADS TO INFORMATION OR KNOWLEDGE NETWORK AND A BETTER CLASSIFICATION OF PATIENTS. AND THIS–FOR THE OBJECTIVE OF PROVING CLINICAL MEDICINE, OOPS. AND THESE OBSERVAL STUDIES GO BACK TO THE INFORMATION COMMONS TO IMPROVE THE PROCESS. IT ALSO INFORMS BIOMEDICAL RESEARCH TO THINK THAT MOAFULT OF US DO HERE–MOST OF US DO HERE AS SCIENTISTS AND THERE’S A–INFORMED MECHANISTIC STUDIES ALSO GO BACK TO THE INFORMATION COMMONS. WHAT WASN’T PART OF THE PROPOSAL BUT ACTUALLY VARGAS AND I WROTE AN EXTENSIVE REVIEW ON PRECISION MEDICINE AND HIS PREVENTION RESEARCH. SO LET’S FIRST DESCRIBE SOME CLINICAL AND EPIDEMIOLOGICAL DATA. AND AS I SAID, I’M GOING TO BE FOCUSING ON LUNG CANCER, AND THIS COMES FROM A REPORT OF THE SURGEON GENERAL IN 2014 THAT I AND JOHN AND OTHER PEOPLE CONTRIBUTED TO AND THIS IS THE 50th ANNIVERSARY DATE OF THE SMOKING AND ANTISMOKING CAMPAIGN IN STARTING IT. AND THESE ARE THE NUMBER OF INDIVIDUALS WHO HAD PREMATURE DEATH AS CALCULATED BY SMOKING OR EXPOSURE TO SECOND HAND SMOKING IN A 50 YEAR PERIOD IT’S CLOSE TO 21 MILLION PEOPLE. AND THESE ARE THE SMOKING RELATED CANCERS. AND ALSO, CANCERS FROM SECOND HAND SMOKE. AND THEN OTHER CAUSES OF DEATHS RELATED TO SMOKING. THIS KIND OF CHART IN WHICH THESE ARE THE CANCERS PER HUNDRED THOUSAND OF THE POPULATION, YEAR OF DIAGNOSIS ISSUES. THIS GOES TO ABOUT 2014 OR SO. AND MALE CANCER, LUNG CANCER, REACHED A PEAK AND IT RAPIDLY FOLLOWING. IT’S ABOUT ALMOST, NOT QUITE HALF OF WHAT IT WAS, AND THE LUNG CANCER HAS PLATEAUED OFF AND MAYBE STARTED TO DECREASE. SO SMOKING IN THE UNITED STATES, THIS IS THE AMOUNT OF CIGARETTES IN TERMS OF SMOKING AS A PERCENTAGE AND THIS IS OBVIOUSLY THE U.S., IT SUESED TO BE LIKE–USED TO BE LIKE THIS IN WHICH OVER 35% OF THE POPULATION WERE SMOKERS. THERE’S STILL POPULATIONS IN THE UNITED STATES IN WHICH THERE’S HIGH LEVELS–EXCUSE ME IN THE WORLD IN WHICH THERE’S HIGH LEVELS OF SMOKING. SO LUNG CANCER IS INCREASING IN THE UNITED STATES AND DECREASING IN THE UNITED STATES DUE TO ANTISMOKING EFFORTS BUT NOT IN MANY OTHER PARTS OF THE WORLD. NOW NOT ONLY ACTIVE SMOKING BUT PASSIVE SMOKING CAN INCREASE THE RISK OF LUNG CANCER. AND THIS IS A WATER COLOR THAT WAS ACTUALLY DONE BY HIRAYAMA THE EPIDEMIOLOGY IN JAPAN. AND THIS WAS A MEETING IN 1981& WHICH I AND A NUMBER OF OTHER PEOPLE ATTENDED AT CAPE SUNION GREECE, AND HE PRESENTED FOR THE FIRST TIME THAT LIFE’S JAPANESE WORKERS WHO SMOKED HAD AN CREASE SAID RISK OF LUNG CANCER. I WILL TELL YOU AT THAT TIME, A VAST MAJORITY OF PEOPLE DIDN’T BELIEVE HIM. AND BUT HE PROVED TO BE RIGHT AND NOW, 50, 80, STUDIES, CONVINCINGLY SHOWED THAT BEING AROUND PEOPLE WHO SMOKE OR EXPOSED TO SMOKE INCREASES THEIR–YOUR RISK OF DEVELOPING LUNG CANCER AND THIS IS A QUOTATION FROM HIPPOCRATES, SOME MEN, IT WAS SORT OF INTERESTING WOMEN IN THOSE DAYS, SOME MEN AND WOMEN, I WILL SAY HAD CONSTITUTIONS OR LIKE WOODED MOUNTAINS, RUNNING LIKE SPRINGS, OTHER OTHERS LIKE THOSE WITH POOR SOIL AND WATER, OTHERS LIKE LAYING RICH AND PASTORS AND PHARMACOKINETICSHS AND OTHERS LIKE THE BEAR DRY EARTH OF THE PLAIN. ESSENTIALLY PEOPLE ARE DIFFERENT FROM 1 ANOTHER. AND IN TERMS OF CONSTITUTION ASK RISK OF DISEASE. SO 28 YEARS LATER WE DECIDED TO DO A STUDY OF LUNG CANCER IN NEVER SMOKERS AND I DECIDED WHEN I WAS GOING TO DO THIS, THAT WAS: IS THERE INCREASED RISK OF SMOKING IN KIDS WHO WERE NEVER SMOKERS BUT WERE EXPOSED TO THEIR PARENTS SMOKE? AND WE DIDN’T DO THIS UNTIL 28 YEARS LATER BECAUSE, THE UNITED STATES WOMEN DIDN’T START SMOKING EXTENSIVELY UNTIL THE SECOND WORLD WAR. AND SO WE HAD TO WAIT UNTIL 50, 60 YEARS LATER THAT LUNG CANCER OCCURS. AND THIS IS SUSAN WHO DID THIS EPIDEMIOLOGICAL STUDY WITH US. AND THE CONCLUSION WAS THAT CHILDHOOD EXPOSE TOWER SECTIONAL ANALYSIS HAND SMOKE AND GENERATEDETEC ALTERATIONS INCREASED RISK AMONG NEVER SMOKER IN 2 SEPARATE COHORTS. IT’S IMPORTANT TO LOOK AT MULTIPLE CO HORD’RE HOTTER WHEN IS YOU–COHORT WHEN IS YOU DO THESE KINDS OF STUDIES AND OTHERS, AND I THINK JILL MADE THAT 1 POINT, TOO. AND INCREASED RISK OF LUNG CANCER WAS TRUE WITH THOSE WHO FIND LEPTIN HAPPEN LO TYPE WITH THE HYPER ACTIVE INNATE IMMUNE SIZE, SO INFLAMMATION AND INCREASING RISK. WHAT WAS SURPRISING TO US AT THE TIME THAT THESE PEOPLE HAD LUNG CANCER IN THEIR 40S AND 50S.SO
LUNG CANCER
