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>>> GOOD AFTERNOON, EVERYONE.
WELCOME TO A SPECIAL WEDNESDAY
AFTERNOON LECTURE.
THE ANNUAL ASTUTE CLINICIAN
LECTURE.
AND ONE OF OUR OWN.
DR. MARSTON LINEHAN WILL BE
SHORTLY COMING UP TO THE PODIUM
TO TELL YOU ABOUT HIS REMARKABLE
RESEARCH OBSERVATIONS IN THE
AREA OF KIDNEY CANCER.
IT'S MY PLEASURE TO HAVE A
CHANCE TO INTRODUCE HIM,
SOMEBODY I HAVE KNOWN FOR
PROBABLY 15 OR 20 YEARS, WHO IS
ABSOLUTELY A LEADER IN THIS
FIELD THAT HAS CONTRIBUTED
AMAZING INSIGHTS INTO THIS
COMMON FORM OF CANCER AND
SOMEONE WHO BOTH RUNS AN AMAZING
LABORATORY, OFTEN THE PLACE WE
BRING SPECIAL DIGNITARIES TO,
LIKE THE PRESIDENT OF THE UNITED
STATES, FOR INSTANCE.
BUT WHO ALSO IS AN ACTIVE
SURGEON DOING IT ALL, AND DOING
IT WITH THE MOST REMARKABLE
PERSONAL INVOLVEMENT THAT YOU
WOULD EVER WANT TO SEE AND A
DOCTOR WHO IS ALSO TAKING CARE
OF PATIENTS AND TREATING EACH
SPECIAL HUMAN INDIVIDUAL WITH A
SPECIAL NEED FOR A MEDICAL AND
SURGICAL CARE.
MARSTON GOT HIS UNDERGRADUATE
DEGREE AT BROWN UNIVERSITY.
WENT ON TO GET THE MD AT THE
UNIVERSITY OF OKLAHOMA AND YOU
MIGHT NOTICE IN HIS PRESENTATION
THERE IS SOME REMNANT OF THAT
PART OF THE COUNTRY THAT STILL
IS AUDIBLE.
HE DID A YEAR OF MEDICINE AT
OKLAHOMA AND WENT ON TO DUKE AND
SURGERY AND ULTIMATELY BECOMING
CHIEF RESIDENT IN UROLOGIC
SURGERY AND AFTER THAT, HE CAME
BACK HERE TO THE MECCA AS A
SENIOR INVESTIGATOR IN THE
SURGERY BRANCH WHERE HE IS NOW
THE CHIEF OF THIER LOGIC
ONCOLOGY BRANCH.
HE ALSO HAS APPOINTMENTS AT GW
BUT MOST OF HIS WORK IS DONE
RIGHT HERE IN THIS REMARKABLE
CLINICAL CENTER.
HE HAS BEEN RECOGNIZED BY
VARIOUS AWARDS, INCLUDING THE
DR. NATHAN DAVIS AWARD OF THE
AMERICAN MEDICAL ASSOCIATION AND
AN ELECTED MEMBER OF THE
INSTITUTE OF MEDICINE.
HIS LONGSTANDING INTEREST IN
KIDNEY CANCER AND THE GENETIC
BASIS OF THIS DISEASE HAS
RESULTED IN REMARKABLE
REVELATIONS, INCLUDING THE BON
HIPEL LIN DO YOU GENE, THE GENE
FOR HEREDITARY PAP LARRY RENAL
CARCINOMA, THE FLCN GENE, HE
WILL TELL YOU MORE ABOUT THESE
THINGS I'M PRETTY SURE.
A TOTAL OF FIVE NEW DISEASES
THAT HAVE COME OUT OF THIS
RESEARCH EFFORT.
AS I'M SURE HE WILL REFLECT ON,
BECAUSE THE TITLE HERE POINTS TO
IT, WHAT WE ARE LEARNING THROUGH
THIS IS NOT ONLY WHAT IS GOING
ON IN TERMS OF THE INSIGHTING
EVENT.
KIDNEY CANCER, BUT HOW THAT
CONNECTS IN A WAY THAT NONE OF
US WOULD HAVE SUSPECTED A FEW
YEARS AGO WITH MET LOLLIC
PATHWAYS THAT KIDNEY CANCER AND
METABOLIC BASE OF DISEASE ARE IN
FACT TIGHTLY INTERLINKED AS THEY
ARE IN HIS TITLE.
SO WE COULD IS NOT A BETTER
PERSON FOR OUR ASTUTE CLINICIAN
LECTURE THIS PARTICULAR YEAR.
IT'S MY GREAT PLEASURE TO ASK
YOU TO HELP ME WELCOME
DR. MARSTON LINEHAN.
[ APPLAUSE ]
>> THANK YOU DR. COLLINS FOR THE
VERY, VERY KIND INTRODUCTION.
I REALLY APPRECIATE IT AND ALSO
I'D LIKE TO ACTUALLY EXTEND MY
THANKS TO THE WONDERFUL MEN AND
WOMEN I HAD THE OPPORTUNITY TO
WORK WITH HERE FOR THE LAST 32
YEARS AND ALSO PARTICULARLY TO
DR. JOHN GAL IN AND THE CLINICAL
CENTER AND HIS STAFF FOR MAKING
THIS A PLACE FOR SOMEONE LIKE
ME, SOMEONE LIKE US, OUR GROUP,
COULD PURSUE THESE IDEAS, STUDY
THESE PATIENTS, OVER THESE YEARS
IN THIS MARVELOUS ENVIRONMENT.
SO, I WANT TO TALK ABOUT KIDNEY
CANCER AND KIDNEY CANCER EFFECTS
WORLDWIDE ABOUT 300,000 PATIENTS
AND IS RESPONSIBLE FOR ABOUT
100,000 DEATHS PER YEAR
WORLDWIDE.
IN THE U.S. IT IS ABOUT 65,000
AFFECTED AND 13,000 DIE.
NOW AS DR. COLLINS MENTIONED,
I'M A UROLOGIC SURGEON.
SO IN OUR AREA, WE WORK ON
PROSTATE CANCER, BLADDER CANCER,
KIDNEY CANCER.
NEW KIDNEY CANCER HAPPENS TO BE
THE MOST LETHAL DISEASE AMONG
THOSE THREE.
GI CANCER ABOUT 25% OF HUMAN
CANCER.
BUT KIDNEY IS THE ONE THAT
CAUSES LOST YEARS OF LIFE.
SO REALLY THE MOST LETHAL
CANCER.
WE ESTIMATE THERE ABOUT 200,000
ALIVE IN THIS COUNTRY TODAY WITH
KIDNEY CANCER.
NOW, IN THE SPIRIT OF THIS
WONDERFUL AWARD WHICH I'M SO
TOUCHED TO BE ASKED TO GIVE THIS
LECTURE, I'M GOING TO SORT OF
WALK YOU THROUGH REALLY, OUR
JOURNEY OVER THE LAST 30 YEARS
IN STUDYING KIDNEY CANCER.
WHEN I CAME HERE AS A YOUNG GUY,
A YOUNG PERSON, IN THE EARLY
80s, I LOOKED AT KIDNEY CANCER
AND I SAID, KIDNEY CANCER, IF
SOMEONE COMES WITH LOCALIZED
KIDNEY CANCER TO SOMEONE LIKE
ME, A UROLOGIC SURGEON, WE CAN
TAKE THAT OUT AND WE DON'T USE
THE C WORD, THE CURE WORD, BUT
WE CAN GIVE THEM 95% 5-10 YEAR
SURVIVAL.
PRETTY MUCH AS NOW, IF THEY CAME
TO US WITH ADVANCED DISEASE, 82%
OF THEM DIED WITHIN 24 MONTHS.
SO WE SAID, IS THERE A WAY WE
CAN DO SOMETHING TO CHANGE THIS?
WE SET OUT EARLY IN THE
80s WITH MY WONDERFUL
COLLEAGUE, BURT, TO STUDY KIDNEY
CANCER, AND OUR HOPE WAS TO
IDENTIFY WE THOUGHT WAS THE GENE
FOR KIDNEY CANCER.
WE HAD NO IDEA IT WOULD BE
GENES.
AND ONE OF THE THINGS IF YOU
REMEMBER ONE THING DURING THIS
TALK PROBABLY IS THIS SLIDE AND
THE NEXT ONE, THAT IS KIDNEY
CANCER IS NOT KIDNEY CANCER.
IN THOSE DAYS, WE TREATED ALL
PATIENTS WITH KIDNEY CANCER THE
SAME.
THE SAME OPERATIONS, GAVE THEM
THE SAME DRUGS IF THEY HAD
METASTATIC DISEASE, NONE OF
WHICH WORKED.
NOW WE KNOW THAT KIDNEY CANCER
IS NOT A SINGLE DISEASE.
IT'S A NUMBER OF DIFFERENT TYPES
OF CANCER THAT JUST HAPPEN TO
OCCUR IN THIS ORGAN.
THEY HAVE DIFFERENT HISTOLOGIES,
DIFFERENT CLINICAL COURSES AND
RESPOND DIFFERENTLY TO THERAPY
AND ARE CAUSED BY DIFFERENT
GENES.
NOW WE STARTED OUT, WATER AND I
AND OUR COLLEAGUES, MICHAEL AND
A NUMBER OF OTHER PEOPLE AND WE
WERE SEEING A LOT OF PATIENTS IN
THE CLINICAL CENTER WITH KID FEE
CANCER AS PART OF THE IL-2
PROGRAM, STEVE ROSENBURG IN THE
SURGERY BRANCH IN THOSE DAYS.
AND WE LOOKED AT TUMORS FROM
PATIENTS WITH LOCALIZED KIDNEY
CANCER AND WE SHOWED THAT THERE
WAS A CONSISTENT LOSS OF A
CHROMOSOME.
OF CHROMOSOME 3 IN THOSE TUMORS
FROM PATIENTS WITH CLEAR CELL
KIDNEY CANCER.
AND WE WERE SO HAPPY ABOUT THIS.
WE PUBLISHED THIS IN "NATURE"
AND WE STARTED TO MAP AND SAID
WE ARE GOING TO FIND THIS GENE
AND THIS LOCATION.
WE MAPPED AND MAPPED AND MAPPED
AND SPENT ABOUT THREE YEARS
DOING THIS.
AND YOU NEVER FORGET THINGS.
I NEVER WILL FORGET WE SPENT SIX
MONTHS TRYING TO REFINE OUR
STRATEGY.
WE TALKED TO EVERYBODY WE COULD.
WE SAW BURT VOGELSTEIN AND
TALKED TO ALL SORTS OF PEOPLE
AND CAME TO THE CONCLUSION THAT
OUR LAB WORKING 13 HOURS A DAY
SIX DAYS A WEEK AND BURT'S LAB
WORKING THE SAME, WITH THE TOOLS
WE HAD AVAILABLE TO US IN THE
MIDDLE 80'S, WE COULD DEFINITELY
FIND A GENE IN THIS LOCATION
WITHIN 54.5 YEARS.
