TODAY, BY THE WAY, IS THE 324th SESSION OF THIS COURSE. SO, SOMETHING MUST BE GOING RIGHT BECAUSE THERE IS A LARGE AND SUSTAINED AUDIENCE ON SITE AND SEVERAL HUNDRED ON LINE, AND THEN IN THE VIDEO ARCHIVE IT'S NOW UP, AS OF YESTERDAY, TO 38 DIFFERENT COUNTRIES. SO PARTICULARLY FOR STUDENTS, WE WANT YOU TO ASK QUESTIONS, SPEAK UP. DON'T GIVE A SPEECH. ASK A QUESTION. AND REALIZE THAT THE WHOLE WORLD IS LISTENING. SO THEY KNOW WHO YOU ARE. SO THE WHOLE PURPOSE OF THIS COURSE, AS YOU KNOW, IS LIGHT THE TWO FOLKS ON THE BROOKLYN BRIDGE, WHICH I KEEP REITERATING. MAKE BELIEVE ONE IS A TRANSLATIONAL SCIENTIST AND THE OTHER IS A BISQUE SCIENTIST AND THEY ARE STANDING THERE IN THE MIDDLE OF THE EAST RIVER TRYING TO LEARN A COMMON LANGUAGE. AND THAT'S BASICALLY WHAT ALL THIS IS ABOUT. SO IT'S A COURSE IN BRIDGE BUILDING, IF YOU WILL. AND YOU MAY RECALL THAT ALTHOUGH MOST OF OUR BRIDGES INVOLVE A DISEASE AND A TRANSLATIONAL PHYSICIAN, A PATIENT AND A BASIC SCIENTIST, WE HAVE ALSO HAD EXTRAORDINARY BRIDGES, ONE THE BRIDGE GOING TO WORK IN THE COSMOS, PARTICULARLY ADVANCED IMAGING TECHNOLOGY. THERE HAVE BEEN BRIDGES TO BIOLOGICAL WORK CONDUCTED IN THE DEEP SEA VENTS UNDER THE FLOOR OF THE OCEAN AND THE FINDING OF ORGANISMS THAT ARE GRANDFATHERS OF INFECTIOUS ORGANISMS THAT ARE PRESENT ON EARTH. SO THERE ARE BRIDGES THAT ARE BROADLY-BASED AND THE WHOLE BASIS OF SCIENCE IS A SERIES OF BRIDGES. IT'S NOT ALL IN ONE DIRECTION. I GUESS YOU COULD SAY, THERE ARE MEN BROOKLYNS. AT ANY RATE, TODAY'S BRIDGE IS A BIT UNIQUE. BUT FOR JUST A MOMENT, WHAT ARE THESE THINGS -- WHAT ARE THESE COMPOUNDS AND ALL JUST GLANCING AT THEM, THEY HAVE SOME IDEA OF WHAT THEY ALL HAVE IN COMMON. SO WHAT THEY ALL HAVE IN COMMON IS THAT THEY ARE BIOLOGICALLY PRODUCED BY LIVING ORGANISMS, OR SPECIES, BY YEAST, BY MICROORGANISMS, BY PLANTS, AND A GREAT VARIETY OF SPONGES AND SO FORTH. AND UNDOUBTEDLY THERE ARE MANY OTHERS BESIDES THE ONES OF I HAVE LISTED HERE AND MANY MORE TO COME BECAUSE THERE IS VERY ACTIVE INTEREST THROUGHOUT THE WORLD LOOKING FOR NATURAL PRODUCTS THAT COULD BE USEFUL IN A CLINICAL SETTING. AND THERE IS A SORT OF UNDERLYING ASSUMPTION THAT THESE PRODUCTS ARE MADE BY THESE LIVING THINGS AS PART OF SOME BIOLOGICAL DEFENSE MECHANISM, PERHAPS, AND THAT SEEMS TO BE THE UNDERLYING THEORY THAT PERVADES US AS WHY THEY ARE THERE AND WHEN PEOPLE ASK THAT QUESTION, WHY DO PLANTS HAVE THIS OR TREES HAVE THIS? BUT TODAY, WE ARE GOING TO V. ANOTHER BRIDGE. THIS IS A BRIDGE BETWEEN A TREE AND CANCER. OUR MAIN SPEAKER, SUSAN BAND HORWITZ, SAID TAXOL IS THE KIND OF STRUCTURE THAT ONLY A TREE WOULD MAKE. NOW IT'S VERY PROFOUND, I THOUGHT REMINDING ME OF ANOTHER PROFOUND STATEMENT, THE FIRST AND LAST LINE OF JOYCE KILMER'S FAMOUS POEM, I THINK THAT I SHALL NEVER SEE A POEM AS LOVELY AS A TREE. POEMS ARE MADE BY FOOLS LIKE ME BUT ONLY GOD CAN MAKE A TREE. SO, THIS TREE IS THE YOO, THE PACIFIC YEW. AND I NEGLECTED TO MAKE A PICTURE OF IT. BUT IT'S BARK IS SOMETHING THAT CAN BE SORT OF PEELED OFF AND SOME OF THESE ARE HUGE TREES. AND THE NATIVE-AMERICANS USED THIS BARK OR THE LEAVES OF THE TREE, IN A GREAT VARIETY OF WAYS, AS YOU CAN SEE, EVERYTHING YOU CAN THING OF TO RUB IT, TO SOAK IT, DRINK A BATH IN IT, SMOKE IT, CHEW IT ON THE WOUNDS, ET CETERA, AND IT ALL HAD TO DO WITH SOME POSSIBLE BENEFIT IN GIVING STRENGTH AND PAIN RELIEF. HOWEVER, IT'S THE WORK OF SUSAN BAND HORWITZ, WHICH WE'LL HEAR ABOUT TODAY, THAT HELPED TO PUT THE PRODUCT OF OF THIS TAXOL ON THE MAP IN TERMS OF BEING A POWERFUL AND UNIQUELY-ACTING ANTI-CANCER DRUG. AND SO TODAY, IT'S PROBABLY ONE OF THE TOP DRUGS USED IN CANCER TEAMO THERAPY AND A VARIETY OF TYPES OF CANCER. -- CHEMOTHERAPY -- AND IT HAS BEEN AROUND PRETTY MUCH, SINCE THE 1970s OR EARLIER. SO WE ARE FORTUNATE TO HAVE TWO OUTSTANDING SPEAKERS TO DISCUSS THIS IMPORTANT QUESTION. THIS IS A REFERENCE FROM THE PNAS, WHICH I WOULD URGE ALL OF YOU TO READ. IT'S A MARVELOUS PROFILE OF SUSAN HOROWETS, HER LIFE IN SCIENCE, A LITTLE BIT OF HER LIFE OUTSIDE OF SCIENCE, AND IT'S EXTREMELY MOTIVATING. SHE AND I HAVE BEEN FRIENDS FOR MANY, MANY YEARS BUT WHEN I READ THIS ARTICLE, I FELT A VERY STRONG EMOTIONAL TOUCH TO REALIZE WHAT IT SYMBOLIZES. I WOULD URGE YOU TO READ THIS. IT IS ON THE DEMYSTIFYING MEDICINE WEBSITE, AND IT TELLS A REMARKABLE STORY. SO, OKAY, OUR FIRST SPEAKER IS GOING TO BE SUSAN BAND HORWITZ. SUSAN GOT HER PH.D. AT BRAND ICE UNIVERSITY IN THE EARLY DAYS OF BRANDEIS, AT A TIME WHEN WOMEN DID NOT FIND IT EASY TO ENTER INTO GRADUATE SCHOOLS. AND WILL BEING A YOUNG AND REALLY UPWARD COMING SCHOOL, HAD AN EXTRAORDINARY DYNAMIC FACULTY, INCLUDING NATHAN KAPLAN, WHO IS A LEADING ENSMOLOGIST AND GREAT MAN OF THE ERA. AND SO SUSAN WENT AND GRADUATED, AND THEN AT THE TIME WHEN SHE HAD TWIN CHILDREN, IT WAS NOT QUITE POSSIBLE TO GO AND TAKE A FULL-TIME JOB SOME PLACE. SHE WAS FORTUNATE IN BEING ABLE TO WORK AT TUFTS UNIVERSITY IN THE DEPARTMENT OF PHARMACOLOGY AS A PART-TIME PERSON. HER WORK THEN TOOK HER INTO THE FIELD OF PHARMACOLOGY, SMALL MOLECULES AND PARTICULARLY THE EMPHASIS THEN WAS THE DEVELOPMENT OF ANTI-FOLIC ACID DERIVATIVES. FROM THERE, SHE WAS AT EMORY FOR A SHORT PERIOD OF TIME. IN 19 -- I FORGOT THE YEAR. 70? 78. OKAY. 67. SHE AND HER HUSBAND, MARSHAL, CAME TO JOIN THE FACULTY AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE, ANOTHER SCHOOL, A NEW SCHOOL, BUT THAT HAD DEVELOPED ABOUT 10 YEARS EARLIER. AND THE PHARMACOLOGY DEPARTMENT THERE SHE APPARENTLY RECENTLY THOUGHT THEY WOULD ONLY BE THERE FOR A SHORT TIME, BUT SHE HAS BEEN THERE FOR EVER SINCE. SHE HAD WORKED ON MECHANISMS OF DRUG ACTION AT A FUNDAMENTAL LEVEL AND WAS DOING OUTSTANDING WORK WHEN SHE WAS APPROACHED ABOUT UNDERSTANDING THE MECHANISMS OF THIS DRUG, TAXOL, WHICH HAD BEEN DESCRIBED IN A THERAPEUTIC SENSE AND A CHEMICAL SENSE, BUT NOBODY KNEW HOW IT WORKED. IT WAS HER WORK WITH TAXOL THAT NOT ONLY PUT THE DRUG ON THE MAP BUT ALSO CATALYZED HER CAREER, WHICH HAS BEEN JUST EXTRAORDINARY EVER SINCE. THIS IS RECOGNIZED BY THE WORLD. AMONG THE MANY AWARDS THAT SHE HAS RECEIVED IS THE CANADIAN GARDENER INTERNATIONAL AWARD, THE AMERICAN CANCER SOCIETY MEDAL OF HONOR, BRISTOL-MYERS SQUIBB AWARD FOR DISTINGUISHED ACHIEVEMENT IN CANCER RESEARCH, ET CETERA. AND SHE IS ALSO AN ELECTED MEMBER OF, WHAT I GUESS ARE THE BIG 4. NATIONAL ACADEMY OF SCIENCES, THE NATIONAL ACADEMY OF MEDICINE, THE ACADEMY OF ARTS AND SCIENCES AND ALSO THE AMERICAN PHILOSOPHICAL SOCIETY. THAT'S THE ONE THAT WAS FOUNDED BY BENJAMIN FRANKLIN. AT ANY RATE, IT'S A GREAT PLEASURE TO HAVE YOU WITH US, SUSAN, BUT IN JUST A MOMENT. NOW, OUR SECOND SPEAKER IS JUNG-MIN LEE, WHO IN THE WOMEN'S MALIGNANCY BRANCH HERE AT THE NATIONAL INSTITUTES OF HEALTH, SHE GRADUATED FROM MEDICAL SCHOOL IN SOUTH KOREA, DID A RESIDENCY AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE -- THIS IS OLD HOME WEEK FOR MANY OF US -- AND THEN A CLINICAL FELLOWSHIP IN BREAST CANCER FUNCTIONAL IMAGING AT MEMORIAL