IS NUMBER 1 WORLD WIDE IN TERMS OF MORTALITY. AND EVERYBODY IN THE DEPARTMENT AS YOU GUYS KNOW HERE, SO, I’M STUDYING PRIMARY LUNG CANCER AS WELL AS REED RYAN, LIVER CANCER, PANCREATIC CANCER IS [INDISCERNIBLE], AND STEPHAN IS STUDYING BREAST AND PROSTATE CANCER. SO WE’RE STUDYING THE MAJOR WORLD WIDE CANCERS. AND THROUGHOUT THE TALK, I’LL BE TALKING ABOUT EARLY STAGE AND EARLY STAGE LUNG CANCER BECAUSE THAT’S THE OPPORTUNITY TO GET THE HIGHEST CURE RATES. BUT THERE’S CERTAIN ASPECTS OF THIS THAT ARE IMPORTANT IN TERMS OF DEVELOPING RISK BIOMARKERS, TO IDENTIFY PEOPLE FOR PRIORITY FOR LOW DOSE CT, THAT’S COMPUTERIZED MAMMOGRAPHY AND ALSO EARLY DIAGNOSIS BECAUSE MEAN OF THESE LESIONS THEN WILL BE DETECTED BY LOCAL CT OR BE19 SO YOU NEED TO KNOW IF IT’S CANCER OR NOT. SO THERE’S DIAGNOSIS OF CANCER AND SURGICAL RESECTION, WHAT NEEDS TO KNOW WHETHER OR NOT THE PATIENT IS AT HIGH RISK FOR RECURRENCE AND IF SO, THEY MIGHT BENEFIT FROM ADJUVANT THERAPY, EITHER IMMUNOTHERAPY OR CHEMO THERAPY. SO LET’S FIRST GO TO THE EXPOSURE. AND THE EXPOSE O STUDIES OF MULTIPLE ENDOCRINE AS OOTLE OOTLE–IT’S CALLED. THIS WAS COINED BY CHRIS WILD, HEAD OF INTERNATIONAL AGENCY FOR RESEARCH ON CANCER AND INCLUDES NOT ONLY EXTERN ALT VIERMS SUCH AS TOBACCO, SMOKE, DIET, SO ON AND SO FORTH BUT INTERNAL DWPT TO WHAT’S DIRECTLY CONNECTED SUCH AS OBESITY, IN PANCREATIC CANCER AND CHRONIC INFLAMMATION. AND THESE TOGETHER CAN LEAD TO RISK AND DIAGNOSIS, CANCER GENOME AND EPIGREEN CELLS NOAM, SUSCEPTIBILITY, DRIVER GENES. OBVIOUSLY FOR CANCER THERAPY BUT UNDERSTANDING CARCINOGENESIS CAN ALSO BENEFIT OUR BIOMARKER STUDIES AND CANCER PREVENTION AND SCREENING STRATEGIES. SO LET’S TALK ABOUT INFLAMMATION FIRST. INFLAMMATION, WILL BE LARGELY INHERITED OR ACQUIRED. CONDITIONS SUCH AS HEMACHROMEATOSEIS, SUCH KHI IS A IRON OVERLOAD DISEASE THAT CREATES THE RISK OF A LIVER CANCER OR INFLAMMATORY VALVE DISEASE OR PANCREATIC CANCER. SO THAT IS ASSOCIATED WITH PAN KRE TINSATTITEIS. BUT MORE OFTEN IT’S ACQUIRED AND IT COULD BE DUE TO VIRUSES, BACTERIA, AND PARASITIC CONDITIONS. I ALSO LIKER TO POINT OUT THE HUMAN APPLIED LOMA VIRUS BECAUSE OF [INDISCERNIBLE] RECEIVED THE LASKER AWARD, 1 OF THE HIGHEST AWARDS IN MEDICAL SCIENCE, JUST QUITE RECENTLY. WHAT ISN’T AN INFECTION ARE CHEMICAL PHYSICAL AND METABOLIC CONDITIONS SUCH AS ACID REFLUX, OBESITY ESOPHAGUS, SMOKING OR MULTIPLE SITES. THE GLOBAL IMPACT IN THE WORLD CANCER REPORT THAT WE PUT TOGETHER IN 2014 IS THAT 2 MILLION CANCERS PER YEAR ARE RELATED TO INFECTION AND OTHER CAUSES OF INFLAMMATION ARE ASSOCIATED WITH MANY MORE CANCERS FOR THE YEAR FOR EXAMPLE, OVER 6 MILLION CANCERS PER YEAR. LET’S GO FURTHER INTO INFLAMMATION, THIS IS A SERIES OF STUDIES THAT WE HAVE DONE AND PUBLISHED ON LUNG CANCER, ENCLOUDING LOOKING AT HEALTH DISPARITY COMPARING AMERICANS TO EUROPEAN AMERICANS AND THE FIRST WAS A PROSPECTIVE STUDY THAT INVOLVED ABOUT A HUNDRED THOUSAND PEOPLE. AND WE FOUND THAT IN A NESTED CASE CONTROL STUDY THAT IL8 AND CRP, THAT’S IN EUROPEAN AMERICANS, INCREASE THE RISK OF LUNG CANCER AT TIME OF DIAGNOSIS, AND THERE WAS ALSO CONTINUED INCREASE IN IL8, IN IL6. BUT NOW WE HAD ENOUGH CASES TO LOOK AT BOTH AMERICANS AND AFTER AMERICANS AND EUROPEAN AMERICANS AND THE AFR-AMERICANS HAD MORE THAN THESE 2 THAN IN IL1 BETA AND IL10, AS AN ANTIINHIBITTOR TO THE CYTOKINE AND FOR SURVIVAL, THE INFLAMMATION, ALSO BECAUSE IT’S RELATED TO SURVIVAL, IN CASE OF LUNG CANCER PATIENTS THIS, IS AGAIN, CONTROL FOR [INDISCERNIBLE], OTHER THINGS THAT ARE IMPORTANT. SO AGAIN, IL6 AND IL8, INCREASE THE RISK OF DYING. AND ANIMAL LECTIN WHICH I TALKED ABOUT A MOMENT AGO, INCREASE TNF ALPHA AND REPEAT IN AMERICANS AND IL10 AND IL12 IN THIS CASE, IN AFRICAN AMERICANS. SO MENTIONED IL6 AND IL8. THIS IS THE EARLIEST STAGE OF LUNG CANCER. SO IT’S LESS THAN 3-CENTIMETERS, NO EVIDENCE OF METASTASIS, LOOKING AT THE NODES, AND WHEN BOTH OF THESE ARE ELEVATED, IN THIS CAP LANMIER PLOT, SO THERE’S A HUNDRED% SURVIVAL AND 0% SURVERIFIAL AND THIS IS SURVIVAL IN YEARS. ONE CAN SEE THAT LOW FOR BOTH, RELATIVELY GOOD SURVIVAL, EARLY STAGE CANCER, 1 IS HIGH, INTERMEDIATE AND IF BOTH ARE HIGH, 75% OF THE PEOPLE ARE DEAD OAIVE THEY HAD THEY AN EARLY STAGE OF KANSZER. I’LL GET BACK TO THAT IN A MOMENT. ALL RIGHT, HOW ABOUT GENOME. A NUMBER OF