SO WE KIND OF ASSUMED THAT WE
THOUGHT WE WERE NICE PEOPLE BUT
ASSUMED THEY WOULDN'T FUND US
FOR THAT LONG.
SO WE TALKED TO A BUNCH OF
PEOPLE.
DR. ANNUITIES ON SAID IF IS
THERE A HEREDITARY VERSION OF
YOUR CANCER, NEWT SON -- YOU
COULD STUDY FAMILIES AND MAKE
YOUR OWN PROBES.
SO THAT IS WHAT WE DID.
WE SET UP A HEREDITARY CANCER
PROGRAM AND AGAIN, SOMEONE LIKE
ME -- WE COULD HAVE NEVER DONE
THIS ANYWHERE ELSE OTHER THAN
HERE AT THE CLINICAL CENTER.
I MEAN, THIS IS JUST TO HAVE ALL
THESE PEOPLE TO WORK WITH.
I THINK MY ASSISTANT TOLD ME THE
OTHER DAY THAT -- SHE SAID, YOU
WORK WITH 147 DIFFERENT PEOPLE
FROM 29 LABS AND BRANCHES FROM
NINE DIFFERENT INSTITUTES AT
NIH.
THIS IS REALLY A TRANS-NIH
PROJECT.
THERE IS A WHOLE NUMBER OF
PEOPLE WHO COULD BE STANDING UP
HERE GIVING THIS TALK BESIDES
ME.
BUT THIS WAS IN THE DAYS BEFORE
THERE WAS A FRANCIS COLLINS OR
BEFORE FRANCIS COLLINS WAS HEAD
OF THE GENOME PROJECT, LET'S PUT
IT THAT WAY.
THERE WAS NO GENOME PROJECT.
SO WE HAD TO BE OUR OWN GENOME
PROJECTED.
THERE WAS NO OTHER WAY.
SO WE SET UP A PROGRAM TO BRING
IN FAMILIES AND EVALUATE THEM
AND DETERMINE WHO IS EFFECTED
AND WHO WASN'T SO WE COULD DO
GENETIC LINKAGE ANALYSIS.
THIS TOOK A ARMY OF COLLEAGUES
TO WORK WITH.
I'M GOING TO TALK ABOUT FIVE
DIFFERENT TYPES OF INHERITED
KIDNEY CANCER THAT WE WORKED ON.
VHL, HEREDITARY RENAL CARCINOMA,
BITTER HOG DUBE, HLRCC AND SDH.
AND I'LL SHOW YOU HOW EACH ONE
IS CAUSED BY A DIFFERENT GENE
BUT ALSO HOW VERY DIFFERENT THEY
ARE.
AGAIN, OVER THE YEARS, WE
HAD THE UNBELIEVABLE OPPORTUNITY
TO EVALUATE NEARLY 1000 FAMILIES
WITH MULTIPLE MEMBERS OF KIDNEY
CANCER.
A LIST UP HERE, WE CALL THIS
FRC.
THIS IS FAMILIAL RENAL CANCER.
WHEN WE STARTED, WE STARTED WITH
VHL.
SO WE HAD VHL AND THEN WE HAD
FRC.
WE DIDN'T KNOW WHAT THE DISEASES
WERE.
THEY WEREN'T NAMED.
WE DIDN'T HAVE ANY GENES FOR
THEM.
SO, EVERYYEAR WE TAKE MORE
PEOPLE OUT OF THE FRC CATEGORY
AND PUT THEM IN NAMED GENE
SYNDROMES.
SO WE ARE GOING TO START WHERE
WE OTHER STAKED, WHICH WAS VHL,
VON HIPEL LIN DO YOU, HEREDITARY
CANCER SYNDROME.
PATIENTS ARE AT RISK, AUTOSOMAL
DOMINANT.
PATIENTS ARE AT RISK AND DEVELOP
TUMORS IN A NUMBER OF LOCATIONS
INCLUDING OF COURSE BILATERAL
KIDNEY CANCER.
THESE PATIENTS ARE AT RISK TO
DEVELOP BILATERAL MULTI-FOCAL
KIDNEY CANCERS AND CYSTS IN THE
KIDNEYS.
IN SCIENCE, WE DON'T SAY ALWAYS
OFTEN.
BUT THESE ARE ALWAYS CLEAR CELL
KIDNEY CANCER.
WE HAVE SEEN THOUSANDS OF THESE
TUMORS THAT DR. MARINO HAS
LOOKED AND THE THEY ARE ALWAYS
CLEAR CELL.
THESE PATIENTS ALSO GET CYSTS IN
THEIR KIDNEYS AND INSIDE THOSE
CYSTS THIS YELLOW MATERIAL IS
CLEAR CELL KIDNEY CANCER.
NOW AGAIN, WE HAVE I THINK 700
KNOCKOUT MICE.
WE HAVE ABOUT 500 CAGES OF
XENOGRAPHED MODELS.
WE HAVE GREAT CELL LINE MODELS
IN THE LAB.
BUT THIS IS OUR MODEL.
THE HUMAN MODEL.
THIS SATURDAY MODEL WE STUDIED
OVER THESE YEARS AND THIS IS THE
MODEL THAT ENABLED US TO MAKE
ANY PROGRESS WE MADE.
WHEN WE LOOK AT THESE PATIENTS
TUMORS OR KIDNEYS, WE ASK IF
THEY HAVE ALL SORTS OF TUMORS.
WE ESTIMATE THEY GET UP TO 600
TUMORS PER KIDNEY.
THEREFORE, WHEN WE DO SURGERY,
WE ARE NOT CURING THESE PEOPLE.
WE ARE SETTING BACK THE CLOCK.
THAT'S OUR APPROACH.
TO GET THEM THROUGH THEIR LIVES
WITH THEIR NORMAL KIDNEYS AND OF
COURSE NORMAL PAN COUNTRIES AND
ADRENAL IN TACT.
PANCREAS.
IT USED TO BE SAID THAT VHL
ASSOCIATED KIDNEY CANCER WASN'T
AGGRESSIVE LIKE REAL KIDNEY
CANCER.
IN MY FIELD THAT WAS PUBLISHED
IN THE ABILITIES.
MY FIELD JUST DIDN'T UNDERSTAND
THE TERM, LEAGUE TIME BIAS.
THESE ARE EXACTLY THE SAME AS
SPORADIC NON-HEREDITARY KIDNEY
CANCERS.
WE ESTIMATE -- THIS IS A PATIENT
WHO CAME TO US WITH A LARGE VHL
TUMOR T SPREAD TO HER CHEST.
METASTATIC DISEASE.
WE ESTIMATE FROM THE TIME OF
THE -- THIS IS ON THE BASIS OF
ABOUT 17,000 TUMOR MEASUREMENTS.
FROM THE TIME OF THE SECOND HIT
IN THIS CANCER GENE, TO TWO
CENTIMETERS, WE ESTIMATE THAT
TIME IS ABOUT 25 YEARS.
SO THIS IS LIKE A LITTLE BIT
LIKE PROSTATE CANCER.
VERY SLOW-GROWING CANCER.
BUT WHEN IT GOATS A CERTAIN
SIZE, IT CAN SPREAD.
SO WE HAVE MANAGED THESE
PATIENTS NOW OVER 27 YEARS, VERY
CAREFUL CONSECUTIVE MANAGEMENT
HERE AT NCI OR NIH.
AND WE HAVE DEVELOPED A CLINICAL
APPROACH.
NOW THE FIRST PATIENT I SAW WITH
VHL, I WAS A YOUNG KID HERE.
AND THE WAY WE MANAGED CANCER IN
MY FIELD, AND I TALKED TO
EVERYONE HERE AND ALL OF MY
COLLEAGUES AND READ LITERATURE
THE WAY YOU HANDLE KIDNEY
CANCER, YOU REMOVE THE KIDNEY.
WELL, I TOOK OUT BOTH OF THAT
PATIENT'S KIDNEYS.
AND YOU KNOW, YOU NEVER FORGET
SOME THINGS.
I'LL NEVER FORGET I TOOK THAT
PATIENT DOWN IN THE OLD ENTRANCE
TO THE HOSPITAL, I TOOK HIM
DOWN, PUT HIM IN A TAXI CAB,
SENT HIM HOME TO BE ON DIALYSIS.
AND I SAID, I DON'T CARE WHAT
THEY SAY, I'M NEVER DOING THIS
AGAIN.
AND WE STARTED THEN DOING
PARTIAL REFLECT MES.
I GOT A LOT OF GAS FOR A WHILE
BUT AFTER A WHILE IT BECAME
ACCEPTED.
WELL, WE OPERATED AND PEOPLE
WOULD GET NEW TUMORS AND WE
WOULD OPERATE AND THE GET NEW
TUMORS AGAIN.
I REMEMBER ONE TIME DURING ONE
OF THESE CASES AND WE WERE DOING
A PATIENT FOR THE THIRD TIME ON
THE SAME KIDNEY AND IN ABOUT 5
YEARS WE ARE GOING TO HAVE TO
PUT ZIPPERS IN THESE PEOPLE.
SO WE STARTED AN APPROACH THEN,
WE DID A BUNCH OF CALCULATION
BUSY METASTASES.
WE DEVELOPED AN APPROACH TO DO
ACTIVE SURVEILLANCE.
WE WOULD NOT OPERATE -- I KNOW
TODAY THAT SOUNDS KIND OF NOT SO
UNUSUAL.
BUT WHEN WE DID THIS, IT WAS --
WE HAD A LOT OF CRITICISM, LET'S
PUT IT THAT WAY ABOUT THIS
APPROACH.
NOT OPERATE ON CANCER.
WE STARTED TO DO ACTIVE
SURVEILLANCE UNTIL THE LARGEST
TUMOR REACHED THREE CENTIMETERS.
AT THREE CENTIMETERS WE
RECOMMEND INTERVENTION.
NOW, IN 27 YEARS, AS OF NOVEMBER
20, 2013, WHEN USING THIS
STRATEGY, WE HAVE NOT YET HAD
ONE SINGLE PATIENT DEVELOP
METASTATIC DISEASE.
NOW SURGICALLY FOR YEARS,
WE WOULD DO OPEN OPERATIONS.
WE NOW HAVE GONE TO A ROBOTIC
APPROACH.
AND WALLY RECENTLY TOOK OUT 54
TUMORS FROM A SINGLE PATIENT'S
KIDNEY WITH THIS ROBOT.
WE HAVE DONE AS MANY AS 74 WITH
AN OPEN OPERATION.
I WANT TO SHOW YOU THIS BECAUSE
MANY OF YOU ARE NOT CANCER
PEOPLE.
I WANT TO SHOW YOU WHEN THEY
LOOK LIKE.