SLOAN-KETTERING. SHE CAME TO NCI FOR ONCOLOGY TRAINING AND SUBSEQUENTLY JOINED THE MOLECULAR SIGNALING SECTION OF THE WOMEN'S CANCER CLINIC. SHE IS AN NIH LASKER CLINICAL RESEARCH SCHOLAR AND WORKS PRIMARILY IN CLINICAL TRIALS AND BASIC MECHANISMS INVOLVED IN DRUG ACTION OF CANCERS WHICH HAVE UNIQUE MARKERS, SUCH AS BRCA OR TRIPLE NEGATIVE BREAST CANCER, ET CETERA. SO WE ARE VERY DELIGHTED TO HAVE BOTH OF YOU WITH US AND LOOK FORWARD TO YOUR TALKS. >> SUSAN BAND HORWITZ: THANK YOU FOR THIS. YOU KNOW EVERYTHING THERE IS TO KNOW ABOUT ME NOW. I'M DELIGHTED TO BE HERE AND THANK YOU ALL FOR COMING. I HOPE THAT WHEN I FINISH AND DR. LEE FINISHES, YOU'LL KNOW A LOT MORE ABOUT TAXOL THAN YOU DO NOW. SO, I HAVE NO DISCLOSURES AND I HOPE YOU'LL LEARN SOMETHING ABOUT THE HISTORY OF THE DRUG, THE MECHANISMS AND ROLE OF NATURAL PROCESSES AND DEVELOPMENT OF DRUGS. SO, HERE WE SEE A BRANCH OF A TREE CALLED TAXIS FOAL QUA. IT IS FROM THE BRANCH OF THIS TREE FROM THE BARK THAT TAXOL WAS ORIGINALLY ISOLATED. AND THIS STORY GOES WAY BACK BECAUSE IT WAS IN THE REALLY IN THE 1950s THAT THE DEPARTMENT OF AGRICULTURE AND THE NATIONAL CANCER INSTITUTE CAME TOGETHER AND SAID, COULD WE FIND SOME NEW DRUGS FROM NATURAL PRODUCTS FOR THE TREATMENT OF CANCER? AND IN 1962 IN THE SUMMER, THEY SENT A GROUP OF COLLEGE STUDENTS, DR. BARCLAY, WHO WAS A YOUNG BOTANIST FROM HARVARD, TOOK THE STUDENTS OUT SIMPLY TO COLLECT PLANTS, TWIGS, BRANCHES, AND THEY WENT PARTICULARLY ON THE WEST COAST AND THE TREES AND BARK FROM THIS TREE WAS ISOLATED FROM OREGON AND IT SAID THAT IT WAS ON THE VERY LAST DAY BEFORE THE STUDENTS WERE GOING BACK TO COLLEGE. AND WE WERE VERY FORTUNATE THAT THE MATERIAL WAS SENT TO TWO TRULY OUTSTANDING MEDICINAL CHEMIST, WHO WERE THEN AT THE RESEARCH TRIANGLE INSTITUTE IN NORTH CAROLINA. YOU HAVE TO REMEMBER IT WAS THE 1960s AND THEY WERE ABLE TO ISOLATE TAXOL FROM THE BARK OF THIS TREE, WHICH IS TRULY AMAZING. IN ADDITION, THEY GOT THE STRUCTURE RIGHT, WHICH WAS VERY DIFFICULT IN THE 1960S. AND THEY ISOLATE TODAY FROM THE BARK AND THE QUANTITY IN THE BARK IS ABOUT.0001 PERCENT THE WEIGHT OF THE BARK. SO THEY REALLY DID A FANTASTIC JOB. I WANT TO JUST MENTION THIS BECAUSE I WOULD BE AMISS IF I DIDN'T. WE LEARNED A LOT MORE RECENTLY ABOUT THESE TREES. AND THIS IS TRUE IN ALL ASPECTS OF SOME OF THE DRUGS WHICH HAVE BEEN ISOLATE FRIDAY NATURAL PRODUCTS. IN THE CASE OF TAXOL, THERE ARE FUNKY THAT LIVE IN THE BARK -- FUNGY -- AND THEY ARE IN A SYMBIOTIC RELATIONSHIP WITH THE BARK AND THEY ARE BOTH RESPONSIBLE FOR THE FACT THAT TAXOL IS MADE BY THE TREE. AND THIS IS A FASCINATING FIELD, BUT THE MORE WE LEARN ABOUT THESE VARIOUS COMPOUNDS, SOME OF WHICH YOU MENTIONED IN YOUR SLIDE, WE FIND THAT THERE IS MORE THAN JUST ONE ORGANISM THAT IS INVOLVED IN THE PREDICTION OF THESE COMPOUNDS. AS YOU ALREADY HEARD, THERE ARE MANY MOLECULES THAT I CAN SAY THAT CHANGED THE WORLD, AND YOU CAN SEE MANY OF THEM ARE FROM NATURAL TROUGH DUCTS, TREES, MOLDS, FUNGUS, PERIWINKLE PLANT AND TAXOL IS ADDED FROM THE YEU TREE. SO HOW DID I EVER START TO WORK WITH TAXOL? I HAD A LAB AT ALBERT EINSTEIN, AN ASSISTANT PROFESSOR. I WORKED ALREADY WITH DRUGS AND I MY LAB WAS VERY INVOLVED IN GLIOMICE IN AT THAT TIME AND I RECEIVED THIS LETTER FROM THE NATIONAL CANCER INSTITUTE. OLD MAIL, WE USED TO PUT A STAMP ON LETTERS. IT SIMPLY SAID, WOULD YOU STUDY THIS COMPOUND IN YOUR SYSTEM? NOW, I HAD NEVER HEARD OF TAXOL. THERE WAS AT THAT POINT, ONE PAPER IN THE LITERATURE THAT WAS THE LANDMARK PAPER THAT MONROE AND COLLEAGUES HAD PUBLISHED IN WHICH THEY SHOWED THE STRUCTURE OF THE DRUG. AND IT WAS CORRECT. AND THIS WAS PUBLISHED IN THE JOURNAL OF MORE THAN CANCER SOCIETY IN 1971. I DIDN'T READ THAT JOURNAL. I DIDN'T KNOW ABOUT IT. TODAY, THERE ARE 28,000 PAPERS THAT HAVE BEEN PUBLISHED WHICH HAVE TAXOL OR ITS GENERIC NAME, PACLITAXEL, IN THE TITLE OF THE PAPER. SO IT'S REALLY QUITE A STORY. WHAT THEY JUST SAID, WILL YOU STUDY IT? IT HAD NOTHING TO DO WITH PROTEIN SYNTHESIS. I HAD A NEW GRADUATE STUDENT IN THE LAB AT THAT TIME. WE WERE LOOKING FOR A THESIS PROJECT FOR HIM AND WE LOOKED AT THE STRUCTURE, WHICH I'LL SHOW YOU IN A MINUTE. IT'S VERY INTERESTING. AND I THOUGHT, WELL,, I SAID TO PETER, IF AFTER A MONTH IT'S NOT INTERESTING, WE'LL HAVE TO GO TO ANOTHER THESIS PROJECT. WE GOT THE 10 MILLIGRAMS. BUT IN BETWEEN, WE WORKED IN THE BRONX IN THE ALBERT EINSTEIN COLLEGE OF MEDICINE AND ONE OF THE REALLY WONDERFUL THINGS IN THE WORLD THAT IS VERY CLOSE TO US, THE NEW YORK BOTANICAL GARDENS AND SOCIETY. WE WENT OVER THERE AND SAID, WHAT DO YOU KNOW ABOUT THIS TREE? THEY SAID IT'S VERY GOOD SPECIMEN. IN GREENWICH, CONNECTICUT AT THE CHURCH. SO WE WENT TO THE CHURCH AND I COULDN'T FIND IT. I WENT INSIDE THE CHURCH AND THEY SAID, IN THE BACK, IN THE CEMETERY YOU'LL FIND THIS TREE. SO HERE IS THE TREE. AND IF YOU GO TO THE BRITISH AISLES, YOU'LL FIND MANY OF THESE TREES IN CEMETERIES BECAUSE IT'S BELIEVED THE ROOTS OF THIS TREE CAN TALKED TO THE DEAD AND REVEAL THEIR SECRETS. THIS TREE IS ASSOCIATED WITH DEATH BECAUSE THE VERY SUPPLE SOFT WOOD. AND IT WAS USED BY ROBIN HOOD TO MAKE THE BOWS AND ARROWS WHICH WERE VERY IMPORTANT IN THE ENGLISH/FRENCH WAR. AND IF YOU READ SHAKESPEARE NOW AND YOU READ TS ELLIOT, YOU'LL READ ABOUT THE YOO TREE AS A SYMBOL OF DEATH. -- YEW TREE. MY GRANDCHILDREN POINTED OUT TO ME THAT IT ISN'T ONLY AN ANCIENT ENGLISH LITERATURE. I'M SORRY TO SAY, 3 1/2 INCH YEW. SO THE YEW TREE IS SOMETHING ASSOCIATED WITH DEATH. NOW I WANT YOU TO JUST LOOK AT THE STRUCTURES OF THESE DRUGS AND -- IS THERE A POINTER ON THIS? OKAY. SO THIS IS THE STRUCTURE OF TAXOL. AND THIS IS THE ACTUAL STRUCTURE THAT IS ISOLATED FROM THE TREE. YOU CAN SEE IT'S VERY COMPLEX, ARCHITECT REALLY COMPLEX. WHEN I SAW THIS FOR THE FIRST TIME, I LOOKED THAT THE STRUCTURE AND IT'S A VERY BEAUTIFUL STRUCTURE. YOU HAVE A 6, 8 AND FUSED 6-MEMBER HERE. YOU HAVE A REALLY UNUSUAL 4-MEMBER RING AND HAVE YOU TWO SIDES. C13 IS VERY IMPORTANT. IT'S THE SIDE CHAIN IS REMOVED, THIS DRUG IS COMPLETELY INACTIVE AND IT'S REFERRED TO AS BACKA TIN. IT'S IMPORTANT NOW BECAUSE HOW IS TAXOL MADE TODAY? IT'S NOT MADE SYNTHETICALLY. THERE ARE SYNTHETIC WAYS OF MAKING IT BUT THEY ARE SO COMPLEX AND STARTING WITH VERY EXPENSIVE MATERIALS, THAT IT'S STILL CHEAPER AND BETTER TO MAKE THE DRUG FROM PARTS OF THE TREE. SO THIS PART CAN BE ISOLATED FROM THE NEEDLES OF THE TREE AND THEN SEMI-SYNTHETICALLY, YOU FIRST WORKED OUT BY BOB AT THE UNIVERSITY OF PENNSYLVANIA, YOU CAN PUT THE SIDE CHAIN ON. THE OTHER WAY THE DRUG IS PREPARED IS ACTUALLY BY TISSUE CULTURE, PLANT TISSUE CULTURE, PARTICULARLY IN GERMANY THEY MAKE A LOT OF TAXOL FROM TISSUE CULTURE. SO THE STORY OF HOW ITS IT'S MADE IS QUITE INTERESTING. THIS IS TAXOL DRUG IN BREAST CANCER. YOU'LL HEAR -- [ INAUDIBLE ] THERE IS CABAZITAXEL WHICH IS ANOTHER DERIVATIVE AND THEN A IMPORTANT DRUG WHICH IS ACTUALLY INJECTABLE SUSPENSION OF PROTEIN PARTICLES. IT'S EXACTLY THE NANOPARTICLE