YEARS AGO, QUITE A NUMBER OF YEARS AGO, ACTUALLY, SEVERAL HUNDRED YORES AGO, WE RECOGNIZE THAT CHIMNEY SWEEPS HAD INCREASED RISK OF SCROATAL SCANSER AND THIS IS DUE PRIMEAR ILLEGALS TOW VARIOUS HYDROCARBONS AND THE APLOTOXIN THAT IS A FUNGUS THAT GROWS ON MOLDY CORN AND GRAIN. ALSO PRODUCES A VERY POTENT CARCINOGEN CAUSES LIVER CANCER AND I MENTION SAID CIGARETTE SMOKE WHICH HAS MULTIPLE–IN FACT IT HAS ABOUT 60 KNOWN CHEMICAL CAR SIN O JENS SO IT’S A REAL WITCHS INTERVIEW–WITCH’S BREW OF CARCINOGENS AND NO WONDER IT CAUSES SO MUCH CANCER AT MULTIPLE SITES. SO QUITE A NUMBER OF YEARS AGO, THE FIRST QUESTION THAT WAS ASKED BY OUR GROUP ALONG WITH MANY RPGHTS WAS WHETHER OR NOT THESE SPECIFIC CARCINOGENS, SUCH AS APPLICATIONS LO TOXICITY INCREASE IN TOXIN, RENAL TOXIN, WITH THE CAUSE MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE AND THE ANSWER WAS YES AND CAUSED VERY CHARACTER FORTIC MUTATIONS SOCIETIED NOT ONLY WITH CANCER BUT ASSOCIATED WITH THE MECHANISM OF ACTION OF THESE VARIOUS AGENTS. NOW MORE RECENTLY, SIR MICHAEL STATIN AND HIS COLLEAGUES AT THE INSTITUTE IN LONDON UTILIZEED EXOME SEQUENCING AND TRIED NUCLEATIZED ANALYSIS AND FOUND THIS IS THE SIGNATURE FOR TOBACCO, THIS IS THE SIGNATURE FOR ULTRAVIOLET LIGHT AND SO ON AND SO FORTH. SO THERE’S 30 DIFFERENT SIGNATURES, ABOUT HALF OF THOSE ARE ASSOCIATED WITH SPECIFIC EXPOSURES, AND FEWER ASSOCIATED WITH JUST AGING AND PEOPLE GET OLDER AND THEY DON’T HAVE THESE OTHER RISK FACTORS, THEY STILL GET CANCER AND THEY HAVE A CHARACTERISTIC TYPE OF MUTATION SIGNATURE. NOW LUNG CANCER, A NUMBER OF YEARS AGO, WAS CLASSIFIED AS SMALL CELL ADENO CARCINOMA OR SCWAIMOUS CELL CARCINOMA AND IN QUECH KRASE MODEL WAS DISCOVERED AND IN 2004 EGFR WAS DISCOVERED AND LASTLY IN 2014, THIS IS THE FAIRLY UP TO DATE, A NUMBER OF DIFFERENT TYPES OF MUTATIONS AND FUSIONS, SUCH AS OUTFUSIONS WERE DISCOVERED. AND ADDED TO THE GENOMIC LANDSCAPE OF LUNG CANCER. I WILL SAY THAT MOST OF THESE THAT HAVE BEEN RECENTLY DISCOVERED ARE IN NEVER SMOKERS. IN FACT [INDISCERNIBLE]. AT ABOUT 14% OF THE LUNG CANCER PATIENTS COMING TO CLINICS NOW ARE NEVER SMOKERS. NOW IS IT PASSIVE SMOKING OR SOMETHING ELSE? SO THE MAJORITY OF CANCERS THAT WE STILL DON’T HAVE THERAPY FOR HAVE KRASE MODEL MUTATIONS. OR THEY HAVE P53 MUTATIONS. SO THE P53 GENE IS MOST COMMONLY MUTATED IN HUMAN CANCER, INCLUDING LUNG CANCER, PARTICULARLY SCWAIMOUS CELL CARCINOMA BUT ALSO ADNO CARCINOMA. AND AS A WILD TYPE, THE GENE AND THE PROTEIN, IT’S A TUMOR SUPPRESSOR, BUT THERE ARE MULTIPLE MUTANT POPS AND SOME OF THESE HAVE LOSS FUNCTION AS A TUMOR SUPPRESSOR AND VARYING DEGREES OF LOSS OF FUNCTION AND OTHERS GAIN OF FUNCTION AS AN ONCOGENE, SO THE P53 HAS SWITCHED FROM BEING A TUMOR SUPPRESSOR GENE TO A TUMOR ONCOGENE. AND THIS WAS CONFUSING IN THE INITIAL 10 YEARS THAT P53 HAS BEEN INVESTIGATE, BUT IT IS QUITE CLEAR NOW. AND IN FACT, THOSE THAT HAVE A GAIN OF FUNCTION MUTATION, HERE IN RED, AGAIN THIS, IS A HUNDRED% SURVIVE AG, THIS IS 0% SURVIVAL THIS, IS TIME IN MOMGHTS. SO THIS IS 5 YEARS. SO THESE INDIVIDUALS HAVE A POOR PROCEEDINGINOSEIS, CONTROLLED FOR VARIOUS OTHER THINGS THAN THOSE WHO HAVE JUST A LOSS OF FUNCTION. SO LET’S LOOK AT THE TRANSCRIPT OHM. SO FIRST NONCOATING RNAs SUCH AS MICRORNAs AND THESE CODING RNAs WERE FIRST DISCOVERED BY VICTOR AMBROS, IN C.ELEGANS AND THAT WAS IN 1993 AND IN YEAR 2000 HIS COLLEAGUE GARY RUVKUN, FOUND HUMAN CELLS THERE WERE THESE SMALL MICRO RMAs. AND THEY FUNCTION BY INHIBITING HUNDREDS OF GENES, THAT THEY REPRESSED BY DESTABLING THE RNA OR TO A LESSER EXTENT INHIBITING TRANSLATION. IT WASN’T UNTIL 2004 THAT CARL O COOCE, DISCOVERED THAT THEY WERE EXPRESS INDEED HUMAN, SPECIFICALLY LEUKEMIA, AND IT’S NOW BEEN SHOWN THAT RISK AND PROGNOSIS AND THERAPEUTIC OUTCOME. SO MOST OF YOU I’M SURE KNOW ABOUT MICRO RNAs, THEY FUNCTION LARGELY BY TRANSLATIONAL REEXPRESSION SO THIS IS A MICRO RNA, SO THE PROTEIN ISN’T MADE OR BY THIS–MORE FREQUENT BY BINDING TO THE MESSAGE FREQUENTLY HAS A A–A NUCLEOTIDE THAT’S DIFFERENT THAN WHAT THE BINDING MICRO RNA WOULD RECOGNIZE AND THE MESSAGE IS CLEAVED. THE MICRO RNA WILL ALSO BIND TO PROTEINS THAT ALTER DIFFERENTIATION. AND ALSO, MICRO RNAs SUCH AS MIRACLE 1 AND 25 CAN BIND TO TOTAL RECEPTORS, BOTH HUMAN AND MOUSE AND LEADS TO