AND ALSO I WANT TO SHOW YOU
THIS.
THIS IS PART OF THE PHENOTYPE.
IN OTHER WORDS, I'M GOING TO
SHOW YOU THIS IS HOW WE MANAGE
THE ONES WITH WITH VHL MUTATION
WITH THE NEXT GENE WHICH WILL BE
MET AND THE THIRD GENE WHICH
WILL BE FALICAL AND DR. COLLINS
MENTIONED, BUT THIS IS VERY
DIFFERENT.
FROM THE WAY WE MANAGE PATIENTS
WITH CREPE CYCLE ENZYME
MUTATIONS AND SECTION
HYDROGENASE.
THIS IS A ROBOTIC PARTIAL
NEPHRECTOMY.
YOU CAN SEE THE TUMOR HERE AND
WITH THE ROBOT JUST COMING RIGHT
AROUND THIS, LIKE PETER PINTO IS
DOING THIS CASE.
IT WAS JUST COMING RIGHT AROUND
THIS TUMOR AND AS YOU CAN SEE,
WE ARE NOT GETTING MUCH OF A
MARGIN: NOW, WE KNOW THIS
TUMOR.
WE KNOW THIS GENE.
AND WE KNOW HOW THIS BEHAVES.
AND WE HAVE NEVER HAD A PROBLEM
WITH THIS AND WE HAVE NOT HAD
ONE PATIENT DEVELOP METASTATIC
DISEASE.
NOW I'LL SHOW THAT YOU IS VERY,
VERY VERY DIFFERENT FROM A
COUPLE OF TYPES OF KIDNEY CANCER
I'LL SHOW YOU IN A MINUTE.
THESE PATIENTS ALSO DEVELOP
TUMORS IN THE ADRENAL GLANCED.
YOU CAN SEE HERE THIS IS AN
8-YEAR-OLD CHILD.
ALSO IN THE PANCREAS.
THEY GET PANCREATIC CYSTS AND
THEY GET PANCREATIC NEURAL
ENDOCRINE TUMORS.
WHICH ARE MA LIGNANT TUMORS
WHICH CAN SPREAD.
THESE PATIENTS ALSO GET TUMORS
IN THE BRAIN AND SPINE.
CEREBELLAR BLASTOMA.
THESE ARE SPINAL BLASTOMAS.
THIS PATIENT HAS TWO.
WE HAVE PATIENTS WHO HAVE
HUNDREDS.
IF YOU WANT TO HAVE A SNAPSHOT
IN YOUR MIND ABOUT WHAT THIS
GENE PATHWAY IS, THIS IS A GOOD
PICTURE.
SO THIS IS ONE THAT ED OLE'
FIELD WAS DOING.
THIS IS THE SPINAL CORD AND THIS
IS THE SPINAL BLASTOMA AND YOU
CAN SEE IT'S VASCULARITY.
IT IS EXTREMELY VASCULAR.
VHL GENE AS I WILL SHOW YOU, IS
AN OXYGEN SENSOR.
SO, WHEN A CELL THINKS IT IS
SHORT OF BREATH, IT NEEDS MORE
VASCULATURE AND NEEDS MORE
ENERGY, IT NEEDS MORE BLOOD, A
BUNCH OF THINGS.
I'LL SHOW THAT YOU IN JUST A
MINUTE.
THESE PATIENTS I MIGHT ALSO ADD
THAT WE COULDN'T HAVE THOUGHT
ABOUT DOING THIS WORK WITHOUT
OUR WONDERFUL COLLEAGUES ED OL
FIELD, RUSS LOONSER, MORE
RECENTLY, KAREN ZAG POL AND.
[ INDISCERNIBLE ]
FROM THE NEUROLOGICAL SUCH
REBRANCH AND WE ARE APPRECIATIVE
OF THEIR SUPPORT OF THEIR WORK
AS WE ARE OF JEFF NORTON AND OUR
COLLEAGUES IN GENERAL SURGERY.
AND IN OPTHALMOLOGY, EMILLIE
CHEW HAS BEEN WITH US HELPING TO
MANAGE THESE PATIENTS AND
WITHOUT THEM, WE NEVER WOULD
HAVE EVER HAVE BEEN ABLE TO DO
THE PHENOTYPE ASSESSMENT AND
NEVER BEEN ABLE TO MANAGE THESE
PATIENTS OVER THE YEARS.
THESE PATIENTS ALSO
DEVELOPED RETINAL ANGIOAS.
THESE ARE BENIGN TUMORS
EXTREMELY VASCULAR.
THIS IS THE FIRST MANIFESTATION
OF VHL.
YOU CAN SEE THESE IN
ONE-YEAR-OLDS.
THAT'S WHY WE RECOMMEND GERMLINE
MUTATION TESTING AT AGE ONE.
BECAUSE PHOTO DYNAMIC THERAPY
CAN ALSO SAVE VISUAL FIELDS AND
IT REALLY MAKES US SICK TO SEE A
PATIENT WHO LOST THEIR VISION
BECAUSE THEY WEREN'T DETECTED
EARLY AND DIDN'T HAVE EARLY
TREATMENT.
THESE PATIENTS ALSO DEVELOP
INNER EAR TUMORS, 12% OF OUR
PATIENTS DEVELOP WHAT IS CALLED
AN EN DOE LYMPHATIC SAC TUMOR
WHICH IS IN THE CANAL, IT'S A
BENIGN PAP LARRY TUMOR.
IF IT PROGRESSES, THESE PATIENTS
CAN LOSE THEIR HEARING.
OUR NEUROSURGEONS AND OUR ENTs
ARE DOING A STUDY TO SEE IF
EARLY SURGICAL INTERVENTION WILL
PRESERVE HEARING IN THIS PATIENT
POPULATION.
SO, WE WANTED TO FIND THIS
GENE.
WE BROUGHT PATIENTS HERE TO THIS
WONDERFUL CLINICAL CENTER,
PERFORMED GENETIC LINKAGE
ANALYSIS AND AGAIN, THIS IS WITH
BETTER AND MIKE AND A NUMBER OF
COLLEAGUES.
AND WE WERE ABLE TO EVALUATE DNA
FROM 4,312 PATIENTS TO DO THIS.
THIS ACTUALLY TOOK US ABOUT 10
YEARS TO DO THIS PROJECT.
LOCALIZED, THE GENE TO THE SHORT
ARM OF CHROMOSOME 3 AND THEN IN
THE SPRING OF 1993, WE WERE ABLE
TO LOCALIZE AND IDENTIFY THE
7th CDNA WE LOOKED AT, G7,
WHICH TURNED OUT TO BE THE VHL
GENE, THE 6th HUMAN CANCER
GENE IDENTIFIED WHEN WE FOUND
THIS.
WE NOW LOOKED AT 371
FAMILIES AND DETECTED VHL
MUTATION IN EVERY SINGLE ONE OF
THEM.
THE MUTATIONS WE SEE ARE REALLY
A CATALOG FOR GRAD STUDENTS IN
GENETICS.
TWO-THIRDS OF OUR TUMORS ARE
FRAMESHIFTS, NONSENSE, ABOUT A
THIRD ARE DELETIONS, ABOUT
TWO-THIRDS OF THOSE ARE PARTIAL
DELETION AND ABOUT A THIRD ARE
COMPLETE DELETION AND ABOUT 5%
OF OUR MUTATIONS ARE MECHANICAL
AND ARE SPLICING DEFECTS.
THEN WE WANTED TO SEE WAS
THIS THE GENE WE LOOKED FOR FOR
SO LONG? NOT A GIVEN THIS WILL
BE THE CASE.
THE LADIES IN THE FAMILIES OR
THE LADY WHO IS NOT IN A
HEREDITARY BREAST FAMILY WHO HAS
BREAST CANCER, IT'S NOT OB CLAWS
BRCA1 OR 2 WILL BE INVOLVED IN
HER CANCER.
SO WE JUST DIDN'T KNOW.
BUT IT TURNED OUT AND WE LOOKED
AT TUMORS FROM PATIENTS WITH
NONHEREDITARY, SPORADIC CLEAR
CELL KIDNEY CANCER, WE FIND A
HYPE PERCENTAGE OF MUTATIONS OF
THIS GENE.
WE FIND MUTATION OF THE GENE AND
LOSS OF THIS GENE MOST RECENT
STUDY, WAS WITH MIKE NICKERSON
AND LEE MOORE OUT OF NCI AND
THAT WAS ABOUT 412 TUMORS AND
NEARLY 90% HAVE EITHER MUTATION
OR METHYLATION OF THAT GENE.
RECENT STUDY OUT OF JAPAN SHOWED
A 95% RATE EVER MUTATION
METHYLATION OR MUTATION OF ONE
OF THE PARTNERS OF VHL GENE.
SO, I THINK IT IS CLEAR TO SAY
THAT VHL IS THE CLEAR CELL
KIDNEY CANCER GENE.
SO WE FIND THAT, WE FOUND
THAT HERE IN CLEAR CELL BUT WE
DON'T FIND IT IN TYPE I PAP
LARRY AND TYPE II PAP LARRY AND
CHROMOPHOBE, ONCOCYTOMA
COLLECTING.
THE OTHER TYPES OF KIDNEY
CANCER.
SO THE FIRST INCLINATION THAT
THERE WAS A GENETIC
DIFFERENTIATION AMONG THE
DIFFERENT TYPES OF KIDNEY
CANCER.
SO WHAT KIND OF GENE WAS THIS?
IT TURNED OUT TO BE A CLASSIC
TWO HIT TUMOR SUPPRESSOR GENE.
WE HAVE MUTATION OF THE GENE AND
LOSS OF THE SECOND COPY OF THAT
GENE.
SO, WE MADE A CELL LINE OF THE
FIRST LINE THAT WAS DESCRIBED AS
A VHL OR AS A CLEAR CELL KIDNEY
CANCER LINE WITH THE VHL
MUTATION, PUT IT IN A MOUSE.
WE MADE ONE SINGLE CHANGE IN
THOSE CELLS.
ONE CHANGE.
WE PUT A NORMAL COPY OF THAT
GENE BACK IN THOSE CELLS AND WE
GET NO TUMOR OR VERY SMALL
TUMOR.
SO, VERY STRONG DATA.
THIS IS A LOSS OF FUNCTION TUMOR
SUPPRESSOR GENE.
THEN WE WANTED TO KNOW HOW
DOES THIS GENE WORK? WE HAD NO
IDEA IN THE WORLD WHAT THIS DID.
SO WE STARTED TO WORK WITH RICK
CLOUZNER IN THE MIDDLE 90s.
AND ROXANNE A POSTDOC IN OUR LAB
WORKING WITH RICK AND HIS
COLLEAGUES AND DID A PRETTY
STRAIGHTFORWARD EXPERIMENT,
IPVHL AND PULLED DOWN THESE TWO
BANDS HERE.