WHICH HAS BEEN A VERY USEFUL DRUG. SO, MOST OF YOU PROBABLY KNOW WHAT TAXOL DOES IS IT INTERACTS WITH MICROTUBULES, A VERY IMPORTANT COMPONNT OF THE CYTOSKELETON AND THE CYTOSKELETON, AS YOU KNOW, IS MADE UP OF MANY DIFFERENT PROTEINS, MAINLY ACTINS, INTERMEDIATE FILAMENTS AND MIKE TUBES WITH HUNDREDS OF PROTEINS THAT ARE INVOLVED. AND THE MICROTUBULES, WHICH IS THE COMPONENT TO WHICH TAXOL BINDS IN THE CELL, IS VERY INVOLVED IN IMPORTANT THINGS IN THE CELL, MITOSIS, ORGANELLES MOVING, MEMBRANES, NERVE CELLS, CHANGING SHAPE, ALL OF THESE THINGS REQUIRE NORMAL MICROTUBULES. AND WHEN TAXOL BINDS TO THE MICRO TUBE, AS I'LL SHOW YOU, AT A SPECIFIC BINDING SITE, THEN WE SEE MANY OF THESE ACTIVITIES OF THE CELL ARE INACTIVE AND DON'T BEHAVE APPROPRIATELY. AND THAT'S WHAT I WANT TO SHOW YOU. SO HERE YOU CAN SEE A NORMAL CELL THAT IS DIVIDING, AND WHEN TAXOL BINDS TO THE MICROTUBULES, IT'S NO LONGER ABLE TO -- THIS ISN'T WORKING. AS YOU CAN SEE, THE MICROTUBULES ARE RESPONSIBLE FOR BREAKING THE -- MOVING THE CELLS APART. AND WHEN TAXOL BINDS TO THESE MICROTUBULES, THEY CAN NO LONGER DIVIDE THE CELLS. BUT WHAT I WANT TO SHOW YOU, IN ADDITION, THE FACT THAT TAXOL BLOCKS CELL DIVISION, IT DOES MANY OTHER THINGS TO CELLS. FOR EXAMPLE, HERE YOU SEE NORMAL CELLS AND YOU CAN SEE THE MICROTUBULES HERE IN RED. THE MICROTUBULES ARE IMPORTANT NOT ONLY IN CELL DIVISION BUT THEY ARE VERY IMPORTANT FOR ALL THE ACTIVITIES THAT TAKE PLACE IN A CELL. FOR AN EXAMPLE, RECEPTINS, ANDROGEN RECEPTINS MOVE ALONG MICROTUBULES. KINASE, VIRUSES CAN MOVE MICROTUBULES. SO THE POINT THAT I'M TRYING TO MAKE THAT IS IMPORTANT, IS THAT TAXOL IS MUCH MORE THAN JUST A DRUG WITH MITOSIS, WHICH IT DOES, IT'S AN ANTIMITOTIC AGENT BUT DOES MANY THINGS TO INTERFACE CELLS WICH ARE PROBABLY VERY IMPORTANT IN THE ANTI-TUMOR ACTIVITY OF THIS DRUG. SO HERE IS A NORMAL CELL AND HERE IS A TAX OL-TREATED CELL. AND WHAT YOU SEE HERE ARE THESE VERY UNUSUAL WINDOWS OF MICROTUBULES. AND IF YOU ARE TREATING A PATIENT WITH TAXOL AND YOU LOOK AT THEIR WHITE BLOOD CELLS, YOU WOULD SEE THE BUNDLES OF MICROTUBULES, WHICH INHIBIT SO MANY FUNCTIONS OF A NORMAL CELL. SO ONE THING THAT YOU CAN DO WITH MICROTUBULES, IS YOU CAN ISOLATE TUBUALS AND HAVE IT IN A TEST TUBE. AND WE USED TO DO THAT BY -- ACTUALLY ISOLATING TUBULIN. TODAY EVERYONE JUST CALLS UP AND ORDERS IT AND IT ARRIVES. BUT WHEN WE DID IT, WE ISOLATED THIS STUFF. IT WAS A PROA THREE DAYS OF WORK. WHAT I WANT TO SHOW YOU IS IN RED, YOU SEE THE NORMAL ASSEMBLY OF SOLUBILITY TUBULINS TO A POLYMER. IN YELLOW IS THE NORMAL SITUATION. YOU MAKE THE MIKE TUBAL AND THIS IS DONE AT 37 DEGREES. NOW IF YOU ADD OR CHANGE THE TEMP, YOU MAKE IT COLD, OR ADD CALCIUM, NORMAL MICROTUBULES DEPOLYMERIZE. IN THE PRESENCE OF TAXOL, YOU ELIMINATE ANY LAG PERIOD AND YOU MAKE MICROTUBULES WHICH DO NOT DEPOLYMERIZE IN THE COLD OR IN THE PRESENCE OF TAXOL. THEY ARE ABSOLUTELY STABLE. AND IF YOU TAKE A NORMAL MICROTUBULE AND ADD TAXOL, YOU INSTANTLY SAFE IT. SO WE KNEW THERE HAD TO BE A BINDING SITE ON THE MICROTUBULE FOR TAXOL. AND THAT SEEMED TO ME THE IMPORTANT THING TO FIND OUT. WHAT IS THE BINDING SITE? HOW DOES TAXOL BIND TO IT? AND HOW DOES IT STABILIZE THE DRUG? AND THOSE ARE THE QUESTIONS I WANTED TO ASK. SO THIS IS A MICROTUBULE. AND YOU HAVE A ALPHA AND BETA THAT COMES TOGETHER TO MAKE A DIMER. THIS DIMER COMES TOGETHER TO MAKE A PROTOFILL MIN OF ALPHA AND BETAS. IT COMES TOGETHER TO MAKE A HOLLOW TUBE WHICH IS A MICROTUBULE AND THIS IS HIGHLY DYNAMIC, AS I SHOWED YOU. AND IT CAN SWITCH FROM SHRINKING ACTUALLY TO RESCUING. AND THIS IS KNOWN AS DYNAMIC INSTABILITY. VERY IMPORTANT FOR THE ACTIVITY OF TAXOL IN ITSELF, AND THESE ARE THE THINGS THAT ARE A LITTLE BIT RATED WHEN YOU ADD TAXOL. -- OBLITERATED. I WANTED TO MAKE A POINT BECAUSE I WANT TO TALK ABOUT THIS. THIS IS THAT THERE ARE NUMEROUS ISOTYPES. THERE ARE EIGHT ALPHAS AND EIGHT BETA DIFFERENT TUBULIN ISOTYPES WHICH WE CLASSIFY BECAUSE THEY ARE IN THE CAR BOXIL END OF THE TERMINUS THAT INTERACTS VARIOUS INTRINSIC PROTEINS IN THE CELL. AND WHAT ONE OF MY IDEAS IS THAT THESE ACTUAL DIFFERENT ISOTYPES ARE VERY IMPORTANT IN THE ABILITY OF TAXOL AND PERHAPS OTHER DRUGS TO WORK. SO AROUND THIS TIME, BECAUSE I WAS WORKING ON GLIOMICE IN, I WAS INVITED TO A MEETING IN HAWAII WHICH WAS A JAPANESE-AMERICAN MEETING BECAUSE THE JAPANESE HAD ACTUALLY ISOLATEDFULLYO MICE IN. AND WHILE I WAS AT THIS MEETING, I MET THE HEAD OF THE DRUG DEVELOPMENT BRANCH AT THE NCI. I WAS VERY EXCITED. BEFORE.- I TOLD HIM ABOUT THIS DRUG, THIS NEW DRUG I HAD, THAT I THOUGHT WAS VERY INTERESTING. AND HE SAID TO ME, OKAY, SUSAN, WHEN YOU GET HOME WRITE ME A LETTER. SO I WROTE HIM A LETTER AND I SAID, I THINK IT'S DIFFERENT FROM ANY OTHER DRUG THAT WE ARE STUDYING AND I PLAN TO PURSUE THIS. REALLY WHAT I WANTED FROM HIM WAS TO TRY TO GET A TAX OL THAT HAD A LABEL ON IT, LIKE A TRILLIAN WE COULD USE TO GET MORE INFORMATION ABOUT THE BINDING OF THE DRUG. AND I NEVER GOT AN ANSWER FROM HIM. SO, WE WENT AHEAD AS OFTEN IS THE CASE AND DO THE THINGS YOURSELF. I HAD A NEW STUDENT WHO WAS ABLE TO PUT IT ON TAXOL AND WE WERE ABLE TO USE IT. BUT LET ME SHOW YOU ONE MORE LETTER THAT I GOT MANY YEARS LATER WHEN MONROE WAS GETTING READY TO RETIRE. HE WROTE TO ME AND HE SAID, SUSAN, DID YOU EVER SEE THIS LETTER FROM JOHN DURO? DEAR MACHINE ROW, CAN YOU HELP THIS POOR GIRL -- MONROE -- I WOULDN'T A POOR GIRL, EVEN AT THAT STAGE IN MY CAREER. SO, WE WERE ABLE TO GET THIS ON TO THE TAXOL AND WILL WE INCUBATED THE TAXOL WITH CELLS, WITH TUBULIN, AND WE RAN THEM OUT ONE GELS AND WE WERE ABLE TO SHOW THAT WITH ALL OF THE LABELS ON THE BETA TUBULIN. AND I MADE A LEAP AND I SAID, THIS IS GOING TO BE A BETA TUBULIN INTERACTING DRUG. AND WE WERE RIGHT. THAT'S WHAT IT WAS. SO THE FACT IS, HOW DO YOU GO ABOUT STUDYING THE INTERACTION OF A DRUG WITH MICROTUBE YULE? THIS IS NOT A COVALENT BOND. SO IT MAKES IT DIFFICULT TO GET A PIECE OF THE MICROTUBULE WITH THE DRUG ON IT. SO WE DECIDED TO GO THE ROUTE OF PHOTO FINNITY ANALOGUE. I WORKED ON THIS WITH MY COLLEAGUES ATINESTEIN, AND WE PREPARED WITH THE HELP OF MANY WONDERFUL CHEMISTS WHO CAME TO OUR AID, WE NEEDED A PHOTO FIENTY ANALOGUE AND WE ALSO NEEDED A RADIOLABEL SO WE COULD FOLLOW IT, A TRADE YUM, AND WE WERE VERY FORTUNATE TO BE ABLE TO DO THESE EXPERIMENTS. SO THIS IS ABOUT A DECADE OF WORK, IN WHICH WE USED EACH OF THESE DRUGS INDEPENDENTLY. THEY ARE ALL FULL-AFFINITY ANALOGUE. THIS IS A 3 POWER ZITO TAXOL. THIS IS TWO METAAZITOA THIS POSITION AND THIS POSITION AND HERE WE HAD A DIFFERENT COMPOUND THAT WE COULD BIND AT THIS MOLECULE. AND WE EACH STUDIED EACH OF THOSE DRUGS. WE INTERACTED WITH THE POLYMER. WE THEN USED HYDROGEN -- ENZYMES. WE GOT THE SMALLEST PIECE WE COULD WITH THE LABEL AND WE THEN ACTUALLY DID OLD-FASHIONED END TERMINAL SEQUENCING, AND WE DETERMINED WHERE THIS WAS BINDING IN THE MICROTUBULE. SO THIS PART OF THE MOLECULE WAS BINDING AT THE BETA 131. THIS PART OF THE MOLECULE WAS TWO METAAZITO BINDING AT BETA 217-231. AND THIS HERE WAS BINDING AT 282. SO WE BEGAN TO GET SOME IDEA OF HOW THE MOLECULE WAS INTERACTING WITH BETA TUBULIN. BUT TOTALLY UNKNOWN TO ME ON THE WEST COAST, THEY WERE DOING BEAUTIFUL WORK DOING X-RAYS AND ABLE TO GET A PICTURE OF 3.7 ANGSTROM OF TAXOL WITH AN ALPHA BETA DIMER AND HERE YOU SEE IT WITH A BETA DIMER. AND ALL OF OUR THINGS FIT IN BEAUTIFULLY WITH THIS WORK. AND HERE WE CAN SEE THE BINDING SITE FOR TAXOL IN THE BETA TUBULIN. THIS IS CALLED THE M LOOP. AND THE IDEA IS WHEN YOU HAVE TAXOL HERE, IT MODIFIES THE M LOOP SO THAT IT BINDS MORE TIGHTLY TO THE S2 LOOP IN THE NEXT BETA TUBULIN AND THEREFORE YOU'RE STABILIZING THE INTERACTIONS. INTERESTINGLY, THE ALPHA TUBULIN AT THE SAME POSITION, WHERE YOU HAVE THE CAPACITY TO BIND TAXOL, THERE ARE ACTUALLY OTHER NINE AMINO ACIDS, SO THE POSITION IS NOT AVAILABLE FOR THE TAXOL TO BIND. AND IN THIS PICTURE, I WANTED TO SHOW YOU THAT THE TAXOL BINDING HERE, HERE YOU HAVE THE BETA TUBULIN AND THE ALPHA TUBULIN.