INCREASE IN IL6 WHICH I TALKED ABOUT A MOMENT AGO IN TNF ALPHA. SO WE START A NUMBER OF YEARS AGO, ACTUALLY IN 2004, 2005, THIS IS 1 OF MY POST DOC CHOS IS AN ASSOCIATE PROFESSOR NOW. AND HYPOTHESIS WAS THAT MICRO RNAs ARE ASSOCIATED WITH LUNG DIAGNOSIS AND PROGNOSIS AND WE FOUND THAT MICRO RNA PROFILES WERE SIGNIFICANTLY DIFFERENT BETWEEN PRIMARY CANCER AND THOSE OF NONCANCEROUS TISSUE AND AMONG DIFFERENT HISTOLOGICAL TYPES OF. IT DID RECOGNIZE SCWAIMOUS VERSUS ADNO VERSUS SMALL CELL. WE FOUND THERE WAS AN INCREASE IN 021 AND MIRAKA 155 AND MIRAKA 106 AND A BETTER DIAGNOSIS AGAIN IN THE EARLY STAGE OF LUNG CANCER, STAGE 1. THIS LED TO COLLABORATION IN WHICH WE PARTICIPATED IN, LOOKING AT MULTIPLE CANCER TYPES, IN FACT, 8 MOST COMMON KINDS OF CANCER AT THAT POINT AND THERE WERE, I THINK ABOUT 300 MICRO RNAs IDENTIFIED WHEN WE DID THIS STUDY THERE WERE WELL OVER 2000 NOW THAT HAD BEEN IDENTIFIED BUT IT WASAVE SIMPLE KIND OF STUDY, IT JUST TOOK MULTIPLE CANCER TYPES AND ASKED THE QUESTION, WHICH OF THESE MICRO RNAs THEY WERE HIGHLY EXPRESSED AND WE FOUND THAT MIR 21 WAS EXPRESSED IN 6 OF THESE MAJOR CANCER TYPES. SO MIRAKA 21–MIR21 IS UPREGULATED NOW IN OVER 18 MAJOR CANCER AND IT IS PROGNOSIS IN 14. SO THIS IS ANOTHER FAIRLY EARLY STUDY THAT WE DID. JAPANESE POST DOCS AT THAT TIME. AND WE COMPARED THE MARYLAND COHORT FROM THE BALTIMORE AREA, TO A NORWEGIAN COHORT VERSUS A JAPANESE COHORT AND THESE ARE CAP LANMIER PLOTS AGAIN, HUNDRED% SURVIVAL AND 0% AND HIGH EXPRESSION IN THE TUMOR VERSUS LOW, THIS IS MEDIAN, THIS IS ABOVE THE MEDIAN AND BELOW THE MEDIAN. YOU CAN LOOK AT THIS AND SAY, WELL, MAYBE [INDISCERNIBLE]. BUT IMPORTANTLY, THIS IS LOOKING AT RELAPSE-FREE SURVIVAL AND HERE WE’RE LOOKING AT CANCER SPECIFIC [INDISCERNIBLE] I ALWAYS PUT [INDISCERNIBLE] THAT THERE’S [INDISCERNIBLE]. SO THIS IS OBSERVATION IS TREATED NOT ONLY IN LUNG CANCER BUT IN PULT PEL OTHER KINDS OF CANCERS AS I MENTIONED AND THESE ARE EXAMPLES OF VARIOUS STUDIES AND ALL OF THESE HAVE BEEN CONFIRMED BY 2 OR 3 ADDITIONAL STUDIES. SO MIR 21 IS INDICATOR OF POOR PROGNOSIS IN MULTIPLE CANCERS. SO WHAT’S THE MECHANISTIC UNDERPINNING OF THIS MICRO RNA IN HUMAN CANCER? FIRST OFF IT’S IN AN AREA OF AMPPLIFICATION. IN THE LATEST REPORT OF LUNG CANCKENER VARIOUS KINDS OF GENETIC CHANGES, GENE AMPLIFICATION AT THIS SITE IS NOW AN IMPORTANT CONTRIBUTOR TO DIAGNOSIS AND PROGNOSIS AND WE THINK THIS IS MIR 21. DECREASED TRANSCRIPTIONAL SILENCING, WE TALKED ABOUT THAT. WE SHOWED PNAS PAPER A NUMBER OF YEARS AGO THAT EGFR MUTATIONS LED TO AN INCREASE IN MIR21. TUMORS THAT HAVE E GFR MUTATIONS AND BREAST MUTATIONS MUTATIONS
AND VICE VERSA BUT KRAS ALSO IS MIR 21. INFLAMMATORY AGENTS AS BALTIMORE SHOWN INCREASED STAT 3 WHICH IS A TRANSCRIPTION FACTOR FOR [INDISCERNIBLE]. AND VARIOUS TYPES OF DISRKS NA DAMAGE ALSO, SO WHAT’S DOWN STREAM OF MIR21? WELL IT’S A WHOLE VARIETY IN THIS IS JUST A SNAPSHOT OF SOME OF THESE TARGETS THAT ARE IMPORTANT AND TUMOR GROWTH AND THE REGION, AND THEN THE MIGRATION AND ALSO CENTER FOR EXCELLENCE ON AGINGS A CERTAIN DNA REPAIR TEAM. AND AS I MENTIONED EARLIER, THAT IT LEADS TO ACTIVATION OF TELOMERE SHORTENING RECEPTOR AND INFLAMMATION. AND THESE ARE AGAIN BY THE PROSHEET LAB IN WHICH THEY FOUND THAT CANCER CELLS RELEASE IN EXOSTUDIES OF MULTIPLE ENDOCRINE, THOSE ARE SMALL POCKETS OF MEMBRANE BOUND VESICLES, LESS THAN–LESS THAN A HUNDRED NANO METERS THAT CARRIED THESE MICRO RNAs TO IMMUNE CELLS TO ACTIVATE THE TELOMERE
TOLL RECEPTOR OR THEY ALSO CARRY THEM TO MILE O SIGHTS, MUSCLE CELLS. AND 1 OF THE MOST DEVASTATING ASSOCIATIONS WITH HUMAN CANCER IS CACHEXIA, AND THAT IS THAT THEY HAVE WASTING OF ALL THEIR MUSCLES. SO THIS IS A CONDITION WITH THE THERAPY AND IT IS JUST A FEW MONTHS AND THEY LOOK LIKE THEY’RE STARVING TO DEATH AND THAT’S–YEAH, AND THEY DIE SO THAT’S CACHEXIA, SO MIR 21 AND THROUGH AGAIN THE INFLAMMATION, MAYBE BLAMING FOR THAT. THAT’S BEING TESTED RIGHT NOW. ALL RIGHT. SO I TALK ABOUT MICRO RNA AS A TRANSCRIPTOME, AND HOW ABOUT PROTEIN CODING GENES. SO WE DID SOME [INDISCERNIBLE] IT’S A FAIRLY SOPHISTICATED WAY OF DOING THE ANALYSIS IN WHICH WE IDENTIFIED 4 GENES THAT ARE ASSOCIATED WITH POOR PROGNOSIS, THE FIRST IS INCROSED NEXT PO, WHICH IS EVOLVED IN THE TRANSPORT NUCLEUS TO THE CYTOPLASM OF