WE WORKED WITH BILLY UP AT THE
RED CROSS AND BILLY SLEPT IN THE
LAB FOR 5 1/2 DAYS TO DO THIS
SEQUENCING.
AND SHOWED THAT THIS BAND HERE,
WHICH HAD JUST BEEN PUT IN THIS
SEQUENCE, SOMETHING CALLED ELONG
IN C.
WE CALLED THAT WEEKEND, RON AND
JOHN CONWAY, MEDICAL RESEARCH
FOUNDATION AT OKLAHOMA CITY,
OKLAHOMA, AND THEY WERE
DUMBFOUNDED BY WHY WE WERE
CALLING THEM.
WE TOLD THEM THIS AND WHATEVER
THIS GENE IS, BINDS VHL AND WE
HAD ANOTHER GENE WE DIDN'T
KNOW -- WE HAD ANOTHER PROTEIN
WE DIDN'T KNOW WHAT THAT WAS.
WE E-MAILED THAT TO THEM AND
THEY SAID THAT IS ELONG IN B.
WHICH THEY HASN'T PUT OR
COMMUNICATE THE ANYWHERE YET.
SO, WE PUBLISHED THIS AND
PUBLISHED THIS IN "SCIENCE" AND
WE WERE VERY HAPPY ABOUT THAT
AND PROUD OF THE WORK BUT IT
DIDN'T HELP US TO UNDERSTAND THE
FUNCTION OF THIS GENE OR THIS
PATHWAY.
UNTIL THIS WILL GEL, WHICH WAS
RUN BY ARM AMIN RICK CLOUZNER'S
LAB AND ARM AMHAD IPVHL AND RAN
A BIGGER GEL.
AND RAN ACROSS THIS BAND RIGHT
HERE THAT HE SEQUENCED, WHICH
WAS A PROTEIN CALLED CULIN 2.
IT WAS AT THE TIME A RECENTLY
IDENTIFIED TUMOR SUPPRESS ARE
GENE FAMILY IN HELMET.
ONCE YOU PUT CUL2 ALONG C AND
BVHL TOGETHER, THEN YOU CAN GO
BACK TO THE MODEL AND MAKE SENSE
OF THIS.
THAT VHL IS PART OF AN E3
UBIQUITIN LIGASE COMPLEX THAT
TARGETS CERTAIN TARGET PROTEINS
IN THE MOST WELL STUDIED ARE
HYPOXIA INDUCIBLE FACTORS, HIF 1
AND 2 FOR UBIQUITIN MEDIATED
DEGRADATION.
THIS WAS DONE BY THE KALE IN AND
MAXWELL GROUP AND OVER THE
YEARS, WE HAVE COME TO
UNDERSTAND THIS IS SIMPLY AN
OXYGEN SENSING SYSTEM.
WHEN THERE IS NORMAL OXYGEN IN
THE CELL, THE COMPLEX CAN TARGET
HIF, DEGRADE IT FOR UBIQUITIN
MEDIATED DEGRADATION.
WHEN IT'S HYPOXIC, NOT ENOUGH
OXYGEN, VHL COMPLEX CAN'T SEE
HIF TO DEGREAT IT AND HIF
ACCUMULATES AND THEN TRIBES
THINGS SUCH AS VEGF, GLUTE 1,
GLUTE 4, THINGS WE KNOW OF AS
CANCER.
HOWEVER, IN OUR CLEAR CELL
KIDNEY CANCERS, WHERE THE VHL
MUTATION, IT'S LIKE THE CELL
THINKS IT IS SHORT OF BREATH.
SO NO MATTER WHAT THE OXYGEN
LEVEL IS, HIF IS NOT DEGRADED
AND IT ACCUMULATES AND YOU GET A
VASCULAR CELL, A CELL THAT IS
MAKING PLATELET-DERIVED GROWTH
FACTOR AND ALL SORTS OF THINGS
TO STIMULATE GROWTH IN THE CELLS
NEXT TO IT AND ITSELF.
SO THIS PROVIDED THE FOUNDATION
FOR THE DEVELOPMENT OFAVE
THERAPEUTIC APPROACH FOR
PATIENTS WITH ADVANCED CLEAR
CELL KIDNEY CANCER, IE TARGETING
THE VHL PATHWAY.
SO AS OF TODAY, SEVEN DIFFERENT
TARGETED THERAPEUTIC DRUGS
APPROACHES, HAVE BEEN APPROVED
BY THE FDA FUR THE TREATMENT OF
PATIENTS WITH ADVANCED KIDNEY
CANCER, PRIMARILY ADVANCED CLEAR
CELL KIDNEY CANCER.
SO, AS THRILLED AS WE ARE ABOUT
THIS, WE ARE NOT HOME YET.
YOU CAN SEE DRAMATIC RESPONSE.
YOU CAN SEE INCREASE IN
SURVIVAL.
BUT, MOST PATIENTS EVENTUALLY OR
MOST OF THE TIMES THIS THERAPY
EVENTUALLY FAILS THESE PATIENCE
AND EVEN THOUGH YOU CAN SEQUENCE
THESE DRUGS, MANY TIMES THEY GO
ON TO DIE OF THIS DISEASE.
JUST RECENTLY, THE CANCER GENOME
ATLAS, WHICH OF COURSE IS A
WONDERFUL PROJECT, I'D SAY IT'S
THE DREAM OF A LIFETIME, THIS
PROJECT, THIS CO-SUPPORTED BY
THE NHGR I AND NCI AND WE WERE
INVOLVED IN THE ONE YOU'RE
LOOKING AT, CLEAR CELL KIDNEY
CANCER.
AND ANOTHER GENES ON CHROMOSOME
3 WHICH HAVE PREVIOUSLY BEEN
SEEN.
THESE GENES ON CHROMOSOME 3 THAT
ARE CENTRAL MERIC TO WHERE VHL
IS, THESE ARE CHROMATIN
REMODELING GENES.
PBRM1 SET D2 AND BAF1.
PRETTY REMARK AGE.
AND THESE TWO GENES SET B2 AND
BAF1 WHEN THEY ARE MUTATED, THAT
CORRELATES WITH AN AGGRESSIVE
PHENOTYPE AND DECREASES
SURVIVAL.
SO YOU ARGUE THAT VHL'S EARLY
THING BUT OVER THE YEARS,
SOMEHOW THESE OTHER GENES HELP
TO SPREAD OR BECOME MORE
AGGRESSIVE.
AND RECENTLY, WE LOOKED AT A
FAMILY AND THIS WAS WORK DONE
WITH LAURA SUBMIT AND KATHY VOKE
AND A NUMBER OF NEME OUR GROUP
ALONG WITH JAMES AT TEXAS
SOUTHWESTERN AND A FAMILY WE
HAVE BEEN FOLLOWING FOR 11
YEARS, LINDSAY COULDN'T FIND VHL
MUTATION.
WE COULDN'T FIND SDH MUTATIONS.
THIS FAMILY CARRIES THE MUTATION
OF THAT GENE I SHOWED YOU BAF1
ON CHROMOSOME 3.
SO WE KNOW NOW THAT THIS GENE
ALSO CAN CAUSE CLEAR CELL KIDNEY
CANCER.
THIS FAMILY HERE.
BUT THE OTHER THING THAT WE
FOUND, AND THIS WAS WORK THAT
REALLY CHRIS REALLY PUT
TOGETHER, AND THAT IS THAT WE
THOUGHT THIS WAS GOING TO BE THE
CASE BUT WE WERE SHOCKED WHEN
SEE SAW THIS.
AND THAT IS THAT HIGH-GRADE,
HIGH-STAGE, VERY AGGRESSIVE
KIDNEY CANCER IN PATIENTS WITH
LOW SURVIVAL, IN OTHER WORDS BAD
DISEASE, THESE PATIENTS TUMORS
UNDERGO A METABOLIC SHIFT.
AND THIS SHIFT LOOKS VERY MUCH
LIKE COUPLE OF OTHER TYPES OF
KIDNEY CANCER I'LL SHOW YOU IN A
MINUTE, WHERE THE TCA CYCLE
ENZYMES ARE SUPPRESSED
SUGGESTING DECREASE IN OXIDATED
PHOSPHORYLATION.
THE ENZYMES FOR GLYCOLYSIS ARE
WAY UP.
ENZYMES FOR THE PHOSPHATE ARE
WAY UP.
SO SUGGESTING DEFENSE AGAINST
OXIDATIVE STRESS.
AMPK IS DOWN, THAT'S GOING TO BE
REOCCURRING THEME.
I'LL COME BACK TO THAT.
AND YOU HAVE EVIDENCE OF
REDUCTIVE CAR BOXALATION OF
GLUTAMINE-DEPENDENT APPROACH FOR
MAKING FATTY ACIDS.
AND INCREASING CELLULAR SINCE
SIS.
SO WE SAW THAT BY DOING THIS
VERY COMPLEX INTEGRATIVE
ANALYSIS OF 480 TUMORS THAT ONLY
PROJECT LIKE TCGA CAN DO.
SO WHAT I HAVE SHOWN YOU IS
THAT VHL CLEAR CELL KIDNEY
CANCER, OXYGEN SENSOR.
OKAY? NOW HOW ABOUT THE OTHER
TYPES? THAT'S ABOUT 75% OF
KIDNEY CANCER IS CLEAR CELL.
NOW HOW ABOUT THE OTHER TYPES OF
KIDNEY CANCER?
I THOUGHT I'D JUST WALK YOU
THROUGH HOW WE GOT A LITTLE BIT
WHERE WE ARE AND AGAIN, IT WAS
ALL PATIENTS SEEN RIGHT HERE IN
THIS BUILDING.
SO THIS WAS THE FIRST ONE.
THIS WAS A LITTLE GIRL OR YOUNG
WOMAN, 21-YEAR-OLD.
SHE CAME HERE FROM OHIO WITH HER
MOM, HER WORRIED MOM, WITH THIS
TUMOR IN HER KIDNEY.
I TOOK THIS OUT.
SHE WENT ON TO DIE EIGHT MONTHS
LATER OF METASTATIC DISEASE.
I WENT OVER TO SEE MARINO, I
WORKED WITH SO CLOSELY AND I
SAID, MARIA WHAT KIND OF KIDNEY
CANCER IS THAT? SHE SAID, IT'S
PAP LARRY KIDNEY CANCER.
I SAID, ALL RIGHT.
SO THEN IN 89, IN MAY, I SAW
ANOTHER YOUNG WOMAN WHO CAME UP
WITH HER MOM FROM
CHARLOTTESVILLE, AND SHE HAD
THIS TUMOR IN HER LEFT KIDNEY.
AND I TOOK THIS OUT.
AND SHE WENT ON TO DIE 10 MONTHS
AFTER THAT OF METASTATIC KIDNEY
CANCER AND HER MOM DIED 14
MONTHS AFTER THAT OF METASTATIC
KIDNEY CANCER.