& THIS IS THE CAR BOXIL END. AND IT'S THE CAR BOXEL END WHICH REALLY IS VERY IMPORTANT BECAUSE THIS DETERMINES WHICH ISOTYPE YOU HAVE AND IT IS ALSO THE PART OF THE MICROTUBULE WHICH INTERACTS WITH MANY OF THE OTHER PROTEINS, WHICH ARE IN THE CELL. SO, THIS IS AN IMPORTANT WAY OF THINKING ABOUT THE IMPORTANCE OF THE ISOTYPES OF THE TUBULIN, WHICH INTERACT WITHIN THE CELL. AND WE HAVE FOUND THAT IN THE PRESENCE OF TAXOL, ALTHOUGH IT'S A DISTANCE, IT MAKES A DIFFERENCE AS TO HOW THESE INTERACT WITH INTRACELLULAR PROTEINS, DEPENDING IF THE TAXOL IS PRESENT IN THE CELL. SO, JUST A LITTLE BIT OF CHRONOLOGY. I'M GOING TO GO BACK TO THE BEGINNING WHEN THE NCI CAME TO START THE COLLABORATION. ACTUALLY WE PUBLISHED OUR FIRST PAPER IN 1979 DEPICTING THIS MECHANISM OF ACTION DESCRIBED, AND IT WAS UNIQUE BECAUSE THERE WERE NO OTHER ANTI-TUMOR AGENTS, WHICH ACTUALLY WORKED IN THIS FASHION. AND NOW OF COURSE WE HAVE OTHER SMALL MOLECULES WHICH DO WORK IN THE SAME WAY. SO, WHAT HAPPENED AFTER THIS, I WANTED TO JUST BRIEFLY GO THROUGH SOME OF THE PROBLEMS, AND THERE ARE LOTS OF PROBLEMS WITH TAXOL. IF YOU LOOK AT THE STRUCTURE, IT'S EXTREMELY HYDROPHOBIC. SO THIS HAS BEEN A CONTINUAL PROBLEM WITH TAXOL, HOW TO GIVE THE TAXOL OUT OF FORMULATED AND AS YOU PROBABLY KNOW, ONE OF THE PROBLEMS IS BECAUSE OF THIS IN SOLUBILITY, IT HAS BEEN USED A COMPOUND WHICH HAS ITS OWN PROBLEMS. IF YOU GIVE CREAMA FORETO A DOG, THE DOG LOSES ITS BLOOD PRESSURE. SO IT'S ALWAYS BEEN A PROBLEM TO KNOW ONE OF THE SIDE EFFECTS FROM TAXOL WHETHER SOME OF THEM ARE DUE TO THINGS LIKE THE CREAMA FOREOR AXE Y'ALLY TO THE DRUG ITSELF. AND THIS HAS BEEN A CONTINUAL PROBLEM. WHEN THE FIRST PATIENT GOT TAXOL, HE DIED. BUT THE DRUG HAD BEEN GIVEN AS EBOWLIS, WHICH SHOULDN'T HAVE BEEN, AND NOW THEN AFTER THAT, THERE WAS A REALLY HIATUS BETWEEN 83 AND 88, WHEN A LOT OF PHARMACOLOGISTS, CLINICIANS, WORKING TOGETHER TO TRY TO GET THIS DRUG BACK INTO THE CLINIC. AND THE REASON IT GOT BACK INTO THE CLINIC IS THAT PATIENTS WERE PRE-TREATED TO OVERCOME THE HYPERSENSITIVITY REACTIONS AND ALSO THE DRUG OF COURSE THE NOT GIVEN AS EBOWLIS. IT WAS GIVEN OVER 24 HOURS. THIS MADE A TREMENDOUS DIFFERENCE. THEN THERE WAS OBVIOUS CLINICAL ACTIVITY WHEN IT WENT BACK INTO THE CLINIC. NOW MANY DRUGS WOULD NEVER HAVE MADE IT. AND IT'S REALLY UNBELIEVABLE WHEN YOU GO BACK AND LISTEN TO THIS STORY, HOW TAXOL OVERCAME SOME OF THESE PROBLEMS. AND I LIKE TO THINK THAT ONE REASON IS THAT WE WERE ABLE TO SHOW THAT THE MECHANISM OF ACTION WITH TAXOL WAS SPECIAL. IT WAS UNIQUE. IT HADN'T PREVIOUSLY BEEN DESCRIBED. AND I THINK THAT WAS IMPORTANT IN THE ABILITY TO PUSH THIS DRUG FORWARD. AND ADVOCATE FOR IT. OF COURSE AT THIS TIME, IT WAS A TREMENDOUS SCARCITY OF THE DRUG TOO BECAUSE IT TAKES ABOUT ONE GOOD-SIDES TREE TO TREAT ONE WOMAN WITH BREAST CANCER. IT'S VERY SMALL AMOUNTS IN THE TREE. IT HAS TO BE PURIFIED. AND SO THIS WAS REALLY A MAJOR PROBLEM. IN SPITE OF THAT, THERE WAS CLINICAL ACTIVITY, PARTICULARLY IN DRUG REFRACTARY OVARIAN AND THEN IN METASTATIC BREAST. AND CONTINUALLY BEING TRIED IN DIFFERENT MALIGNANCIES AND DIFFERENT COMBINATIONS, RADIATION, IMMUNOTHERAPY, BUT IN 1991, THERE WAS A COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT DEVELOPED CALLED THE CRADA. TODAY YOUNG PEOPLE CAN'T UNDERSTAND WHY THERE WERE NO PATENTS. I MEAN PEOPLE SAY THEY WANT TO PATTEN A THING AND -- BUT THE FACT IS, IN THE 60s AND 70s, PEOPLE DIDN'T PATENT EVERYTHING AND MONROE NEVER PATENTED THESE DRUGS HE ISOLATED. WE NEVER THOUGHT OF HAVING A USE OF PATENT. AND THEN HERE IS A DRUG THAT THE NCI HAD DONE MOST OF THE CLINICAL TRIALS ON. THERE WAS NO PATENT AND NO DRUG COMPANY WANTED TO PICK IT UP. SO, THE NCI DEVELOPED A CRADA AND THAT WAS A COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT WHERE A COMPANY COULD GET THE DRUG AND HAVE EXCLUSIVITY FOR SEVEN YEARS AND BRISTOL-MYERS SQUIBB PICKED IT UP. AND THAT'S HOW THAT HAPPENED TO HAPPEN. SO, THEN AND I MUST SAY TO THEIR CREDIT, BRISTOL, THEY GOT THE DRUG ON THE MARKET. THEY STOPPED THE USE OF THE TREE AND THEY STARTED ISOLATING JUST THE BACK TIN PART AND SEMI-SYNTHETICALLY PUT ON THE SIDE CHAIN AND THAT'S HOW THEY GOT ENOUGH DRUG TO DO THE CLINICAL TRIALS ALL OVER THE WORLD. AND AFTER THAT, IT WAS APPROVED FIRST IN 92 FOR REFRACTARY OVARIAN AND THEN BREAST AND NON-SMALL LUNG CARCINOMA AND IT CONTINUES TODAY TO BE APPROVED AND TRIED WITH ALL DIFFERENT KINDS OF THERAPY. SO I JUST WANT TO MENTION ONE THING. WHEN BRISTOL-MYERS SQUIBB TOOK THIS OVER, THEY DECIDED THAT THEY WANTED THEIR NAME TO BE TAXOL, ALTHOUGH TAXOL WAS THE NAME THAT MONROE GAVE THAT DRUG. TAX FROM THE SPECIES AND OL FROM ALCOHOL. THE FACT THAT IT WASN'T ALCOHOL AND HE NAMED IT TAXOL. SOMEHOW BRISTOL WAS ABLE, WITH I GUESS A LOT OF HIGHLY-PAID LAWYERS TO GET THAT TO BE THEIR TRADEMARK AND THEY WROTE TO ME AND EVERYONE ELSE AND SAID, YOU CAN NOT USE THAT WORD ANYMORE. YOU HAVE TO USE THE WORD, PACLITAXEL. ANYWAY, THAT'S HOW WE GOT TO THIS POINT. NOW, THERE ARE OTHER TODAY, MICROTUBULE STABILIZING AGENTS, WHICH IN MANY WAYS ARE LIKE TAXOL BUT HAVE SOMEWHAT UNIQUE BINDING SITES DIFFERENT FROM TAXOL. THAT ARE MICROTUBULE STABILIZING AGENTS, OF COURSE TAXOL. THE OTHER ONE THAT IS APPROVED FOR METASTATIC BREAST, ALTHOUGH I DON'T KNOW HOW MUCH IT IS USED, IS [ INAUDIBLE ] WHICH COMES FROM A BACTERIA WHICH WAS ISOLATED FROM IN EAST GERMANY FROM A SOIL SAMPLE FROM SOUTH AFRICA. THESE THREE DRUGS ARE FROM THE SEA. THIS IS FROM THE SPONGE THAT IS IN THE BAHAMAS AND MY LAB HAS WORKED A GREAT DEAL ON THIS DRUG TRYING TO MODIFY IT TO MAKE IT USEFUL AGENT. AND THIS ONE COMES FROM SEA SPONGES FROM AUSTRALIA. AND WE HAVEN'T HAD ENOUGH OF THOSE BECAUSE THEY ARE DIFFICULT TO SYNTHESIZE TO REALLY DETERMINE IF THEY WOULD BE USEFUL AGENTS IN THE CLINIC. SO, THIS WHOLE STORY HAS MANY DIFFERENT ASPECTS. AND I WAS GOING TO TALK MORE ABOUT THE MICROTUBULE ISOTYPES BUT THE TIME IS GOING SO I'M NOT GOING