MICRO RNAs AND OTHER THINGS, BRCA 1. WHICH YOU [INDISCERNIBLE] RELATE TO BREAST CANCER BUT HIGH LEVELS OF BRCA 1 ARE ACTUALLY GENO TYPES. BECAUSE INSTABILITY. THE HIP 1 ALPHA IS ASSOCIATED WITH–REACHED THE OXYGEN DETENTION AND A TUMOR SUPPRESSOR BEING DISCOVERED HERE AT THE NARCOTICS CI, OF DLC 1 AND IS 12 DIFFERENT INDEPENDENT COHORTS, AGAIN, STAGE 1 OF CANCER AND AS 1 CAN SEE IF YOU LOOK AT THE LOWER CORTILE, WHICH IS THE GREEN, THE LOWER CORTILE OR THE HIGHEST CORTILE, HIGHEST CORTILE, IN EACH OF THESE CASES, LEADS TO POOR SURVIVAL. SO AGAIN THIS IS THE PRINCIPLE OF LOOKING FOR IT IN THE INDUSTRY AND IF YOU FIND IT, AND IF YOU FIND IT IN MULTIPLE COHORTS IT PROBABLY IS VALID. THIS IS JUST COMPARING STAGE 1 A, VERSUS STAGE 1 B. STAGE 1 A IS 3-CENTIMETERS STAGE 1 B IS 5-CENTIMETERS AND IN BOTH CASES THERE’S NO EVIDENCE OF METASTASIS IN THE LYMPHNODES BUT I’LL GET TO THE POINT THAT THEY DO HAVE MICRO METASTASIS. SO THIS IS LOOKING AT STAGE 1. THIS IS MULTIPLE STUDIES. MOST OF THEM JUST LOOK AT OVERALL SURVIVAL WHICH IS LESS EFFORT THAN RELAPSED FREE SURVIVAL AND SPECIFIC SURVIVAL THAT WE PREFER BUT IN EACH CASE, IS A PROGNOSIS. SO THE NEXT QUESTION HERE WE ASK AND YOU COULD ASK IS HOW ABOUT IF YOU COMBINE BOTTOM LINE, THE PRINCIPLE IS THAT THEY’RE STATISTICALLY INDEPENDENT OF EACH OTHER. IT MAKES SENSE TO THAT, THE COMBINATION, SO, THIS WAS HYPOTHESIS, THAT HIRO AND ICHIRO TOASTED AND COMPARING THE 4 PROTEIN CODING GENES WITH MICRO RNA MIR 21. SO THIS IS JAPANESE STUDY AND SHOULD AGAIN RELAPSE FREE. SO THIS IS COMPARING THE 14 SIGNATURES I MENTIONED BEFORE WITH–WHICH IS UP HERE. WITH A MIR 21 WHICH IS SHOWN HERE. EACH OF THEM LEADS TO ASSOCIATED WITH POOR PROGNOSIS AND YOU PUT THE 2 TOGETHER AND AGAIN, IT’S A SIGNIFICANTLY DECREASE IN PROGNOSIS. THIS IS THE U.S. NORWAY COHORT. AND THIS IS POOR GENE SIGNATURE FOR PROGNOSIS. THIS IS SMEAR 21 FOR PROGNOSIS AND IF YOU PUT THEM TOGETHER MUCH POORER PROGNOSIS AND AGAIN THIS IS SPECIFIC CANCER WORK OUT, AND 7 LAPSE 3 SURVIVAL. SO WHAT’S THE PRINCIPAL? WELL THE PRINCIPAL IS IF WE TAKE NONCODING RNAEXPZ CODING RNAEXPZ COMBINE THEM YOU SHOULD GET LOW RISK, INTERMEDIATE RISK AND HIGH RISK. WHY IS THIS MIGHT BE THE CASE? WELL, IN BOTH THE RNAs, THEY GET IT BUT EACH BIOMARKER GIVES YOU TOPICS BUT THEY’RE DIFFERENT FROM EACH OTHER, SO THEY’RE MISS CLASSIFICATION SAYS COMPARED TO BETTER AND MORE SPECIFIC SURVIVAL. IS THIS TRUE IT LUNG CANCER? NO. WE’VE FOUND IS TRUE IN COLOON CANCER AND ADENO CANCER AND AS WAS JUST MENTIONED, ALSO IN BREAST CANCER. SO NOW LET’S MOVE TO THE EPI GENOME. AND THIS IS THE ANNA ROBLES IN THE LAB, A STAFF SCIENTIST AND SHE TESTED THE HYPOTHESIS THAT INTEGRATED BIOMARKER CLASSIFIED STAGE 1 LUNG CANCER ADENO CARCINOMA BASED ON INDEPENDENT MRNA, MICRO RNA AND DNA METHALATION BIOMARKERS WILL FURTHER IMPROVE PROGNOSTIC CLASSIFICATION. SO THIS IS 3 BIOMARKERS TOGETHER. NOW IF WE HAD ALREADY BEEN PUBLISHED BY MANUEL ESTERKS, LLA, THAT THESE 3, 4, 5 GENES THAT WERE DNA METHALATED WERE [INDISCERNIBLE] WITH POOR PROGNOSIS. HE SAID WELL, WHY DIDN’T YOU LOOK AT ALL 5 OF THEM? WELL THIS IS BY UNIVARIED ANALYSIS SO IF HE DID MULTIVARIANT ANALYSIS WHICH WE DID, WE FOUND THAT THERE ARE ALL DEPENDENT ON EACH OTHER. SO WE CHOSE HOXA9 TO DO ANALYSIS, WHICH IS REPRESENTATIVE OF THE TOTAL BUT IN MOST REPRESENTATIVE. AND WE ADDED MIR21, THE 14, THE SIGNATURES NATURE. HOXA9, MIR21, THE 14 SIGNATURE IS HERE AND WE FOUND THAT ALL 4–ACTUALLY ALL 3 ARE POSITIVE,& THAT’S IN THE RED, THE PROGNOSIS IS STAGE 1 LUNG CANCER IN STAGE 1 LUNG CANCER IN STAGE 1 B, AND 5-MILLIMETER IN SIZE, AND THIS IS BOTH, ARE ASSOCIATED WITH POOR PROGNOSIS. SO THESE ARE STATISTICALLY AND MECHANISTICALLY INDEPENDENT OF EACH OTHER AND YOU CAN SHOW THIS BY DOING THESE KINDS OF ANALYSIS AND FURTHER ANALYSIS. SO NOW LET’S LOOK TO THE METRICS TAB O LOAM. LET’S LOOK AT METABOLISM. SO THIS IS METABOLISM, WE’VE BEEN LOOKING AT THIS FOR YEARS NOW, MAJDA IS NOW AT FDA AND EWY IS NOW AT OHIO STATE AND OUR INITIAL STUDY WAS AN UNBIASED METRICS TAB O LOAMICS AND THE HIGHWAY POGHT SIS WAS DISCOVERED BY BIOMARKERS IS ASSOCIATED WITH RISK, PROGNOSIS AND THERAPEUTIC OUTCOME, AGAIN OF LUNG CANCER. NOW 1 THING THE LIQUID BIOPSIES, 1 OF THE PROOFS WE DECIDED TO DO WAS ACTUALLY [INDISCERNIBLE]. HERE’S A NICE