I SAID, MARIA, WHAT IS THIS?
AND SHE SAID, MARSDEN, IT'S PAP
LARRY KIDNEY CANCER.
I SAID, ALL RIGHT.
SO THIS IS A PATIENT THAT WE
SAW, THIS FAMILY WE SAW IN MARCH
OF 92.
SO THIS MAN CAME UP AND HE WAS
71 YEARS OLD.
HE HAD METASTATIC KIDNEY CANCER
AND HE HAD TUMORS IN BOTH
KIDNEYS.
DISEASE IN HIS CHEST, EVENTUALLY
WEPT ON TO DIE OF METASTATIC
DISEASE.
HIS SISTER CAME UP WITH THEM AND
SHE HAD TUMORS IN BOTH KIDNEYS,
GROW TO BE VERY LARGE TUMORS AND
HIS SON CAME UP WHO AT THE TIME
WAS 42.
AND HE HAD TUMORS IN BOTH HIS
KIDNEYS.
SO I START WITH THIS GUY, WITH
THIS DISORDER FIRST.
THIS WAS PAP LARRY.
I SAID MARIA, WHAT IS THIS? SHE
SAID T IS PAP LARRY KIDNEY
CANCER.
SO THIS OBVIOUSLY RAN IN
FAMILIES.
THIS HAD NOT BEEN DESCRIBED.
YOU CAN SEE OWL THE MEMBERS WHO
HAD KIDNEY CANCER ON IT.
AUTO ZOOMAL HEREDITARY KIDNEY
CANCER.
ULTRARARE DISORDER.
BILATERAL MULTIFOCAL TUMORS IN
THE KIDNEY.
YOU CAN SEE THIS.
YOU CAN SEE WE ESTIMATE THESE
PEOPLE GET UP TO 2000 TUMORS PER
KIDNEY.
IT'S ALWAYS TYPE I PAPILLARY
KIDNEY CANCER.
AGAIN, WE DEVELOPED A SIMILAR
APPROACH AND THAT IS, IF WE HAD
PEOPLE WITH METASTATIC DISEASE,
YES, WE HAVE.
BUT WE DEVELOPED AN APPROACH
HERE TO INTERVENE WITH A LARGEST
TUMOR REACHES THREE CENTIMETERS
AND 21 YEARS SINCE 1992, WE HAVE
NOT HAD ONE PATIENT DEVELOP
METASTASES WHO WERE MANAGED IN
THIS FASHION.
SO, WE BROUGHT PEOPLE TO THIS
MARVELOUS CLINICAL CENTER AND
DID GENETIC LINKAGE ANALYSIS,
PRIMARILY LAURA SMITH AND BURT
AND MIKE NICKLESON, AND
LOCALIZED THIS TO LONG ARM OF
CHROMOSOME 7.
LOOKED AT A NUMBER OF THINGS,
INCLUDING THESE CANDIDATE GENES
AND THE GENE FOR THIS DISORDER
TURNED OUT TO BE MET.
MET AS YOU KNOW, AND WHICH IT
WAS -- WHICH DONBA TAROT HAD
SHOWN THAT HGF IS THE LIGAND FOR
THIS CELL SURFACE RECEPTOR
CALLED MET.
SO THIS IS WHAT WE FIND IS
MUTATIONS IN THE TYROSINE KINASE
DOMAIN OF THIS.
SO THIS IS A DOMINANT GENE.
VHL TUMOR SUPPRESSOR GENE.
THIS IS AN ONCOGENE: SO THESE
ARE THE ACTUAL MUTATIONS WE SEE
IN THE TYROSINE KINASE DOMAIN OF
THIS GENE.
SO WE LOOKED AT AND ANALYZED DNA
AND SEEN 12 FAMILIES.
THERE IS ONLY 25 FAMILIES KNOWN
IN THE WORLD.
SO THIS IS A ULTRARARE DISEASE
BUT AN IMPORTANT DISEASE IN MANY
WAYS BECAUSE MET IS NOW SUCH AN
IMPORTANT DISEASE IN LUNG
CANCER, STOMACH CANCER AND A
NUMBER OF THINGS.
SO, WE DESCRIBED AN EARLY ONSET
FORM OF THIS DISEASE.
LAURA SUBMIT DID.
AND THESE MUTATIONS WERE HERE IN
THE ATP BINDING DOMAIN SO THAT
COULD EXPLAIN WHY WE SEEN SUCH
AN AGGRESSIVE PHENOTYPE IN THOSE
PATIENTS WITH THAT MUTATION.
SO WE WERE HAPPY ABOUT THAT AND
HAPPY TO FIND THE GENE AND HAPPY
TO BE ABLE TO TELL PATIENTS WHO
IT EFFECTED WHO WASN'T HAPPY TO
MAKE THE DIAGNOSIS.
HOWEVER, WHAT WE REALLY WANTED
TO DO WAS TO HOPEFULLY WITH ALL
OF THESE DISORDERS, TO DEVELOP
AN APPROACH FOR THERAPY.
SO, THIS SHOULD BE
STRAIGHTFORWARD.
AND I'D SAY IT WILL BE BUT IF
YOU THINK IT WOULD BE IN A WAY.
SO, RON IN OUR GROUP, HEAD OF
OUR MOLECULAR THERAPEUTICS
PROGRAM, CONDUCTED A TRIAL USING
A DRUG CALLED FRET NIB, DUAL
KINASE VEGF RECEPTOR AND MET
RECEPTOR INHIBITOR.
SO I'LL JUST SHOW YOU ONE
PATIENT.
SO THIS IS THAT FIRST FAMILY I
SAW.
THIS WAS THE 42-YEAR-OLD SON.
WHEN WE SAW HIM IN THE SPRING OF
92, I'D SEEN THESE OTHER
FAMILIES WITH HORRIBLY
AGGRESSIVE DISEASE AND HAD THESE
PEOPLE DIE.
WE DIDN'T KNOW THE DIFFERENCE
THEN BETWEEN THIS TYPE OF
HEREDITARY PAPILLARY KIDNEY
CANCER -- KNOWN DID -- AND THE
OTHERS.
SO I TOOK OUT THIS PATIENT'S
LEFT KIDNEY.
I WOULDN'T DO IT AGAIN.
I WOULD DO A PASSIONATE.
BUT IN THE SPRING OF 1992 I TOOK
OUT HIS LEFT KIDNEY YOU SEE
HERE.
IN JUNE OF THAT YEAR, OF 92, WE
TOOK OUT 12 TUMORS FROM HIS
REMAINING RIGHT KIDNEY.
SOLITARY RIGHT KIDNEY.
SO DID FINE.
GOING BACK AND FORTH TO SCHOOL,
BACK AND FORTH TO PTA MEETINGS
AND BACK TO WORK TO LITTLE
LEAGUE BASEBALL GAMES.
DEVELOPS TUMORS AGAIN AS WE HAVE
COME TO UNDERSTAND HAPPENS, AND
IN THE FALL OF 2000, WE TOOK OUT
59 ADDITIONAL TUMORS FROM HIS
REMAINING RIGHT KIDNEY.
THAT'S 71 TUMORS SO FAR.
THAT'S OKAY.
HE HAS A LITTLE RENAL INSISTY.
HIS EGFR IS 51 OR 54.
HE IS DOING OKAY.
HOWEVER, IN ABOUT 2006, HE
STARTS TO DEVELOP NEW TUMORS IN
THAT KIDNEY AND HIS LARGEST
TUMOR IN THAT RIGHT KIDNEY
REMAINING RIGHT KIDNEY IS 3.4
CENTIMETERS.
WE DON'T LIKE THAT.
WE DON'T WANT HIM TO DIE OF
METASTATIC DISEASE LIKE HIS
FATHER DID.
SO, RON PUT HIM ON THIS DRUG.
WHEN HE CAME BACK THE FIRST
TIME, HIS TUMOR HAD GONE FROM
3.4 TO 2.5.
AND THE UROLOGIC ONCOLOGY FELLOW
SAID, DR. MARSTON LINEHAN, WAIT
A MINUTE.
THIS GUY'S TUMOR IS 2.5.
HE SAID, HE IS NO LONGER A
SURGICAL CANDIDATE.
I SAID, RIGHT.
I SAID, THAT'S WHAT WE ARE
WORKING TOWARDS.
WE ARE WORKING TOWARDS MAKING
THESE NON-SURGICAL DISEASES.
SO, AFTER 49 CYCLES OF FORET
NIB, HIS TUMORS BECAME ALMOST
NONDEDUCTIBLE.
THIS WAS HIS LARGEST DOWN TO
1.4.
HE HAD A NUMBER OF OTHER TUMORS
WHICH BASICALLY DISAPPEARED.
NOW ARE WE HOME YET? NO.
BUT, THIS WAS THE FIRST TRIAL
TARGETING A PAPILLARY KIDNEY
CANCER GENE SHOWING THAT THIS IS
PROOF OF PRINCIPLE OF AN EFFECT
AND I'LL JUST SHOW YOU THIS
SLIDE.
THIS IS 39 TUMORS IN NINE
DIFFERENT PATIENTS.
AS YOU CAN SEE, EVERY SINGLE ONE
OF THEM HAS GOTTEN SMALLER WITH
THERAPY.
SO WE GET READY TO START A
NEW TRIAL WITH A PURE MET
INHIBITOR AND WE HAVE A NUMBER
OF OTHER APPROACHES THAT WE HAVE
DEVELOPED HERE.
SO WE WILL SEE.
I'M HOPEFUL.
THE THIRD ONE IS -- THIS
WAS THAT FIRST PATIENT I
MENTIONED TO YOU, THE ONE FROM
OHIO.
THAT WAS PAPILLARY KIDNEY
CANCER.
SO, WE MADE A CELL LINE FROM
THIS.
AND WITH COLIN COOPER -- WE
SHOWED THAT THERE WAS A
TRANSLOCATION FROM THE FIRST
CHROMOSOME TO THE X CHROMOSOME.
AND THEN, WITH COLIN COOPER IN
ENGLAND, SHOWED WHAT WAS
HAPPENING
HAPPENING IS A GENE ON
CHROMOSOME 1 WAS GOING TO A GENE
ON THE X CHROMOSOME CALLED TFE3.
AND THIS WAS THE FIRST
DESCRIPTION OF TFE3 KIDNEY
CANCER.
WE NOW KNOW THAT TFE3 IS PART OF
A FAMILY OF TRANSCRIPTION
FACTORS.
TFE3, TFEB AND MITF WHICH CAN
ALL CAUSE KIDNEY CANCER.
MITF A GERMLINE ALTERCATION THAT
CAUSES KIDNEY CANCER IN MELANOMA
AND WE NOW KNOW THAT TFE3 KIDNEY
CANCER IS ONE PENALTY 5% OF
KIDNEY CANCERS BUT IN THE
CHILDREN AND YOUNG ADULTS, IT'S
20-45%.