TO SPEND A LOT OF TIME ON IT. LET ME JUST SAY THAT THERE ARE MANY ISOTYPES. THERE ARE EIGHT ALPH ALLIESO TYPES AND EIGHT BETA ISOTYPES. AND THESE ISOTYPES ARE QUITE SIMILAR AND THEY ARE -- THE CAR BOXIL END FINDS THE ISOTYPES AND EACH ISOTYPE IS THE PRODUCT OF A DIFFERENT GENE. IT'S A RATHER COMPLICATED STORY BUT THERE ALSO IS A LOT OF POST TRANSLATIONAL PODIFICATIONS. THIS GIVES YOU THE BETA TUBULIN ISOTYPE AND VERY BRIEFLY, NOTHING WAS KNOWN ABOUT BETA 5. WE MADE A HUMAN ANTIBODY SPECIFICALLY FOR BETA 5 USING THE CAR BOXIL END. IT'S A VERY GOOD ENT BODY. AND NOTHING WAS KNOWN ABOUT THE CELLULAR EXPRESSION SO WE DID EXPERIMENTS. THIS IS ALL DONE BY A GRADUATE STUDENT. WE DID IMMUNOCHEMISTRY TO DETERMINE WHERE BETA 5 WAS. AND IT WAS QUITE INTERESTING BECAUSE AS YOU CAN SEE, IT'S IN GLANCED, IT'S IN DUCTS, IT'S IN ISLETS AND IT SEEMED TO BE IN PLACES OF SECRETION. SO I CAN SHOW YOU HERE IT IS BETA 5 IS IN SECRETION. YOU SEE IT HERE IN THE PANCREATIC DUCTS, IN THE BILE DUCTS. YOU SEE IT MUCH MORE IN LACTATING BREASTS THAN IN NORMAL BREASTS. AND WE ALSO SEE BETA 5 TUBULIN IN MALIGNANCIES, LUNG AND INVASIVE BREAST. NOTHING WAS KNOWN ABOUT BETA 5 TUBULIN UNTIL WE WENT AND WERE ABLE TO MAKE THIS EXCELLENT ANTIBODY TO BETA 5 TUBULIN. I'LL JUST END BY SHOWING YOU A DROP ABOUT BETA 3 TUBULIN. BETA 3 IS KNOWN AND THERE ARE ANTIBODIES TO IT. WE WERE VERY INTERESTED IN WONDERING, DOES A DRUG LIKE TAXOL BIND DIFFERENTLY TO BETA TUBULIN ISOTYPES OR ARE THEY GOING TO BIND THE SAME TO ALL OF THEM? AND IT'S KNOWN THAT BETA 3 TUBULIN, WHICH IS HERE, WE ASK THAT QUESTION WITH THE ANALOGUE AND WE DEVELOPED THIS KIND OF ABILITY TO SEPARATE THE DIFFERENT ISOTYPES OF BETA TUBULIN. WE USED TRITIATED AFFINITY LABELING AND WHAT WE WERE ABLE TO SHOW IS THAT BETA 3, WHICH IS INVOLVED MORE WHEN YOU HAVE DRUG RESISTANCE, MUCH LESS TAXOL BINDS TO BETA 3 THAN LET'S SAY, TO BETA 2. THIS IS VERY INTERESTING, THAT THERE MAY BE A DIFFERENCE IN THE WAY THAT TAXOL BINDS TO BETA TUBULIN ISOTYPES. AND THIS WORK WAS DONE, A VERY COMPLEX SET OF EXPERIMENTS BUT THEN WE LOOKED VERY CAREFULLY AT THE SEQUENCE OF THE DIFFERENT ISOTYPES, AND WE FOUND ONE CHANGED IN THE BETA 3 TUBULIN. AND SO, WHEN WE LOOKED AT YOU DOING A MOLECULAR DYNAMIC SIMULATION TO DETERMINE THE FREQUENCIES THAT TAXOL BINDS TO THIS DIFFERENT ISOTYPE, WHAT WE FOUND WAS THAT WHEN YOU HAD BETA 3 THAT THE BINDING WAS FOR A MUCH SHORTER TIME. THAT IS THAT THE CONFIRMATION OF BETA 3 THAT CAN ACCOMMODATE TAXOL EXISTS FOR A VERY SHORT TIME. SO THE AMOUNT OF BINDING OF TAXOL INTO THE BETA 3 ISOTYPE IS REDUCED FROM HERE TO OTHER ISOTYPES. SO THIS RAISES A VERY INTERESTING QUESTION TO ME. IF YOU HAVE A TUMOR THAT HAS DIFFERENT ISOTYPES IN IT, CAN THAT HELP TO DETERMINE HOW THE TAXOL BINDS? BECAUSE THE TRUTH IS, THAT IF YOU HAVE 100 PATIENTS WITH OVARIAN CANCER, 50 WILL RESPOND TO TAXOL AND 50 WON'T. WHY? WE HAD NO IDEA. COULD IT BE ONE OF THE CONTRIBUTING FACTORS PERHAPS IS THAT DIFFERENT TUMORS HAVE DIFFERENT ISOTYPES AND THE AMOUNT OF TAXOL THAT BINDS TO THE DIFFERENT ISOTYPES IS DIFFERENT? AND THIS IS JUST AN IDEA THAT WE HAD WHETHER THIS WILL PAN OUT. I REALLY DON'T KNOW. SO THESE ARE PRETTY MUCH THE CONCLUSIONS I HAVE NOW, THAT TUBULIN ISOTYPES MAY HAVE A ROLE IN RESPONSIVE TUMORS TO TAXOL AND OTHER DRUGS AND THEREFORE KNOWING THE ISOTYPE CONTENT OF TUMORS MAY AFFECT TAXOL TREATMENT IN VARIOUS WAYS. AND THERE ARE MANY PEOPLE OF COURSE WHO HAVE WORKED ON THESE PROBLEMS OVER THE YEARS. I'M VERY GRATEFUL TO ALL OF THEM. I JUST WANT TO ESPECIALLY MENTION CHOP IN YANG AND HALEY WHO HAS BEEN WITH ME FOR A LONG TIME AND HAVE CONTRIBUTED DRAMATICALLY TO THIS WORK. THANK YOU VERY MUCH. [ APPLAUSE ] >> [ OFF MIC ] >> NO, WE HAVEN'T. THESE ARE COMPLICATED EXPERIMENTS AND WE HAVEN'T BEEN ABLE TO DO THAT. BUT WHAT WE DO KNOW IS THAT THESE OTHER DRUGS AND PARTICULARLY THE ONE I WORK WITH, IT BINDS TO BETA TUBULIN AND IT BINDS IN THE TAXOL BINDING SITE BUT NOT EXACTLY AT THE SAME SITE. SO IN FACT, ONE OF THE THINGS WE ARE LOOKING AT NOW IS WHETHER TAXOL AND DISK ADERMIA LIED CAN WORK TOGETHER AND BE SYNERGISTIC BECAUSE THEY BIND WITHIN THE SAME SITE BUT SLIGHTLY DIFFERENTLY. THANK YOU. >> SUSAN, COULD YOU ISOLATE THE FUNKY FROM THE YEU TREE AND GROW THEM SEPARATE FROM THE TREE AND USE THAT AS A SOURCE? WOULD THAT NOT WORK? I COULDN'T DO THAT BUT PEOPLE THAT WORK HAVE DONE THAT AND THEY PRODUCED SUCH A TINY TINY AMOUNT THAT IT IS USELESS. YES. THAT'S A OTHER WHOLE AREA AND A VERY COMPLEX AREA. DIFFERENT FUDGY CAN BE ASSOCIATED WITH TAXOL AND DIFFERENT TREES AND THE INTERESTING THIS IS THOUGH THEY END UP WITH TAXOL, THE PATHWAY OF ENZYME DIFFERS DEPENDING ON WHAT FUNGI ARE IN THE TREE. BUT THE INTERESTING THING IS THAT, WHERE THEY ARE DOING TISSUE CULTURE, AND I DON'T REALLY UNDERSTAND THIS, BUT THEY CLAIM THAT THEY ONLY HAVE THE DNA FROM THE TREE. AND THEY ARE ABLE TO MAKE THIS DRUG IN TISSUE CULTURE. SO IT'S COMPLEX, OBVIOUSLY, BUT I THINK IN NATURE, WE KNOW THIS SIM BEEOSEIS BETWEEN THESE. AND FOR EXAMPLE, DISK ADERMIA LIED WHICH GROWS IN THE OCEAN, THERE YOU HAVE ALL KINDS OF ORGANISMS INTERACTING, MANY DIFFERENT KINDS OF BACTERIA WHICH ONLY GROW IN THE OCEAN AMONG OTHER THINGS, SO NATURE IS COMPLEX. WHAT CAN I TELL YOU? >> THANK YOU. >> [ OFF MIC ] >> I THINK THE PRE DOMINANT SITE IS THE MICROTUBULE, BUT THERE ARE A NUMBER OF PAPERS, AND I THINK THEY ARE CORRECT, WHERE IT COMBINES TO BCL2, AND I HAVE NEVER STUDIED IT PERSONALLY. I DON'T KNOW WHAT THE MEANING IS. MAYBE YOU KNOW MORE THAN I DO. BUT, YES, THAT IS IN THE LITERATURE, DEFINITELY. >> SUSAN, SOME PATIENTS BECOME RESISTANT TO TAXOL. HOW DOES THAT WORK? >> OKAY. I THINK PATIENTS BECOME RESISTANT TO ALL ANTI-TUMOR DRUGS AND IT'S A VERY COMPLEX THING. FACILITY IT WASN'T SO COMPLEX, SOMEONE WOULD HAVE FIGURED IT OUT. MANY YEARS AGO, PROTEINS WERE ON THE SCENE AND PEOPLE SAID, NO MORE RESISTANCE. OF COURSE THAT HADN'T PROVEN TO BE TRUE AT ALL. THERE ARE SO MANY MECHANISMS THAT ARE INVOLVED IN RESISTANCE. THERE ARE SOME PAPERS IN THE LITERATURE INDICATING THAT TAXOL MAY BE RESISTANT BUT THEN THERE MAY BE OPERATIONS IN THE MICROTUBULE. IN MY EXPERIENCE, AND WE HAVE LOOKED, WE HAVE NEVER -- NEVER BEEN ABLE TO SEE THIS. AND MOST PEOPLE HAVEN'T BEEN ABLE TO REPEAT THESE EXPERIMENTS. IN THE LABORATORY, WE HAVE MANY CELLS THAT ARE RESISTANT TO TAXOL BECAUSE OF ALTERATIONS AND MUTATIONS IN THEIR ACTUAL MICROTUBULES. IN NATURE, A NORMAL SITUATION, I DON'T THINK ANYONE HAS BEEN ABLE TO FIND THAT KIND OF INDICATION. THERE ARE SOME MICROTUBULE DEPOLYMERIZING DRUGS THAT ARE USED AT VERY LOW DOSE FOR DISEASES LIKE GOUT AND FAMILIAL MEDITERRANEAN FEVER AND VERY EFFECTIVE IN TAKEN DAILY. IS TAXOL -- HAS TAXOL BEEN LOOKED AT FOR A LOW-DOSE APPLICATION IN THE WAY THAT OTHERS HAVE AND FOR ANY PARTICULAR DISEASE? >> TO THE BEST OF MY KNOWLEDGE, NO. I MEAN I DIDN'T TALK ABOUT THIS BUT TAXOL IS VERY TOXIC DRUG. PATIENTS WHO TAKE IT, IT'S A PRETTY MISERABLE DRUG TO TAKE. AND I DON'T