PAINTING OF A DUTCH PHYSICIAN LOOKING AT URINE AND IT’S BEEN REPORT THAD HIPPOCRATES, AND PHYSICIANS OF HIS TIME AND HISTORY AND TIME TASTED URINE FOR DIAGNOSIS OF DISEASE AND THINGS SUCH AS DIABETES, OTHERS DIDN’T KNOW WHAT TO DO. WHEN I WENT TO MEDICAL SCHOOL, MANY YEARS AGO AS TERREMENTIONED, WE DIDN’T HAVE TO TASTE URINE. THANK GOD. BUT WE HAD SOME VERY SIMPLE TESTS FOR DOING THAT. THIS SHOULD A VERY IMPORTANT QUOTATION FROM ARM STRONG, HE SAYS PHYSIOLOGIST, FROM THE LIQUID WINDOW THROUGH WHICH PHYSICIANS FELT CONFUSED THE BODY’S INNER WORKERRINGS, URINE LED TO THE BEGINNINGS OF LABORATORY OF MEDICINE. SO THEN WE DID AN UNBIASED SCREEN OF LITERALLY THOUSANDS OF POTENTIAL METABOLITES AND IN RANDOM FORCE CAME UP WITH 4 OF THEM THAT WERE STATISTICALLY AND MECHANISTICALLY INDEPENDENT OF EACH OTHER, KRE TINSA TIEN RIBOICIDE WHICH HAD NEVER BEEN DESCRIBED BEFORE, AND IT’S A METABOLITE, SO THAT’S NEVER BEEN DESCRIBED BEFORE, YOU CAN–YOU CAN’T HAVE PROTEINS THAT ARE ONLY KNOWN, OR MOLECULES THAT ARE ALREADY KNOWN, BUT SOMETHING THAT’S EVER, EVER BEEN DISCOVERED, YOU CAN STILL HAVE THEM. AND IT’S IN A FIELD OF ACID AND IT’S SOFT AND THIS IS THE DPLIEK O LIPID YET TO DISCOVER. SO THESE ARE CAP LANMIER PLOTS IF YOU PUT ALL 4 OF THESE TOGETHER, AGAIN THIS IS LUNG CANCER, A VERY POOR PROCEEDINGINOSEIS, LESS THAN 10% AT 5 YEARS, AND ALL OF THESE ARE POSITIVE IN THE URINE AND WE CAN NOW MEASURE THESE IN SERUM AND PLASMA. SO THIS IS JUST THE HAZARD RATIOS THAT GO UP WHEN YOU MAKE THESE KINDS OF COMBINATIONS. NOW 1 OF THE IMPORTANT QUESTIONS WHEN WE STARTED DOING THESE STUDIES WAS KRE TINSA TIEN RIBOICIDE WAS FOUND IN TUMORS AND WHAT WE FOUND IF TUMORS RELATED TO WHAT YOU FIND IN URINE. SO YES IT IS FOUND IN LUNG CANCERS AT RELATIVELY HIGH LEVELS COMPARED TO THE NONTUMOR AREA. AND IF YOU COMPARE CERATIEN RIBOICIDE IN THE TUMOR TO THAT WHICH IS IN THE URINE THIS, IS THE CORRELATION ANALYSIS, ABOUT 26 AND PNTS 006 SNP. AND RIGHT NOW WE’RE ASKING THE QUESTION: IF SERUM OR PLASMA CORRELATE WITH THIS AND THIS AND TRIANGULATE AND GIVE US SOME OTHER SET OF BIOSPECIMENS FOR THESE KINDS OF ANALYSIS. WITH OUR COLLEAGUES AT VANDERBILT WHO HAVE DONE A PROSPECTIVE STUDY OF AFRICAN AMERICANS AND EUROPEAN AMERICANS AGAIN ABOUT A HUNDRED THOUSAND CONTROLS, SO WOO DID A STUDY, LUNG CANCER IN THESE INDIVIDUALS AND WE FOUND THAT IN THE MULTIVERSION ANALYSIS THAT THE ODDS RATIO ARE QUITE HIGH WITH THE CRE2 RIBOICIDE AND THE ARE–ADMINISTRATIVA MEANIC ACID, THAT ACTUALLY GETS THE TEANGSZ OF THE DIAGNOSTIC COMMUNITY. HOWEVER, WHEN WE ELECTRIC AT AFRO AMERICANS IT WAS UPELEVATED SO THERE IS A SOMETHING THAT IN URINE THAT WE’RE INTERESTED IN FINDING OUT ABOUT. SO HOW ABOUT USING THIS AS A SCREENING FOR LUNG CANCER IN HIGH RISK EUROPEAN AMERICANS. IF YOU PUT THESE TOGETHER ALONG WITH LOW RISKS SUCH AS SMOKING AND OTHER RISK FACTORS, YOU FIND THAT IN THIS ROCK CURVE WHICH LOOKS AT AND SENSITIVITY AND SPECIFICITY, THIS IS STRAIGHT LINE WITH COMBINATION IS GREEN AND THE ODDS–THE ASSOCIATION UNDERTHE CURVE IS,.–ACTUALLY IT’S OVER HERE. IT’S CLOSE TO .95, BETWEEN .86 AND 89. WE PUT EVERYTHING TOGETHE WHICH IS HERE AND THIS IS A SUMMARY THAT’S USEFUL AND SOMETHING THAT AGAIN, THE IH HAS RIGHT. SO AS YOU ALL KNOW INVESTIGATORS AT [INDISCERNIBLE] HERE AND HERE AND HAVE KD–SALLY WABUT THE PATENTS AND THE RESEARCH ARE FROM [INDISCERNIBLE]. SO I MENTIONED LOW DOSE CT A MOMENT AGO. AND THIS IS A LANDMARK STUDY THAT WAS PUBLISH INDEED NEW ENGLAND JOURNAL OF MEDICINE IN 2011 IN WHICH THEY COMPARED CHEST X-RAYS WITH AND LATER STAGE AND EXPLAIN THE ACTUALLY WE DOT CANCER BORN MORTALITY BY 20% AND THIS IS SOME OF THE SPECIFICS BACK HERE THAT OVER 50,000 INDIVIDUALS WERE ANALYZED. THESE WERE PRIMARILY HEAVY SMOKERS WITH THE AGE GROUP AND 2 DIFFERENT GROUPS ABOUT THE SAME NUMBER OF INDIVIDUALS. THERE’S A VERY IMPORTANT FINDING THOUGH. AND THAT’S THE [INDISCERNIBLE] OF 96%. AND I’LL MAKE THAT POINT A LITTLE MORE STRINGENTLY IN A MOMENT. THE KINDS CANCER THAT WERE DETECTED BY LOW DOSE CT WERE PRIMARILY STAGE 1 A AND 1 B, WITH THE LUNG CANCERS. HERE, AND HIGH FALSE-POSITIVE RATE. SO THIS IS A ILLUSTRATION OF WHAT THIS MEANS, SO THIS IS A STAGE AND THESE ARE ALL CHAIRS IN THE AUDIENCE AND LIKE WE TWOAPT KD–SALLY KOIPLE NIGHTS AGO, FANTASTIC IF I SAY, AND