SO THIS IS THE MOST COMMON TYPE
OF KIDNEY CANCER IN CHILDREN AND
YOUNG ADULTS.
AND WE ARE WORKING VERY HARD AND
YOU'LL BE DEVELOPING A
THERAPEUTIC APPROACH TARGETING
TFE3 AND WE ARE VERY ENCOURAGED
ABOUT THE PRECLINICAL RESULTS WE
HAVE AND WE ARE HOPING TO START
CLINICAL TRIALS THIS YEAR
TARGETING THIS TYPE OF KIDNEY
CANCER.
SO THIS IS THESE 3 GENES HERE.
SO NEXT, I'M GOING TO SHOW YOU
OUR FOURTH TYPE OF KIDNEY CANCER
AND KIND OF HOW WE GOT INTO
THIS.
SO, WE WERE SAYING WE WILL SEE
ANYBODY WITH MULTIPLE MEMBERS OF
THE FAMILY WHO HAVE KIDNEY
CANCER.
AND WE SAW THIS FAMILY WHO AT
THE TIME WAS THOUGHT TO HAVE
BILATERAL MULTI-FOCAL,
ONCOCYTOMA, AND THESE IDENTICAL
TWINS.
AND WE FOUND A TUMOR IN THE
FATHER.
SO WE THEN SENT LETTERS OUT TO
PHYSICIANS AROUND THE COUNTRY
ASKING FOR FAMILIES WITH
FAMILIAL ONCOCYTOMA.
AND WHAT HAPPENED WAS THE
FOLLOWING: WE SAW A PATIENT,
GLAD IN R.IS GLENN WAS WORKING
WITH US AT THE TIME.
AND SHE CALLED ME AND SAID,
MARSDEN, WE HAVE A PATIENT UP
HERE IN THESE ONCOCYTOMA
FAMILIES THAT HAS FUNNY SKIN
BUMPS.
I SAID, LET'S BIOPSY THEM AND
SEE WHAT PAUL DERA, THE
PATHOLOGIST AT THE TIME HERE AT
NCI, THINKS.
WE DID.
PAUL CALLED ME AND SAID, MARS
DEN, THESE PEOPLE HAVE SOMETHING
THAT RUNS IN FAMILIES.
I SAID, I KNOW IT.
IT RUNS IN MY FAMILY.
HE SAID NO, IT RUNS IN FAMILIES.
I SAID, I HAVE A FAMILY HERE.
HE SAID NO, IT'S BEEN DESCRIBED.
HE SAID IT WAS DESCRIBED BY
THREE GUYS IN 1977.
IT'S CALLED BURT HOG DUBE.
THEY DESCRIBE CUTANEOUS LESIONS
THAT RUN IN THESE FAMILIES.
SO WE THEN WENT ON TO -- THESE
PATIENTS CAN GET VERY OBVIOUS
CUTANEOUS FIBROFA LICK GNOMA OR
GET SUBTLE ONES.
THEY ARE BENIGN TUMORS.
WE RECRUITED THESE FAMILIES AND
SHOWED KIDNEY CANCER RUNS IN
THESE FAMILIES.
THEY CAN BE SOLITARY.
THEY CAN BE BILATERAL,
MULTIFOCAL.
THEY CAN BE LARGE.
THEY CAN METASTASIZE.
THE PATHOLOGY HERE IS DIFFERENT.
YOU CAN GET DIFFERENT TYPES OF
PATHOLOGY.
VHL IS ALWAYS CLEAR CELL.
WITH HPRC, IT'S ALWAYS TYPE I
PAP.
HERE, WE SEE ABOUT A THIRD GET
CHROME PHOBE KIDNEY CANCER.
ABOUT 60% HYBRID ONCOCYTIC
KIDNEY CANCER AND WE SEE A FEW
CLEAR CELLS AND A FEW
ONCOCYTOMEAS.
WE CAN SEE THOSE DIFFERENT HIS
TOLLAGES IN THE SAME FAMILY AND
SAME PATIENTS.
SOMETIMES IN THE SAME KIDNEY.
WE ESTIMATE THESE PATIENTS GET
UP TO 3000 TUMORS PER KIDNEY.
SO, AGAIN, OUR SURGERY IS NOT
CURING THEM BUT WE ARE SETTING
BACK THE CLOCK BUT USUALLY IF WE
DO GOOD SURGERY, MOST OF THESE
PATIENTS, ONLY NEED ONE KIDNEY
OPERATED ON PER LIFETIME.
SO WE DO THREE CENTIMETERS.
WE RECOMMEND SURGICAL
INTERVENTION AND AGAIN THIS IS
96, 17 YEARS NOW, NOT ONE
PATIENT DEVELOPED METASTATIC
DISEASE WHEN MANAGED IN THIS
FASHION.
SO, WE WANTED TO FIND THE GENE
AND WE BROUGHT THEM INTO THIS
MARVELOUS FACILITY.
AGAIN, THIS WAS WITH LAURA
SMITH, BURT, MICHAEL NICKERSON.
WE USED THE FIBROFOLLIC LOMAS AS
OUR MARKER.
AND LOCALIZED THIS TO THE SHORT
ARM OF CHROMOSOME 17 AND IN THE
FALL OF 2002, IDENTIFIED THE
FLCN GENE AND WE DETECTED
MUTATION OF FLCN NOW IN 97% OF
229 FAMILIES IT'S PRETTY
REMARKABLE CHANGE AS WE SEE IN
THIS GENE.
WITH VHL, WE SEE NONSENSE,
MISSENSE, FRAMESHIFT, COMPLETE
DELETION, PARTIAL.
HERE, MOST OF THE MUTATIONS,
ALMOST ALL OF THEM, ARE
MUTATIONS PREDICTED TO TRUNCATE
THE PROTEIN.
USUALLY IT'S A FRAMESHIFT OR A
STOP.
IT IS PRETTY UNBELIEVABLE.
WHY THAT IS, WE DON'T KNOW
EXACTLY.
WE ARE HAPPY TO BE ABLE TO
MAKE THE DIAGNOSIS AND TELL IN
THESE FAMILIES WHO IS EFFECTED
AND WHO IS NOT AND WHO NEEDS
SCREENING AND WHO DOESN'T.
WE AND OTHERS HAVE SHOWN THESE
PEOPLE ALSO GET LUNG CYSTS.
92% OF OUR PATIENTS GET
PULMONARY CYSTS.
YOU CAN SEE THEY CAN BE VERY
PROMINENT.
THIS IS ONE DAVE OPERATED ON FOR
US.
TWO OF THEM.
BUT WHAT WE WANTED TO DO WAS
UNDERSTAND WHAT KIND OF GENE
THIS IS.
IS THIS A TUMOR SUPPRESSOR GENE?
IS IT AN ONCOGENE? KATHY VOGUE
DID THIS STUDY WHERE SHE LOOKED
AT A NUMBER OF TUMORS FROM
PATIENTS LIKE THIS PATIENT THAT
WE OPERATED ON.
AND SHE FOUND 70% OF THEM HAD A
SECOND HIT.
NOW IN OTHER WORDS THIS IS A
TWO-HIT MODEL.
SO YANG MADE A CELL LINE, THE
ONLY ONE IN THE WORLD, FOLLIC
LEGAL DEFICIENT CANCER CELL
LINE.
MAKES TUMORS IN MICE.
FOLLIC LIN WAS PUT BACK IN AND
IT'S LIKE VHL, YOU GET NO TUMOR
OR VERY SMALL TUMOR.
SO WE WANTED TO KNOW HOW THIS
GENE FUNCTIONS.
SO, THIS IS THE WORK OF LAURA
SCHMIDT AND A NUMBER OF OTHERS.
AND A BABA RAN THIS GEL WHERE
IPd FLICK LIN AND PULLED DOWN
THIS PROTEIN HERE WHICH TURNED
OUT TO BE A PROTEIN WE NAMED
FLICK LIN INTERACTING PRO TIN 1.
FNIP1 AND THIS BAND RIGHT HERE
IN THIS CHANGE -- THIS ONE BAND
CHANGED OUR ENTIRE FOCUS.
OUR ENTIRE DIRECTION OF OUR WORK
IN KIDNEY CANCER BECAUSE THIS
PULLED DOWN THE GAMMA SUBUNIT OF
AMPK.
AND AS YOU KNOW, AMPK IS THE
GRAND CENTRAL STATION OF ENERGY
SENSING IN THE CELL.
SO THIS REALLY WAS WHAT GAVE US
THE FIRST INCLINATION THAT
KIDNEY CANCER IS FUNDAMENTALLY A
METABOLIC DISEASE.
SO WE NOW KNOW THAT FLICK LIN
BINDS FNIP1 AND 2 WHICH BIND
AMPK AND THIS PUTS THIS THEN IN
THE LKB1, TS1TS2 mTOR PATHWAY.
NOW THERE IS A LOT WE DON'T KNOW
BUT IS THERE SAY LOT WE DO KNOW
AND AGAIN, WE HAVE SHOWN THAT
DEFICIENT FLICK LIN KNOCKED OUT,
YOU GET TO, 1 AND TO, 2
ACTIVATED AND -- TORQUE 1 AND
TORQUE 2.
AND THE CURRENT WORK SHOWS THIS
COMPLEX IS RIT CALL TO
ACTIVATION OF AMPK, CERTAINLY BY
THINGS LIKE FIN FORM AND
METFORMIN.
SO WE THINK THAT MAYBE THROUGH
LKB1, NOT TOTALLY SURE BUT WE
WILL SEE.
BUT THIS IS A BASICALLY A
FUNDAMENTALLY METABOLIC PATHWAY.
SO, WE ARE WORKING ON THE
FOLLOWING APPROACH AND WE ARE
GEARING UP TO DO POTENTIALLY DO
CLINICAL TRIALS TARGETING EITHER
TORC1 OR 2 IN THIS HEREDITARY
CANCER SYNDROME AND WORKING ON
OTHER PATHWAYS.
BACK TO THIS 18-YEAR-OLD YOUNG
WOMAN THAT CAME UP FROM
CHARLOTTESVILLE.
AFTER SHE DIED, HER MOM DIED, WE
TRIED AND TRIED.
YOU REGRET THINGS YOU DO IN LIFE
AND I REGRET I DIDN'T DRIVE TO
CHARLOTTESVILLE AND GO TO THE
POLICE OFFICE AND TRY AND FIND
THIS FAMILY.
WE COULDN'T FIND THEM.
WE LATER FOUND OUT WHAT
HAPPENED.
THE CHILDREN WEPT WITH THE
STEPFATHER WHO HAD A DIFFERENT
LAST NAME.
WE COULDN'T FIND THEM.