KNOW ANYTHING ABOUT LOW-DOCETAXEL, ALTHOUGH THERE ARE A NUMBER OF PAPERS. I THINK ONE WAS BY BRUCE CHABNER, IF I REMEMBER CORRECTLY, ABOUT LOW-DOCETAXEL OVER A LONG PERIOD OF TIME. SO LOOK BACK AND LOOK AT THOSE PAPERS. >> I WANT TO SAY SOMETHING ABOUT THE PHARMACOLOGY OF TAXOL. NOT ITS MECHANISM OF ACTION, BUT THIS HYDROPHOBIC MOLECULE IS PUT INTO THE BODY. WHERE DOES IT GO? AND WHY DOESN'T IT EFFECT THE LIVER, FOR EXAMPLE? BUT IT AFFECTS THE BILE DUCTS. DO WE UNDERSTAND THAT? >> WE DON'T UNDERSTAND THAT. IT'S A VERY HYDROPHOBIC DRUG. IT CERTAINLY GOES TO THE HYDROPHOBIC SITES IN TUBULIN. AND AS I SAID, IT'S A VERY TOXIC DRUG. SO OBVIOUSLY IT HAS A LOT OF EFFECTS, AND ONE OF THE MAJOR SIDE EFFECTS HAS A NEUROPROBLEM IN WHICH PATIENTS HAVE A LOT OF PROBLEMS WITH THEIR ARMS AND THEIR LEGS AND I'M SURE DR. LEE WILL TALK ABOUT THAT. SO THE PHARMACOLOGY, IN TERMS OF HALF-LIFE OR THINGS LIKE THAT, I MEAN, WHEN YOU GIVE A DRUG ONCE EVERY THREE WEEKS, THE CONCENTRATION OF THE DRUG IS GOING TO BE EXTREMELY DIFFERENT THE DAY AFTER THE PATIENT GETS IT AND A WEEK AFTER THE PATIENT GETS IT. AND WE KNOW THAT TAXOL DOES DIFFERENT THINGS AT DIFFERENT CONCENTRATIONS. BUT I CAN'T REALLY ADD MORE TO THAT. >> ARE THERE ANYMORE QUESTIONS NOW? OKAY. WE'LL GIVE YOU AN OPPORTUNITY AFTER DR. LEE SPEAKS. THANK YOU VERY MUCH. [ APPLAUSE ] THANK YOU SO MUCH FOR YOUR WONDERFUL TALK. SO NOW SWITCHING GEAR TO THE MORE CLINICAL SIDE. I'M A CLINICAL TRIALIST AND ALSO MEDICAL ONCOLOGIST, MY MAIN FOCUS IS FOR OVARIAN CANCER AND I'M STRICT IN OBGYN PHYSICIAN AND MEDICAL ONCOLOGIST. SO ANYWAY, I HAVE NO DISCLOSURE AND HUMBLE GOVERNMENT SERVANT. SO WHEN I THINK ABOUT OVARIAN CANCER, ONE NAME JUST COMES TO MY MIND, ROSEANNEA FRANKLIN. SHE DID AMAZING JOB IN TERMS OF DISCOVERY OF DNA STRUCTURE BUT UNFORTUNATELY SHE WAS DIAGNOSED WITH OVARIAN CANCER IN 1956. AND TWO YEARS LATER, SHE DIED FROM THIS. WHICH IS A VERY SAD HISTORY. SO, IN 1950s AND 1960S, EVEN EARLY 1970s, WHAT IS SURVIVAL OF OVARIAN CANCER? BECAUSE MANY PEOPLE DIDN'T EVEN MAKE A TWO-YEAR TIME POINT. ABOUT HALF OF THE PEOPLE MADE A TWO-YEAR TIME POINT AFTER DIAGNOSIS. SO OVARIAN CANCER WAS BAD AT THE TIME. SO WE DIDN'T MAKE ANY PROGRESS IN TERMS OF TREATING OVARIAN CANCER. AS YOU SEE HERE, THIS IS RELATIVELY RARE DISEASE. IT'S NOT AS COMMON AS BREAST OR LUNG CANCER AS YOU SEE HERE. BUT OVER THE PAST MANY DECADES, WE HAVE MADE SOME PROGRESS. THE FIRST SURGERY HELPS IN TERMS OF CONTROLLING THE TUMORS. AND WITH DEVELOPMENT, WE MADE SOME PROGRESS AND AS SUSAN SAID, TAXOL CAME IN THE CLINIC AND ALSO THERAPY AND NOW WE ARE DEALING WITH MORE TARGETED AGENT TO IMPROVE THE SURVIVAL OF OVARIAN CANCER. IN 1990S, 80s, WE MADE PROGRESS. SO NOW IN 2020, WE ARE HOPING WE ARE MAKING MORE PROGRESS. SO THESE DAYS, ABOUT 40% OR 45% OF WOMAN CAN MAKE 5-YEAR TIME POINT. VERY LOW PROGRESS, BUT AS SUSAN SAID, AS SHE REVIEWED THE HISTORY, THERE IS SO MUCH HARD WORK BEHIND-THE-SCENES TO EVEN THOUGH YOU SEE ONE OR TWO YEARS, INCREMENTAL, IT'S NEVER REALLY MINIMAL CHANGES. THERE ARE SO MUCH HARD WORK DONE BEHIND-THE-SCENES WITH THE CLINICIANS AND SCIENTISTS. SO AS I SAID, OVARIAN CANCER IS RELATIVELY RARE DISEASE, EVEN FOR THE PAST FEW YEARS, IT DIDN'T EVEN MAKE A TOP 10 MOST COMMON CANCER IN THE UNITED STATES. BUT WHEN IT COMES TO FRACTURED DEATH RATE, WHICH MEANS HOW MANY PEOPLE DIE FROM DISEASE AFTER DIAGNOSIS, THIS IS MOST LETHAL GYNECOLOGIC CANCER IN UNITED STATES, ALMOST TWO THIRDS OF WOMEN DIE FROM OVARIAN CANCER. WHEN I SAY OVARIAN CANCER IT'S NOT A SINGLE DISEASE. IT HAS DIFFERENT HISTOLOGY AND DIFFERENT SUBTYPES BASED ON THE MORPHOLOGY AS YOU SEE HERE. HIGH-GRADE OVARIAN CANCER IS VERY COMMON. IT LOOKS VERY UGLY. POORLY DIFFERENTIATED FORM AND LOW GRADE SISTO OVARIAN CANCER IS LESS DIFFERENTIATEDDED ABOUT RARE SUBTYPES ARE SHOWED HERE. SO BESIDES OUR UNDERSTANDING ON HISTOLOGY, WE ALSO HAVE NOW BETTER UNDERSTANDING ON THE CHARACTERISTICS. SO THIS IS THE MOST COMMON ACCOUNTS FOR ALMOST 80% AND ENDOMETRIAL ARE SUBTYPE. BUT ALONG THE HIGH-GRADE OVARIAN CANCER, THE MOST COMMON SUBTYPE, WE NOW UNDERSTAND ALMOST HALF OF THE HIGH-GRADE OVARIAN CANCER HAS DNA DAMAGE REPAIR PATHWAYS. SO AS YOU HAVE HEARD, BRCA1 AND TWO DRAMATIC ARE HELLATIVELY COMMON IN -- RELATIVELY COMMON IN HIGH-RISK OVARIAN CANCER. WHAT MATTERS IN THIS GENOMIC AREA, BECAUSE THIS TREATMENT IS TAXOL AND CHEMOTHERAPY. AS I PREPARE THIS TALK, I LEARNED A LOT IN TERMS OF HISTORY. I CAME TO KNOW THAT PHASE I CLINICAL TRIAL IN 1987, WHICH SHOWS THE FIRST PKD TAXOL IN CANCER PATIENTS. AND AFTERWARDS, THE TAXOL, YOU NEED ACTIVITY ESPECIALLY IN OVARIAN CANCER PATIENTS WERE PUBLISHED A FEW YEARS LATER. WHY IT IS IMPORTANT? BECAUSE AT THE TIME, EVERYONE THAT IS TREATED WITH PLASMID, CISPLATIN OR CO-PLATINAS A SINGLE THERAPY BUT UNFORTUNATELY MORE PATIENT PROGRESS IN THE THERAPY. SO THERE WAS NOT MANY OPTIONS AT THE PLATINUM THERAPY. TAXOL ACTUALLY SHOWS A SIGNIFICANT POLYMERASE ACTIVITY IN REFRACTARY OVARIAN CANCER PATIENTS, WHICH LED TO THE FAA APPROVAL OF TAXOL FOR PLATINUM REFRACT RALLY ON OVARIAN CANCER IN 1992. AND THEN, WHAT ABOUT WE PUT THE TAXOL IN THE SETTING RATHER THAN GIVING THE -- AFTER PATIENTS DEVELOPED THE PLATINUM RESISTANCE? SO THE CLINICAL TRIAL USED THE PLATINUM CYTOXAN TO COMPARE WITH PLATINUM CISPLATIN HERE, PLUS TAXOLOGY. SO THEY WANTED TO COMPARE WHICH COMBINATIONS ARE BETTER WHEN PATIENTS HAD FIRST -- WHICH INCLUDES FIRST SURGERY AND FOLLOWED BY CHEMOTHERAPY. AS YOU SEE HERE, THIS STUDY IS OPENED IN 1990. AT THE TIME TAXOL WAS NOT FDA APPROVAL. SO TAXOL WAS USED AS DRUG AT THE TIME. SO THIS STUDY WRAPPED IT UP FOR THE PATIENT ABOUT 400 PATIENTS BEEN 1 1/2 YEARS AND THEN STUDIES SHOWED THAT CARBOTAXOL CELT THE MILESTONE IN TREATMENT OF OVARIAN CANCER. AND THEN, AFTERWARDS, THE MANY CLINICIANS WONDER IF MORE IS BETTER? DO WE HAVE TO MIX-AND-MATCH MANY DRUGS OR CARBOPLATIN TAXOL, TWO-DRUG COMBINATION IS ENOUGH? SO YOU MAY THINK THIS IS A CRAZY IDEA BUT AT THE TIME, THAT WAS A VERY EXCITING IDEA. SO, WOULD CARBOPLATIN TAXOL WHICH IS NOW DOSING 175 MILLIGRAM EVERY TWO WEEKS, OVER THREE HOURS AS A CONTROL GROUP AND THEY ADDED WHETHER THESE DRUGS OR CHEMOTHERAPIES. AND THEN WINNER WAS CARBOPLATEN COMBINATION. IN THIS CASE, LESS THE BETTER. IF YOU GIVE MORE CHEMOTHERAPIES IT COULD GIVE MORE TOXICITY WITHOUT GIVING MORE BENEFIT. SO IN THIS CASE, THE CLINICIANS CONFIRMED CARBOPLATIN AND TAXOL COMBINATION IS A WINNER. WE DON'T HAVE OTHER DRUGS. BUT WHAT ABOUT YOU MAY THINK AFTER SUSAN'S TALK YOU MAY THINK CLINICIANS ARE CRAZY, BUT WE ACTUALLY THOUGHT REALLY HARD, WHICH IS A BETTER WAY, WHICH IS MORE EFFECTIVE WAY TO IMPROVE THE CLINICAL ACTIVITY OF TAXOL-BASED THERAPY. SO NOW THE CLINICIANS, THE SCIENTISTS ALSO CAME UP WITH IDEA, SHOULD WE GIVE THE PLATINUM TAXOL BEFORE SURGERY? OR AFTER SURGERY? BECAUSE SURGERIES ARE VERY IMPORTANT. TAKING OUT OLD TUMORS CAN MAKE A HUGE DIFFERENCE IN PATIENT OUTCOME. SO WHAT ABOUT GIVING THE CHEMOTHERAPY BEFORE THE