LOW DOSE CT, DETECTS 3 OR 3 AND HALF OF THESE INDIVIDUALS. THESE ARE THE PEOPLE WHO WHO ARE SCREENED. SO LOGO CT IS NOT ONLY PRACTICE NOW,–AND THESE ARE THE RISK FACTORS FOR BEING ELIGIBLE THE EIGHTH FRAME, THE 30 YEAR PACK OF HISTORY OF SMOKING THAT QUIT WITHIN 15 YEARS OF CURRENT SMOKING AND WE NEED TO IDENTIFY HIGH RISK AND INSIDE THE [INDISCERNIBLE]. AND NEVER AND [INDISCERNIBLE] HAVE IT FUNDED FOR THESE STUDIES SECOND, IS PRIORITIZEATION. MAYBE I’LL GO–WE’RE ABOUT TO THE END. NEXT SLIDE TO THAT, BUT THERE’S–NOW ABOUT 10 MILLION PEOPLE THAT ARE ELIGIBLE WITH THESE CRITERIA. SO THERE’S A NEED TO PRIORITIZE THOSE INDIVIDUALS FOR LOW DOSE CT BECAUSE THE CURRENT CAPACITY IS LESS THAN 200,000 PER YEAR IN THE UNITED STATES. AND WE WERE TALKING ABOUT 9, 10 MILLION PEOPLE WHO BASICALLY ADMITTING THOSE PEOPLE ARE EXTREMELY NEGATIVE OR HAVE [INDISCERNIBLE]. SO, IT WOULD BE IMPORTANT TO IDENTIFY INDIVIDUALLY FOR PRIMATESSOR SCREENING. SECOND IS FOUND BY LOGO CT AND 96 OF THE HUNDRED LIGANDS. AND WHICH 1S ARE ACTUALLY BENIGN. SO WE NEED BETTER DIAGNOSTIC TO MAKE A CLINICAL DIAGNOSIS, TODAY, ABOUT HALF THE PEOPLE GOING TO SURGERY IN THE UNITED STATES, AND THE MANY DIFFERENT HOSPITALS THAN HAVE A POSITIVE LESION BY LOGO CT HAVE A BENIGN TUMOR SO DOING SURGERY AND CRACKING SOMEONE’S CHEST IS NOT A BENIGN PROCEDURE, SO IF YOU WOULD LIKE TO MINIMIZE THOSE PEOPLE THAT YOU DO SURGERY ON TO REMOVE THE TUMOR INSTEAD OF CANCER. AND THEN THERE’S THE QUESTION OF DISCIPLINARY NAG NOOF THETIC BIOMARKERS EVEN FOR STAGE 1 LUNG CANCER. SO, THE GOAM OF–GOAL OF PRECISION MEDICINE IS TO IDENTIFY 20% OF THE STAGE 1 LUNG CANCERS WHOSE CANCER ROLE WAS [INDISCERNIBLE]. ABOUT 25-30% OF THESE PEOPLE HAVE MICROMETASTASIS. AND 1 OF THE QUESTIONINGS IS IF YOU GET THERAPY, WITH THE METASTASIS, WILL THAT BE MORE EFFECTIVE THAN THE WAY IT EVER RETURNS TO THE SIZE OF [INDISCERNIBLE]. THAT’S HYPOTHESIS TO BE TESTED. SO AGAIN WE HAVE STAGE 1 A, STAGE 1 B, THESE ARE THE DIFFERENT SIZES, MIGHT UNDERGO SURGERY BUT SOME PEOPLE WILL BE LOW RISK OF DEVELOPING METASTASIS IN THE STAGE 1 A OR STAGE 1 B, BUT SOME OF THESE PEOPLE WILL BE HIGH RISK. SO 1 OF THE GOALS OF PRECISION MEDICINE IS TO USE THESE INFORMATION TO DECREASE THE FALSE-POSITIVE RATE, DECREASE FINANCIAL COST, IMPROVE PATIENT CARE AND GIED MECHANISTIC STUDIES. AND PARTLY THE PATIENT CARE, THOSE ARE LOW RISK OF RECURRENCE, OBSERVATION AND MAYBE ROUGH ATOM DOING LOW DOSE CT AT VARYING TIME INTERVALS AND THOSE AT HIGH RISK GIVING THEM THE OPTION AS THE IMMUNOTHERAPY OR CHEMO THERAPY. SO THESE ARE COLLEAGUE THAT HAVE DONE MOST OF THIS WORK AND THEY HAVE THEIR OWN LABORATORIES NOW SO I WANT TO THANK THEM AND I WOULD BE HAPPY TO TAKE ANY QUESTIONS THAT YOU MIGHT HAVE. THANK YOU. [ APPLAUSE ]>>SO HOW MANY OF HAVE YOU A MEMBER OF YOUR FAMILY THAT HAS LUNG CANCER? I’M SURPRISED NO 1’S HOLDING UP THEIR HANDS. IT’S PROBABLY–[INDISCERNIBLE]. NOT ME, FORTUNATE SO IT’S A VERY COMMON THING, MOST COMMON CANCER. SO QUESTIONS? YES?>>[INDISCERNIBLE].>>YES.>>[INDISCERNIBLE].>>YES.>>[INDISCERNIBLE].>>SO THE QUESTION IS A GOOD 1, THERE ARE GROUPS WHO NEVER GET LUNG CANCER. THEY MIGHT DIE OF CHRONIC AFFLICTED PULL MONITORARY DISEASE, EMPHYSEMA, LOTS OF TIME WHERE IS THEY HAVE A HEART ATTACK, BUT THERE ARE PEOPLE WHO HAVE BEEN SMOKERS INTO THEIR 70S, 80S, MAYBE EVEN 90 BUT THEY’RE ARE VERY RARE. BUT THOSE ARE VERY INTERESTING CASES TO INVESTIGATE AND JUST WANT TO TAKE THAT CANCER TO WHAT JILL WAS TALKING ABOUT, THOSE PEOPLE LIVE 4 OR 5 YEARS, WHAT’S DIFFERENT ABOUT THEM THAN THOSE THAT DO NOT. SO, LOOKING AT EXTREME SURVIVAL IS 1 OF THE PRIORITIES AT NCI NOW TO TRY TO AIRKS DENTIFY THOSE INDIVIDUALS, AND WHY? THAT’S THE IMPORTANT QUESTION. WHY? WHAT’S THE MECHANISM OF LONG-TERM SURVIVAL. IS IT MORE THAN JUST [INDISCERNIBLE]. OTHER QUESTIONS, YES?>>[INDISCERNIBLE].