BETWEEN THE TIME WE SAW HER AND
WHEN WE SAW HER FIRST COUSIN,
HER BROTHER DIED, HER MOTHER
DIED, HER UNCLE DIED, HER
GRANDMOTHER HAD DIED AND HER
GREAT-AUNT AND LATER ON, HER
COUSIN.
VERY ADVANCED DISEASE AND ENDED
UP DYING OF THIS DISEASE.
SO THIS IS A VERY LETHAL FORM OF
KIDNEY CANCER WHICH WE INITIALLY
DESCRIBED IN 95 WHICH WAS
REDESCRIBED AND RENAMED, BETTER
DESCRIBED IN 1999 AND GOES NOW
BY THE NAME OF HEREDITARY
LIOMATOSIS RENAL CELL CANCER.
THESE PATIENTS ARE AT RISK TO
DEVELOP BOTH CUTANEOUS AND
UTERINE BIOMIOMAS AND AN
AGGRESSIVE FORM OF KIDNEY
CANCER.
AUTO SOMAL DOMINANT HEREDITARY
CANCER SYNDROME.
THESE CUTANEOUS LESIONS ARE
TUMORS OF THE.
[ INDISCERNIBLE ]
WHICH IS IN THE BASE OF THE HAIR
FOLLICLE.
THIS IS LIKE AN ENERGY SENSOR.
NORMALLY WHEN YOU GET COLD, THIS
CONTRACTS.
YOUR HAIR STAND ON END AND TRAPS
HEAT.
HERE, IT'S LIKE IT NEVER STOPS
CONTRACTING AND THEY FORM THESE
TUMORS.
AND WE WORKED WITH MARIA TURNER
AND SO HAPPY NOW TO WORK WITH ED
ON THIS AND THIS IS THE PATIENT
WE SAW JUST RECENTLY.
THESE CAN BE EXTREMELY
SYMPTOMATIC.
WE LOST A PATIENT -- IT WAS A
FAMILY MEMBER OF ONE OF OURS WHO
TOOK HIS LIFE.
JUST COULDN'T DEAL WITH IT.
THESE CAN BE VERY SIMPLE MATTIC
AND WE ARE HOPING TO DEVELOP A
BETTER APPROACH TO THERAPY.
APOLOGIZE FOR THAT.
THESE PATIENTS ALSO GET UTERINE
LIE OH, MY OHMS.
-- LEIOMYOMAS.
THEY ARE VERY EARLY ONSET.
89% OF OUR WOMEN WHEN THESE
FAMILIES ARE AFFECTED WITH
UTERINE LEIOMYOMAS AND 50% OF
THE WOMEN HAD HYSTERECTOMIES IN
THEIR 20S.
CATASTROPHIC PHENOTYPE FOR
WOMEN.
CURRENTLY, OUR
GUIDELINECOLOGICKIC SURGEONS,
PAM AND HER COLLEAGUES, DO --
GYNECOLOGIC -- WE HAD FOUR
BABIES HERE AFTER
MYOMECTOMIESES.
THEY GET VERY AGGRESSIVE KIDNEY
CANCERS.
A 21-YEAR-OLD CAME UP FROM
MIAMI.
I TOOK OUT THAT WITH JEFF
NORTON.
A BIG OPERATION.
TOOK THAT OUT.
THIS YOUNG MAN LIVED 17 MONTHS,
DIED OF METASTATIC DISEASE.
THIS IS A PATIENT WHO CAME, YOU
CAN SEE THE COUPTANEOUS -- THEY
DON'T TEND TO CROSS THE MID
LINE.
THEY DON'T TEND TO.
YOU CAN SEE WE BIOPSIED IT.
HE WAS 32 YEARS OLD AND HIS
FATHERED DIED AT AGE 35 OF
METASTATIC DISEASE.
WE SCREENED HIM AND FOUND THIS.
THEY GET CYSTS IN THEIR KIDNEY
AND GET SOLID TUMORS AND THEY
CAN GET TUMORS INSIDE THE CYSTS.
HE HAD THAT.
HE HAD THIS ASSIST WITH A VERY
SMALL TUMOR, 1/2 CENTIMETER.
NOW WHEN HE SHOWED UP, WE WERE
JUST SCREENING HIM AND HE
ALREADY HAD A LARGE TWO
CENTIMETER NODE.
SO THESE SPREAD EARLY.
VERY DIFFERENT THAN THE OTHER
ONES I SHOWED YOU.
MARIA HAS DESCRIBED THIS AND
THIS IS PRETTY MUCH OF A -- I
DON'T FINISH I SAY UNIQUE BUT
PATHOPNEUMONIC PICTURE FOR THIS.
SHE CAN JUST LOOK AT THE PATH
AND TELL YOU WHAT THIS IS.
THIS IS A FORM OF TYPE II
PAPILLARY KIDNEY CANCER
CHARACTERIZED BY A RANGE OF NUKE
OLE' I WITH THESE VERY PROMINENT
PERRY NUCLEAR HALO.
WE SEE THIS DISEASE IN
10-YEAR-OLDS.
WE SEE IT IN 77-YEAR-OLDS.
THIS IS A LIFE-LONG RISK FOR
CANNER.
CANCER.
VERY TRICK TOW MANAGE
CLINICALLY.
THIS PATIENT WAS 24.
CAME TO US WITH THIS CT SCAN, I
DON'T KNOW.
I CAN'T CALL THAT.
IS THAT JUST A ASSIST OR
SOMETHING INSIDE THATANIST SO WE
SAID COME BACK IN THREE MONTHS
AND LET'S DO AN MRI.
WE DID AN MRI AND WE COULDN'T
CALL THAT.
SO WE SAID COME BACK IN NINE
MONTHS.
WE DID THIS CT AND I CAN'T CALL
THAT.
I DON'T REALLY KNOW.
WE DID THE MRI AND WE SAID, WE
DHAL A DOUBLE BUMP.
SO WE OPERATED.
WHEN WE OPERATED, AND THIS
OPERATION WAS DONE BY NETTY, WE
WENT WAY WIDE ON THIS KIDNEY.
THIS WAS LOWER POLE.
WE WENT ALL THE WAY UP TO THE
HIGH LAND AND ALMOST DID A
MEME -- HEMINEPHRECTOMY.
YOU CAN SEE -- HANG ON.
THERE WE GO.
SO, YOU CAN SEE WE DID BASICALLY
A HEMINETERRIFIC ME.
WHEN MARIA CALLED ME, SHE SAID
YOU HAVE TO LOOK AT THIS.
SHE SAID, THAT 24-YEAR-OLD YOU
OPERATED ON SHE SAID, YOU GOT
TUMOR HERE IN THE ASSIST LIKE
YOU EXPECTED.
BUT LOOK AT THIS.
YOU HAVE TUMOR INFILTRATING
THROUGHOUT THE FRENCH MAN.
I SAID DON'T TELL ME -- PA
REVEREND MA.
YOU HAVE A 4 CENTIMETER MARGIN.
BUT THIS IS HALFWAY THERE.
I SAID WE COULDN'T SEE IT ON
IMAGING.
YOU COULDN'T SEE THE MARGIN
SURGICALLY.
SHE SAID, YES.
SO WE MANAGED THESE VERY
DIFFERENT THAN THE OTHER TYPES.
THIS WAS ONE THAT ADAM DID
RECENTLY.
IS THAT ANYTHING? IT'S HARD TO
KNOW.
SO WEAR ON THE SIDE OF INTERVENE
FIGURE WE ARE NOT SURE.
IS THERE SOMETHING IN THERE? HE
DID A PARTIAL.
MAYBE.
THE PARTIAL NEPHRECTOMY ON THAT
AND MARIA SAID YOU HAVISTS AND
TUMORS IN THE CYSTS.
SO I SAY THAT IS AN ALLIGATOR
WASN'TING TO POUNCE AND THEN YOU
ALSO HAVE TUMOR INVASIVE IN
THERE.
THIS HAS TO BE HANDELED WITH KID
GLOVES.
A VERY FRIGHTENING DISORDER.
IN THE INTEREST OF TIME, I'M
GOING TO SKIP OVER THIS PATIENT
AND TALK ABOUT THIS ONE.
SO WE RECOMMEND IMAGING EVERY
YEAR.
THIS IS A LADY WE ASKED IF YOU
DO IT EVERY YEAR, WE FIND SMALL
LESIONS WE GET THEM OUT.
PATIENTS DO FINE.
THIS LADY WE ASKED OR SAW HER IN
'03.
HER IMAGING WAS FINE.
NOTHING THERE.
IN '06 SHE HAD IMAGING ON THE
OUTSIDE.
THREE YEARS LATER.
EVERYTHING WAS FINE.
AND THEN IN DECEMBER OF 2010, I
GOT A CALL FROM THE UNIVERSITY
OF MARYLAND.
THEY SAID WE THINK WE HAVE ONE
OF YOURS THERE.
I SAID, WHAT DO YOU GOT? THIS
LADY HASN'T HAD IMAGING IN FOUR
YEARS.
THESE NOSED.
10-59 NOSED POSITIVE.
SHE IS NOW BEING TREATED FOR
ADVANCED DISEASE.
SO WE DO NOT RECOMMEND ACTIVE
SURVEILLANCE.
WE TREAT THESE VERY DIFFERENTLY
THAN THE OTHER TYPES OF KIDNEY
CANCER.
AND WE DO SURGERY AND GO VERY
WIDE.
THIS GENE IS ON CHROMOSOME 1.
THE GENE FUMEERATE HYDROTAZE.
WE EVALUATED 186 FAMILIES.
WE FOUND FH MUTATION IN 98% OF
THESE FAMILIES.
THIS IS A TWO-HIT LOSS OF
FUNCTION TUMOR SUPPRESS ARE
GENE.
THIS IS THE HLRC KIDNEY CANCER
CELL LINE.
YOU PUT FH BACK IN, NO TUMORS.
IT'S PRETTY REMARKABLE.
JUST A ENZYME.
SO, WE SAID, HOW ON EARTH COULD
LOSS OF CREB CYCLE ENZYME -- WHY
DIDN'T THAT KILL THE CELL? WE
SHOWED JUST THE OPPOSITE THAT
THESE CELLS IS NO LONGER A
CYCLE.
IT'S LINEAR.
BUT THESE CELLS SHIFT TO A
GLUTAMINE DEPENDENT REDUCTIVE
CAR BOXALATION PATHWAY, WHICH BY
THE WAY GIVES US A NUMBER OF
NOVEL TARGETS ALONG THE WAY
WHICH WE CAN TARGET.
AND WE SHOWED IN THE LAB AND
PRIMARILY YANG DID THIS WORK,
THAT THE FH DEFICIENT CLEAR CELL
KIDNEY CANCER DOESN'T TAKE UP
OXYGEN.
THESE CELLS OXIDATIVE
PHOSPHORYLATION, THE TCA CYCLE,
ELECTRON TRANSPORT CHAIN ARE
IMPAIRED AND THESIS CELLS RAMP
UP GLYCOLYSIS.