SURGERY? YOU KIND OF -- TUMOR CELLS AND THE SURGERY MAYBE MORE EASIER AND MORE CONCRETE TAKING OUT THE OLD TUMOR CELLS. THE SURGERY GIVEN CHEMOTHERAPY LATER. IT TURNS OUT EITHER YOU GIVE THIS BEFORE SURGERY OR AFTER SURGERY, IT DOESN'T MAKE A HUGE DIFFERENCE. STILL TAXOL AND CARB BILL ERLOTNIB IS A WINNER. NOW JAPANESE THOUGHT OF, WHAT ABOUT WE GIVE THE PACLITAXEL MORE OFTEN? THE STANDARD TREATMENT IS GIVING EVERY THREE WEEKS IN COMBINATION WITH THE CARBOPLATIN. SO THEY USE THE PACLITAXEL 80 MILLIGRAM, A LITTLE BIT LOWER DOSE BUT WEEKLY EVERY WEEK. THE SAME SCHEDULES. IN THIS CASE, AS SUSAN MENTIONED, DIFFERENT SCHEDULES MAKE DIFFERENT TOXICITIES. WHEN PACLITAXEL WAS GIVEN EVERY WEEK, IT ACTUALLY CREATES A MORE PROBLEMS AND MORE BONE MARROW TOXICITIES, SOMETIMES TOXICITIES MORE SIGNIFICANT BUT AS YOU ALSO NOTICE, 80 TIMES 3 IS A MORE DOSE, 240 MILLIGRAMS COMPARED TO 180 MILLIGRAMS GIVEN EVERY THREE WEEKS. SO IT TURNS OUT EVEN THOUGH IT GIVES MORE SIDE EFFECTS, IN THE SETTING OF THE HUGE DIFFERENCE PHARMACOLOGYICALLY, BUT THE JAPANESE PATIENT POPULATION IT IMPROVED SURVIVAL WITH WEEKLY PACLITAXEL WHEN IT IS GIVEN EVERY WEEK. WHICH HAD BEEN ALSO STUDIED IN PATIENTS, WHICH DOESN'T SHOW MUCH DIFFERENCE. EACH MAY HAVE DIFFERENT METABOLISM AND ALSO DIFFERENT SUSCEPTIBILITIES. THEN NEXT QUESTION IS, WHAT IS THE WAY WE DELIVER? WHETHER WE CHANGE THE DELIVERY INTRAVENOUSLY VERSUS INTRAPERITONEALLY? SO 172 IS A CLINICAL TRIAL TO INVESTIGATE, LETS GIVE THE PACLITAXEL NOT NECESSARILY INTRAVENOUSLY BUT INTRAPERITONEALLY. SO ONCE PATIENTS HAD THE SURGERY, THEY REMOVED TUMORS FROM THE ABDOMEN AND THEN PATIENTS HAVE INTRAPERITONEAL PORES BESIDES GETTING THE PACLITAXEL INTRAVENOUSLY ON THE DAY ONE. THEY ALSO GET THE TAXOL INTRAPERITONEALLY. INTERESTINGLY ENOUGH, GIVEN THE CHEMOTHERAPY, INTRAPERITONEALLY IMPROVED SURVIVAL, NOT ONLY PROGRESS IN TERMS OF SURVIVAL BUT ALSO SURVIVAL. WHICH IS A POSSIBILITY BY GIVING INTRAPERITONEALLY MAY IMPROVE DELIVERY OF THE CHEMOTHERAPY TO THE MICROTUMORS AT THE TIME WHEN PATIENT HAS AFTER THE SURGERY. SO, OFFER TREATMENT, WHICH MEANS ONE PATIENT HAD FIRST DIAGNOSIS, THE SURGERY IS CONSIDERED TREATMENT. SURGERY FOLLOWED BY THE CHEMOTHERAPY WHICH INCLUDES TAXOL, AND PACLITAXEL AND CHEMOTHERAPY IS A TREATMENT OVER THE PAST MANY DECADES. AND AS I SAID, INDEPENDENT OF HISTOLOGY, WHETHER A PATIENT HAS HIGH GRADE OR LOW GRADE CLEAR CELL, CHEMOTHERAPY IS STILL STANDARD OF CARE TREATMENT WHETHER THEY HAVE DIFFERENT GENOMICS, WHETHER THEY HAVE BRCA MUTATIONS OR NO BRCA MUTATIONS OR CYCLIN A1. TAXOL PLUS BASIC CHEMOTHERAPY IS A STANDARD TREATMENT OPTION. INTRAPERITONEAL CHEMOTHERAPY MAY BENEFIT THE SELECTED PATIENT POPULATIONS. SO, OVER THE PAST DECADE, WE WANTED TO IMPROVE IN TERMS OF MANAGEMENT OF THE OVARIAN CANCER TREATMENTS. SO TAKE IT TO THE NEXT LEVEL FROM THE STANDARD OF TREATMENT USING THE TAXOL AND PLATINUM-BASED CHEMOTHERAPY. AS I SAID, STANDARD TREATMENT INCLUDES A CHEMOTHERAPY UP TO 6 OR 7 CYCLES WHICH MEANS AFTER THE SURGERY, A PARENT GET A CHEMOTHERAPY ABOUT 5 OR 6 MONTHS MONTHS. AND THEN THEY STOP THE TREATMENT BECAUSE EACH CHEMOTHERAPY CAN CAUSE A SIDE EFFECT, NEUROPATHY, ESPECIALLY FROM THE TAXOL. SOMETIMES VERY SIGNIFICANT. AND PEOPLE DON'T WANT TO LOSE THE HAIR FROM TAXOL BECAUSE WHEN I SEE MY PATIENTS IN THE CLINIC, THEIR QUESTIONS, THE FIRST QUESTION WHENEVER I EXPLAIN OTHER INVESTIGATIONAL DRUGS, THEY ASK WILL I LOSE THE HAIR? HAIR IS REALLY -- YOU MAY THINK IT'S A MINOR THING BUT LOSING HAIR IS A VERY IMPORTANT. SO UNFORTUNATELY, HAIR LOSS, NEUROPATHY, IS ONE OF THE COMMON SIDE EFFECTS FROM TAXOL. SO MOST PEOPLE ACTUALLY -- OR PATIENTS WITH OVARIAN CANCER STOP TREATMENT AFTER 5 OR 6 MONTHS OF CHEMOTHERAPY. SO WHAT WE DID WAS IMPROVE THE UNDERSTANDING ON GENOMICS. IN CONNECTION WITH PHASE III CLINICAL TRIALS, USING THE PARP-INHIBITOR WHICH ESPECIALLY FOR BRCA MUTANT TUMORS. SO THE PATIENT AFTER CHEMOTHERAPY AT THIS TIME POINT, THEY WILL RANDOMIZE EITHER PARP MAINTENANCE UNTIL THEY HAVE PROGRESSION OR -- [ INAUDIBLE ] IN THIS STUDY, THEY GIVE THE MAINTENANCE PARP-INHIBITOR UP TO TWO YEARS TIME POINT AND BRCA MUTANT MAINTENANCE SHOWS SIGNIFICANT IMPROVEMENT IN PROGRESS SURVIVAL WHICH LED TO FDA APPROVAL OF PARP-INHIBITOR IN BRCA MUTANT IN CANCER PATIENT IN 2018. AND ALSO IN TERMS OF OTHER DRUGS, WE HAVE MADE A PROGRESS IN THE MANAGEMENT OF OVARIAN CANCER INCLUDING ANGIOGENNICS, WHICH INCLUDES ANTIBODIES. AS I SAID, CARBOPLATEN PLUCKS PACLITAXEL IS A STANDARD OF CARE TREATMENT AFTER SIX CYCLE, THE STANDARD TREATMENT IS STOP CHEMOTHERAPY. WHAT ABOUT WE CONTINUE THE BEVACIZUMAB AS MAINTENANCE BECAUSE OVARIAN CANCER ANGIOGENESIS IS VERY IMPORTANT IN TERMS OF THE RESISTANCE AND ALSO THE REOCCURRENCE. SO BEVACIZUMAB IS CONTINUED IN THIS GROUP FOR 14 MONTHS AND THEN THEY SHOW SIGNIFICANT IMPROVEMENT IN PROGRESSION-FREE SURVIVAL. SO THIS STUDY LED TO THAT FDA APPROVAL FOR BEVACIZUMAB MAINTENANCE IN OVARIAN CANCER IN 2018. SO, THE FOUNDATION WE ACTUALLY IMPROVE THE SIGNIFICANT SURVIVAL BENEFIT IN OVARIAN CANCER SETTING IN TERMS OF TAXOL AND PLATINUM. BUT NO NOW WE HAVE LEARNED AFTER THE ACTIN, THE FRONT LINE CHEMOTHERAPIES MAINTENANCE WHICH IS PARP-INHIBITOR FOR BRCA MUTATION CARRIERS AND BEV SUES MAB FOR -- MADE SIGNIFICANT IMPROVEMENT. BUT UNFORTUNATELY, REOCCURRENCEY IS COMMON IN OVARIAN CANCER. SO AS YOU SEE HERE, THE OVARIAN CANCER DOESN'T REALLY FORM A SINGLE DISEASE. KIND OF SCRATCH TO THE PARTINIUM T LOOKS VERY UGLY BUT UNFORTUNATELY THIS IS REAL. AND SOMETIMES SYMPTOMS ARE VERY VAGUE AND IT CAN MAKE US SAD AND MOST PATIENTS PRESENT WITH ADVANCED AGE AND TUMORS THAT ARE SPREAD OUT. ONE OF THE CHALLENGES IN OVARIAN CANCER DIAGNOSIS IS SOMETIMES THEY ARE VERY NON SPECIFIC BECAUSE NAUSEA, WHICH DOESN'T USUALLY TRIGGER OVARIAN CANCER IN YOUR HEAD. SO MANY PEOPLE SOMETIMES DON'T THINK ABOUT CANCER POSSIBILITY WHEN THEY HAVE VERY NON-SPECIFIC SYMPTOMS. SO UNFORTUNATELY, ABOUT MORE THAN HALF OF PATIENTS EVEN THOUGH THEY HAVE WONDERFUL DRUGS, THE RECURRENCY IS VERY COMMON. SO WHEN PATIENT HAS REOCCURRENCE, NOW COMBINATION TREATMENT IS STANDARD OF TREATMNT, WHICH IS A CHEMOTHERAPY NECOMBINATION WITH BEVACIZUMAB. SO THIS IS A STUDY WHICH LED TO THE FDA APPROVAL OF A CHEMOTHERAPY AND THE BEVACIZUMAB COMBINATION. SO COMPARED TO THE CHEMOTHERAPY ALONE, WHEN IT'S COMBINED WITH THE BEVACIZUMAB, IT SHOWED THE SIGNIFICANT IMPROVEMENT IN PROGRESSION-FREE SURVIVAL. SO WHEN WE LOOK AT THE MORE DETAILED, PHYSICIANS CHOOSE THE SINGLE-AGENT CHEMOTHERAPY TO COMBINE WITH THE BEVACIZUMAB. BUT WHEN THEY USE TAXOL THE BENEFIT WAS GREATER. SO EVEN THOUGH IT'S COMBINED WITH THE BEVACIZUMAB, TAXOL IS THE WINNER TO DRIVE THE MOST CLINICAL BENEFIT. SO, NOT ONLY USED IN THE SETTING WITH A COMBINATION OF CARBOPLATIN, TAXOL IS A VERY ACTIVE FOR THE PLATINUM-RESISTANT RECURRENT DISEASE AS A COMBINATION WITH BEVACIZUMAB AS SINGLE-AGENT WITH PACLITAXEL. SO NOW WE HAVE ALSO BETTER UNDERSTANDING IN TERMS OF TAXOL AS SUSAN BRIEFLY