>>YES. SO THE QUESTION RELATES TO HEALTH DISPARITY. PARTICULARLY AFRICAN AMERICAN VERSUS EUROPEAN AMERICANS AND THERE ARE SOME STUDIES IN WHICH YOU KNOW STATUS AND WHOLE VARIETY OF OTHER THINGS AND MULTIPLE SCENARIOS ARE PART OF THE STUDY. AND THE RISK FACTOR STUDY THAT WE DID WITH THE PEOPLE AT VANDERBILT, THEY DID ALL THAT WITHOUT FACES OF INDIVIDUALS THAT PARTICIPATE IN THE STUDY OF AFRICAN MORE THANS VERSUS EUROPEAN AMERICANS. SO 1–ONCE YOU CONTROL FOR THAT, SO THAT IN FACT, MANY OF THOSE SOCIAL FACTORS THAT YOU’RE TALKING ABOUT, MAYBING TALKING ABOUT ARE NOT THE REASON FOR SURVERIFIAL FOR OR STRESS FACTORS. IN FACT, REED RYAN IN OUR GROUP HAS SOME EVIDENCE THAT AFRO AMERICANS MAY ACTUALLY LIVE LONGER AND HAVE LESS CANCER, LUNG CANCER THAN EUROPEAN AMERICANS. THAT’S A VERY STARTLING FINDING THAT’S BEEN SHOWN IN A COUPLE STUDIES. SO WHY? SO WHETHER IT’S LOOKING DOWN AT SNPs, IT’S ASSOCIATE WIDE DIFFERENT CANCER TYPES AND RISK AND JILL TALKED ABOUT THAT AND THAT’S A VERY ACTIVE VARIANT OF LOOKING AT GENE EXPRESSION ANALYSIS AND VARIOUS OTHER THINGS. SO, HEALTH DISPARITIES, AGAIN, IT’S A HIGH PRIORITY AT THE NATIONAL CANCER EN–STRATEGIESITUTE, NOT ONLY AT CCR BUT ALSO DIVISION OF KANGSER EPIDEMIOLOGY AND THERE ARE SOME PEOPLE WHO ARE VERY MUCH INVOLVED WITH THAT. AND I HOPE YOU GO ON.>>[INDISCERNIBLE].>>NO. INCREASE. NO. THAT WAS VERY IMPORTANT QUESTION. WHAT’S THE CRITERIA FOR ACCESS TO CARE AND DIAGNOSIS? AND A STUDY THAT I TALKED ABOUT AND SOME OF THESE OTHER STUDIES, THAT HAS BEEN ADDRESSED. SO IT’S NOT JUST ACCESS TO CARE OR IT’S–ALSO IN TERMS OF [INDISCERNIBLE] EUROPEAN MARKETS, EVEN THOUGH IN AVERAGE, AFRO AMERICANS HAVE LESS ACCESS TO CARE, BUT THAT’S NOT THE REASON FOR THE LUNG CANCER.>>THANK YOU.>>ALL RIGHT SO–>>[INDISCERNIBLE].>>SO YES, MANY YEARS MENTHOL CIGARETTES WHICH ARE 80% OF THE CIGARETTES THAT AFRICAN AMERICANS COMPARED TO ABOUT 20% OF EUROPEAN AMERICANS. THAT WAS THOUGHT TO BE A CAUSE AND A CONTRIBUTOR TO LUNG CANCER, AND THE RATIONAL WAS, WELL, MENTHOL SORT OF ANESTHETIZES THE THROAT AND SO YOU CAN SMOKE AND INHALE MORE DEEPLY AND HOLD THE SMOKE IN MORE, AND SO, OUR COLLABORATOR BILL WATT WHO USED TO BE HERE AT NCI PUBLISHED THE DEFINITIVE PAPER ABOUT 2 YEARS AGO IN TERMS OF THE NATIONAL CANCER INSTITUTE THAT NO, MENTHOL CIGARETTES WERE NOT RESPONSIBLE FOR–THEY WERE NOT ANY DIFFERENT THAN REGULAR CIGARETTES IN AFRO AMERICAN OR EUROPEAN AMERICANS AND AGAIN REED RYAN IN OUR GROUP THAT’S NOW [INDISCERNIBLE]. SO VERY NICE HIGHWAY POGHT SIS MECHANISTICALLY VERY ATTRACTIVE, BUT HAPPENED TO BE WRONG AND IT’S CALLED THE SCIENTIFIC METHOD AND [INDISCERNIBLE]. THE LAST THING I’LL SAY, IF THERE’S NO MORE QUESTIONS, FREQUENTLY I ASK WHEN I GIVE TALKS AND THE 1S I SELDOM REFUSE ARE THOSE GUY GRADUATE STUDENTS
STUDENTS AND POST DOCS AT VARIOUS MEDICAL SCHOOLS AND THEY USUALLY HAVE 1 PERSON THEY CAN TALK TO EACH YEAR. SO THE QUESTION IS, HOW MANY OF YOU ARE TRYING TO PROVE YOUR HYPOTHESIS? AND I’M NOT GOING TO ASK YOU TO HOLD UP YOUR HAND OR NOT, BUT ABOUT HALF THE PEOPLE WHO ARE GRADUATE STUDENTS AND POST DOCS IN THE UNITED STATES AND THESE MULTITELESCHOOLS THAT I–MULTIPLE SCHOOLS I GO TO SAY THEY’RE TRYING TO PROVE A HYPOTHESIS. THAT’S NOT THE SCIENTIFIC METHOD. THEY’RE TRYING TO DISPROVE THE HYPOTHESIS. AND TRYING TO PROVE YOUR HYPOTHESIS THAT YOUR [INDISCERNIBLE] HAS LEADS TO MANIPULATION DATA AND THE MENTOR ISN’T ACTUALLY LOOKING AT PRIMARY DATA, KD–SALLY WELL TO RETRACTION OF A PAPER INCLUDING THE VERY BEST SCIENTIST YOU KNOW INCLUDING THOSE WHOSE PUBLISHED PAPERS IN CELL, CANCER CELL, NATURE AND A LOT OF THOSE PAPERS HAVE BEEN RETRACT SAID BECAUSE THE POST DOC IS [INDISCERNIBLE]. HYPOTHESIS, THAT IS [INDISCERNIBLE] BY THE [INDISCERNIBLE]. SO DON’T DO THAT.>>OKAY, THANK YOU.>>[ APPLAUSE ] [LAUGHTER]

9 Comments

  • Reply Raj Patel June 21, 2019 at 9:42 pm

    👌👍

  • Reply Raj Patel June 21, 2019 at 9:43 pm

    Why is she here if she has allergic reaction?

  • Reply Raj Patel June 21, 2019 at 9:44 pm

    I hope she is not allergic by the time we Rdone with 1:59th hour

  • Reply Raj Patel June 21, 2019 at 9:44 pm

    Sorry but please laugh

  • Reply Raj Patel June 21, 2019 at 9:45 pm

    Bottle neck is right

  • Reply Raj Patel June 21, 2019 at 9:46 pm

    Research should not be because u want a paycheck for your family

  • Reply Raj Patel June 21, 2019 at 9:46 pm

    I like this live session

  • Reply Raj Patel June 21, 2019 at 9:46 pm

    I will turn the floor to you sweetie!!!

  • Reply Raj Patel June 21, 2019 at 9:48 pm

    Forget the files, let's go to beach and discuss! Do you smoke cigars? All students should be on the beach by now to listen to this amazing knowledge and opportunity!

  • Leave a Reply