SO THIS IS A SHIFT TO AEROBIC
GLYCOLYSIS.
IT'S LIKE A WARBERG MODEL.
YANG SHOWED THAT IF YOU TAKE A
VHL KIDNEY CANCER CELL LINE,
CLEAR CELL, A V MUTATION AND YOU
GROW IT IN CULTURE AND PUT TO
THE IN LOWS GLUCOSE T LAUGHS AT
YOU.
BUT IF YOU TAKE THESE CELLS,
MOST ACTIONER AGGRESSIVE TYPE,
THEY ARE SENSITIVE.
SHE NUTS A LOW GLUCOSE THEY ALL
DIE.
SO THEY ARE VERY SENSITIVE TO
THIS.
CLINICALLY, WHAT WE FOUND IS
THIS FRANCEALATES STEP-BY-STEP
TO OUR PATIENTS.
SO, THESE PEOPLE -- TRANSLATES.
THEY LIGHT UP LIKE A CHRISTMAS
TREE.
IT'S SAD.
YOU CAN PICK UP EVERY ONE OF
THESE TUMORS.
THIS PATIENT GROWS TO METASTATIC
DISEASE.
RON IS LOOKING AT THE PET
SCANNING ON THESE PATIENTS.
YOU CAN SEE THIS PATIENT AND
THIS WAS THOUGHT TO BE NORMAL.
THE CT SCAN.
IS THIS VASCULAR OR SOMETHING?
WE DID A PET SCAN AND MAN.
54-YEAR-OLD RADIOLOGIST.
THIS PATIENT HERE IS THERE
SOMETHING IN THERE? WE ARE NOT
SURE.
WHY YES, THERE IS.
WELL, IF YOU LOOK AT THIS CHEST,
I DON'T KNOW.
THESE VESSELS.
WHICH ONE OF THESE? WHAT IS
GOING ON? THE CELL IS RIGHT
THERE.
EVEN THIS SKIN LIGHTS UP.
REMEMBER THIS GUY? LOOK AT
THIS.
UTERUS IN THESE LEIOMYOMAS LIGHT
UP.
THEY LOSE THE SECOND ALLELE AND
SHIFTED TO AEROBIC GLYCOLYSIS.
SO TRACY SHOWED THE FOLLOWING.
THAT IN THESE CELLS, THIS IS
COUNTERINTUITIVE.
BUT WHAT HAPPENS IS, THEY
BECAUSE OF GLYCOLYSIS, EVEN
THOUGH OX PHOS IS SHUT DOWN AND
EVEN THOUGH THIS IS INEFFICIENT,
GLYCOLYSIS GOES UP SO MUCH THAT
THEY MAKE A LOT OF AT.
AND AMPS SUPPRESSED IT'S
INHIBITEDDED.
THAT TELLS THE CELL TO GROW.
IT SAYS, I GOT A LOT OF ENERGY.
SO IT HAS A LOT OF EFFECT, DROWN
STREAM EFFECTS ON THE IRON
TRANSPORTERS STABILIZING HIF.
HOWEVER, JUST KEEP THIS IN MIND.
DECREASE AMPK.
NOW, CAROL TREATED THESE CELLS
WITH METFORMIN AND NOW LOOKING
AT OTHERS AND SAW VERY DRAMATIC
EFFECT.
SHE COULD HAVE A HUGE EFFECT ON
THE INVASION OF THESE CELLS AND
WHEN SHE IS COMBINED IT IN
PRECLINICAL MODELS IN VITRO AND
IN-VIVO, WITH OTHER TARGETED
AGENTS TARGETING OTHER PARTS OF
THIS PATHWAY, YOU CAN CURE-ALL
THESE ANIMALS.
SO, THIS, WE THINK, TARGETING
THE METABOLIC BASIS OF THIS HAS
SOME SIGNIFICANT POTENTIAL.
NOW, WITH LIN AND JEN ISSACS, WE
SHOWED THAT WHEN HYDROTAZE IS
KNOCKED OUT, FUMEERATE GOES UP.
AND FUMEERATE IS FUNDAMENTALLY
AN ONCOPROTEIN.
AND THIS WAS THE FIRST STUDY TO
SHOW THIS.
FUMEERATE OUTCOMPETES FOR
BINDING HYDROXYLASE AND
ESSENTIALLY POISONS IT.
SO WHAT YOU END UP WITH THEN IS
A VHL INDEPENDENT MECHANISM FOR
DYSREGULATION OF HIF DEGRADATION
AND FUMER EIGHT HYDROTAZE
DEFICIENT KIDNEY CANCER.
SO, THESE CELLS THEN DEVELOP, OR
THEN GET A LOT OF VEGF GLUTE 1
AND GLUTE 4 GOES UP.
WE SAY, THESE GUYS NEED THAT.
THEY NEED THE VASCULATURE.
THESE CELLS MIGHT BE SENSITIVE
TO TARGETING VASCULATURE BECAUSE
THEY ARE SO DEPENDENT ON
GLUTAMINE FOR THEIR SURVIVAL
EVEN THOUGH THEY ARE SO
AGGRESSIVE.
SO, RON RAN A PILOT TRIAL.
NOW DOING A BIGGER TRIAL WITH
TARGETING WITH BEVACIZUMAB TO
ELOT NIB.
AND POTENTIAL TOW TARGET MAYBE
GLUCOSE TRANSPORT GLYCOLYSIS.
NOW, HOW CAN I PUT THIS.
TWO DIFFERENT SITE REVIEWS I WAS
TOLD THIS DOESN'T WORK.
WHAT DO YOU THINK? AND I SAID,
WAIT A MINUTE, YOU'RE TALKING
ABOUT CLEAR CELL KIDNEY CANCER.
THAT'S A DIFFERENT GENE.
A DIFFERENT DISEASE.
HERE IT MIGHT.
AND WE SEEN DRAMATIC RESPONSE.
THIS IS ONE OF THE FIRST
PATIENTS.
UP UNTIL THIS POINT, THIS
DISEASE, WE LOST EVERY ONE OF
THEM TO METASTATIC DISEASE.
IT WAS REALLY NOT TREATABLE.
THIS IS THE WOMAN WHO CAME TO US
42-YEAR-OLD, WHO HAD SURGERY ON
THE OUTSIDE AND THE DOCTOR
DIDN'T REALIZE IT WAS HLRC AND
DIDN'T REALIZE HU TO GO WIDE.
HE DID A REGULAR PARTIAL NEFRACT
ME AND LEFT A LOT OF DISEASE ON
THE KIDNEY AND HER ABDOMEN.
WE HAD POPSY PROOF AND
EVERYTHING ELSE.
AND YOU CAN SEE IT ON THE PET
SCAN.
NOW BOTH HER SISTERS DIED OF
METASTATIC KIDNEY CANCER AS DID
HER FATHER.
RON PUT HER ON THIS APPROACH
WITH BEVACIZUMAB AND ELOT NIB.
AFTER THREE MONTHS SHE HAD A
COMPLETE RESPONSE.
SHE LATER DEVELOPED A NEW SMALL
TUMOR IN ABOUT 3 1/2 YEARS AND
WE TOOK OUT, INDEPENDENT
SEPARATE TUMOR.
SHE IS NOW SEVEN YEARS OUT AND
WE CANNOT FIND EVIDENCE OF
DISEASE.
SO, I THINK WHAT I'M GOING TO DO
IS CONCLUDE BY SAYING THAT WHAT
I HAVE SHOWN YOU IS THAT KIDNEY
CANCER IS FUNDAMENTALLY A
METABOLIC DISEASE MADE UP OF A
NUMBER OF DIFFERENT TYPES OF
CANCER, DIFFERENT HISTOLOGIES
AND DIFFERENT CLINICAL COURSES
CAUSED BY DIFFERENT GENES, AND
THAT EACH OF THE KIDNEY CANCER
GENES THAT ARE CURRENTLY KNOWN,
EACH ONE OF THEM, EFFECTS THE
CELL'S ABILITY TO SINCE OXYGEN,
IRON, OR NUTRIENTS OR MOST
OBVIOUSLY IN THE TCA CYCLE, CREB
CYCLE, FUMEERATE AND
DEHYDROGENASE ENERGY.
AND IT'S OUR HOPE THAT TARGETING
THE METABOLIC BASIS OF KIDSNY
CANCER WILL PROVIDE THE
FOUNDATION FOR THE DEVELOPMENT
OF AN EFFECTIVE FORM OF THERAPY
FOR PATIENTS WITH THIS DISEASE.
I WANT TO ACKNOWLEDGE MY
WONDERFUL COLLEAGUES.
I HAD THE HON OUR TO WORK WITH
AND MY COLLEAGUE, BURT ZA BAR,
MY COLLEAGUES, IN OUR GROUP AND
ULB AND ALSO LYNN KNICKERS AND
DON AND KATHY AND TRACY AND HER
GROUP, OUR COLLEAGUES IN
NEUROSURGERY, ENT, GENERAL
SURGERY, OPTHALMOLOGY,
ENDOCRINOLOGY, WHO WE COULDN'T
HAVE DONE THIS WORK WITHOUT.
I ALSO WANT TO MENTION DR. RAM.
PETER PINT OH, ADAM, MARIA
MERRINEO WHO HAS BEEN BY OUR
SIDE FOR 27 YEARS MANAGING THESE
PATIENTS, PETER AND BRAD, THE
TWO BEST RADIOLOGISTS I EVER
MET, AND THE MOST SENSATIONAL
GROUP OF UROLOGIC ONCOLOGY
FELLOWS AND FINALLY THE MOST
GIFTED, ACCOMPLISHED, TALENTED
AND COMMITTED GROUP OF
INDIVIDUALS TO WORK WITH US, TO
MANAGE OUR PATIENTS, OUR NURSING
AND PATIENT MANAGEMENT STAFF,
OUR PHYSICIANS ASSISTANTS AND
RNs AND AN INCREDIBLE GROUP OF
PATIENT CARE COORDINATORS AND
DATA MANAGERS.
THANK YOU VERY MUCH.
[ APPLAUSE ]
>> THANK YOU, HAS DIN FOR
TYPIFYING WHAT WE HOPED THIS
LECTURE WOULD BE AND DOING IT SO
ELEGANTLY.
THE HOUR IS GETTING A LITTLE
LATE SO WHAT WE ARE GOING TO
RECOMMEND IS, WE ARE GO GOING TO
HAVE A RECEPTION FOR MARSDEN IN
THE LIBRARY HERE, IN THE LOUNGE.
YOU ARE ALL WELCOME TO COME AND
DISCUSS INFORMALLY WITH MARSDEN
AND EACH OTHER, THE INCREDIBLE
OPPORTUNITIES FOR KIDNEY CANCER
THAT HE DESCRIBED.
SO THANK YOU VERY MUCH.
[ APPLAUSE ]