MENTIONED, BESIDES TAXOL IN INTERRUPTS MICROTUBULES, WE HAVE BETTER UNDERSTANDING OF HOW TAXOL INTERACTS WITH IMMUNE MICRO-ENVIRONMENT AND ALSO IMMUNE DIFFERENT CHEMOKINES AND DENDRITE CELLS. I'M NOT GOING OVER THESE DETAILS TODAY BUT WE ARE MAKING PROGRESS IN TERMS OF UNDERSTANDING THIS SPECIAL DRUG NOT ONLY TARGETING THE MICROTUBULE BUT HOW IT INTERACTS WITH MICRO-ENVIRONMENT ESPECIALLY IMMUNOMODULATIONS. SO BASED ON THE CONCEPTS AND HYPOTHESES THAT ARE ONGOING, AND 4 OR 5 PHASE III CLINICAL TRIALS COMBINING TAXOL, CARBOPLATIN, WITH IMMUNE CHECKPOINT INHIBITOR IN OVARIAN CANCER. LET'S SEE HOW IT WORKS. THE DATA WILL BE AVAILABLE. SO, I WANT TO TAKE OPPORTUNITY TO INTRODUCE WHAT IS GOING ON IN THE OVARIAN CANCER BESIDES THE MICROTUBULE TARGETING AGENTS. SO THERE ARE ALSO NOW MANY AS TARGETED AGENTS, ESPECIALLY PARP-INHIBITOR, WHICH IS FDA APPROVED FOR BRCA MUTATION OVARIAN CANCER AS IS ALLCOMERS AND CANCERS. I HAVE BEEN INVOLVED IN THE PARP HIN HIBITOR STEWSIES AND CLINICAL SIDE AND TRANSLATION SIDE. SO COMBINED WITH PARP-INHIBITOR AND AGENTS WHICH IS NOW FACED WITH CLINICAL TRIALS AND THE LITERATURE, WE COMPARE THIS COMBINATION WITH TAXOL. SO LET'S SEE. TAXOL IS AMAZING DRUG. WE STILL USE TAXOL AS STANDARD ARM. AND ALSO AS I SAID, IMMUNOMODULATION IS A REALLY IMPORTANT PART OF RESEARCH TOPIC IN OVARIAN CANCER. SO I HAVE BEEN WORKING ON THE PARP-INHIBITOR IN COMBINATION WITH ANTI-PKD1. I HAD SHOWN SIGNIFICANT CLINICAL ACTIVITY IN ONE AND TWO CLINICAL TRIALS AT THE NCI CLINICAL CENTER. IN CONCLUSION, OVARIAN CANCER IS ONE OF THE LEADING CAUSES OF DEATHS IN WESTERN COUNTRIES. AND STANDARD OF CARE INCLUDES TAXOL AND CHEMOTHERAPY WHICH HAS BEEN A WINNER FOR MANY, MANY DECADES. AND INTRAPERITONEAL CHEMOTHERAPY BENEFIT THE SELECT POPULATION. UNFORTUNATELY, OVARIAN CANCER REOCCURRENCE IS COMMON AND PACLITAXEL IS A STILL VERY ACTIVE WHETHER IT IS IN COMBINATION WITH BEVACIZUMAB OR AS THERAPY WITH TAXOL IN THE WEEKLY SETTING. BUT THERE ARE MANY HIGHLY-EFFECTIVE AND LESS TOXIC THERAPIES FOR OVARIAN CANCER PATIENTS. SO I LIKE TO THANK AGAIN FOR INVITATION AND ALSO LISTENING TO YOUR AMAZING TALK SUSAN. IT'S HONOR TO MEET WITH YOU AND THANK YOU VERY MUCH FOR YOUR ATTENTION. [ APPLAUSE ] >> THANK YOU VERY MUCH, DR. LEE. DO WE HAVE SOME QUESTIONS, PLEASE? MAYBE WHILE WE ARE WAITING, COULD YOU DEFINE, HOW DO YOU DEFINE LACK OF PROGRESSIVE DISEASE? WHAT ARE THE MARKERS THAT YOU USE WITH OVARIAN CANCER TO DECIDE WHETHER THIS SITUATION IS PROGRESSING, STABLE? >> SO, 125 HAS BEEN PROPOSED AS A MARKER TO FIND OUT WHETHER PATIENT HAS NO REOCCURRENCE OR REOCCURRENCE. SO WHEN IT COMES TO THE TREATMENT FOR THE RECURRENT DISEASE, C125 SOMETIMES CAN GO UP BECAUSE IT'S GLYCOPROTEIN SO IT CAN GO UP WITH INFLAMMATION. SO, WHEN WE SEE INCREASING C125, WE ALSO SEE -- CLINICIAN HAS TO SEE THE PATIENT TO EXAM THEM. SO IF PATIENT HAS CLINICAL SYMPTOMS AS SOME DISEASE REOCCURRENCE IN IMAGING, THAT'S THE TIME WE SAY, YOU HAVE UNFORTUNATE REOCCURRENCE. BUT IF SOMEONE HAS ONLY C125 INCREASE, WE CONTINUE TO MONITOR. >> SO IT'S CONSIDERABLE DEPENDENT UPON THE PATIENT'S SYMPTOMS AND SIGNS? >> THAT IS CORRECT. THERE IS RANDOMIZED STUDIES DONE IN AUSTRALIA WHICH THE C125 NUMBER ONLY WITHOUT ANY CLINICAL SYMPTOMS AND IMAGINGS AND TUMORS ACTUALLY TREATING 125 DOESN'T IMPROVE ANY BENEFIT IN TERMS OF SURVIVAL. >> THANK YOU. BOTH OF YOU. HAVE YOU USED TAXOL IN -- I HAVE USED TAXOL IN MY LABORATORY ON NEUTROPHILS. I'M AMAZED IT'S COMPATIBLE WITH LIFE. IT'S SO DRAMATIC IN TERMS OF WHAT IT DOES TO CELLS, AS YOU DESCRIBED. MY QUESTION RELATES TO ONE OF YOUR LAST COMMENTS ABOUT USING IT IN COMBINATION, FOR EXAMPLE, WITH CHECKPOINT INHIBITORS. IT SEEMS TO ME THAT WHAT YOU WANT WHEN YOU USE A CHECKPOINT INHIBITOR IS ACTIVATION OF THE IMMUNE RESPONSE IN ITS FULLEST EXTENT. AND SOMETIMES IT GOES TOO VIGOROUSLY AND YOU GET PROBLEMS WITH THAT. BUT, WOULDN'T TAXOL BE IN AFFECT DOING JUST THE OPPOSITE? >> THAT'S VERY IMPORTANT POINT BECAUSE STILL WE HAVE VERY LIMITED UNDERSTANDING HOW THIS DRUG INTERACTS WITH ALL DIFFERENT IMMUNE STIMULATORS AS IMMUNE SUPPRESSIVE CELLS. SO NEUTROPENIA, IS A VERY COMMON SIDE EFFECT AND IN TERMS OF P RAS AND ALSO T CELLS, WE STILL HAVE VERY LIMITED UNDERSTANDING. IN CLINICAL EXPERIENCE, I TRAINING WITH TAXOL DOESN'T DIMINISH IN RESPONSE TO IMMUNE POINT IN COMBINATION. SO I ABSOLUTELY AGREE. WE STILL HAVE TO DO MORE CLINICAL RELEVANT TRANSLATIONAL STUDIES HOW IT WILL INTERACT IN THE HUMAN STUDY. >> THIS MAY BE AN UNFAIR QUESTION. >> IF SO SUSAN CAN ANSWER. >> BUT GIVEN THE INCREASED RISK OF OVARIAN CANCER WITH BRONCO POSITIVE -- BRCA POSITIVE AND DIFFERENT THE CURRENT STATUS OF TREATMENT -- GIVEN THE CURRENT STATUS OF TREATMENT. IF A PATIENT CAME TO YOU THAT IS BRCA POSITIVE BUT DID NOT YET HAVE OVARIAN CANCER, WOULD YOU RECOMMEND PROPHYLACTIVE REMOVAL OF THE OVARIES? >> THAT'S A VERY FAIR QUESTION ACTUALLY. SO ARE YOU ASKING HOW WE CREATE THE HIGH-RISK GROUP VERSUS THE PROPHYLACTIC DRUG OR SOMETHING? BECAUSE CURRENT -- ESPECIALLY FOR BRCA MUTATION CARRIERS, BECAUSE DEPENDING ON THE BRCA1 AND BRCA2, BECAUSE BRCA1 MUTATION CARRIERS TEND TO DEVELOP OVARIAN CANCER, BREAST CANCER EARLIER THAN BRCA2 MUTATION CARRIERS. SO STANDARD CARE IS, AFTER THEY HAVE THEIR CHILDREN WITH THE PROPHYLACTICKECTOMY AFTER CHILD BEARING AGES, AND THEN ALSO DO SCREENING FOR BREAST CANCER IF THEY DON'T WANT TO DO PROPHYLACTIC MASTECTOMY WITH IMAGING, ALTERNATING MAMMOGRAM AND BREAST MRI EVERY 6 MONTHS. SO THOSE ARE THE STANDARD PROPHYLACTIC APPROACH FOR BREAST AND OVARIAN CANCER FOR BRCA MUTATION CARRIERS. IN TERMS OF ANY PROPHYLACTIC DRUG FOR BRCA MUTATION CARRIERS, CURRENTLY THERE ARE NO DRUGS APPROVED TO PREVENT BREAST AND OVARIAN CANCER. I READ PROPOSAL WHETHER WE CAN USE A PARP-INHIBITOR AS PROPHYLACTIC DRUG IN THIS SETTING, BUT AS WE BRIEFLY MENTIONED, EACH DRUG HAS ITS OWN SIDE EFFECTS. THERE ARE VERY SMALL PERCENTAGE OF MYELO DYSPLASTIC SYNDROME OR AML WITH PARP INHIBITORS AS WITH OTHER CHEMOTHERAPIES. SO CURRENTLY THIS TREATMENT IS >> I JUST REFERRING TO SURGERY. THANK YOU. >> THOSE ARE INTERESTING QUESTIONS. AND WE ARE ACTUALLY LOOKING IN MY LAB NOW ON ISOTYPE IN FALLOPIAN TUBES, WHICH PRESUMABLY THE IDEA THAT THE FALLOPIAN TUBE IS VERY IMPORTANT TO SECRETIONS THAT ARE INVOLVED IN THE DEVELOPMENT OF OVARIAN CANCER. AND WE FIND THAT IN BRCA PATIENTS, BRCA1 AND TWO PATIENTS, WE SEE A LARGE AMOUNT OF SPECIFIC ISOTYPES WHICH WE KNOW IS INVOLVED IN SECRETION. SO, WE WONDER -- I THINK THE THEORY IS THAT OVARIAN CANCER STARTS IN THE FALLOPIAN TUBES AND THAT PARTICULAR ISOTYPES THAT COULD BE INVOLVED IN SECRETION OF CELLS FROM THE FALLOPIAN TUBE TO THE OVARY, WHICH IS SITUATED VERY CLOSELY, AS YOU CAN SEE IN THE SLIDE, COULD BE IMPORTANT. SO THOSE ARE SOME OF THE THINGS WE ARE ACTUALLY INTERESTED IN AND HOW OVARIAN CANCER FORMS. >> THAT'S GOOD COMMENT. THANK YOU. >> ARE THERE ANY OTHER QUESTIONS OR COMMENTS? IF NOT, THANK YOU BOTH VERY MUCH FOR YOUR VERY IMPORTANT TALKS. [ APPLAUSE ]