>> GOOD AFTERNOON.
AND WELCOME TO TODAY'S CLINICAL
CENTER GRAND ROUNDS.
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TODAY WE ARE HONORED TO HAVE
DR. SHRINIVASAN, HE IS A SENIOR
INVESTIGATOR AT THE CANCER
RESEARCH, DEPUTY DIRECTOR OF THE
CANCER RESEARCH, AND HEAD OF THE
INSTITUTE'S MOLECULAR CANCER
SECTION.
YOU'RE O LOGIC ONCOLOGY BRANCH
WHERE HE LEADS THE STUDY FOR
KIDNEY CANCER.
HE EARNED HIS MEDICAL DEGREE
FROM BANG ALOR, AND COMPLETED
HIS Ph.D. AT THE MD ANDERSON
SCHOOL OF MEDICINE.
FOLLOWING HIS RESIDENCY TRAINING
AT THE UNIVERSITY OF NEW YORK AT
STONY BROOK AND THE UNIVERSITY
OF TEXAS HELT SCIENCE CENTER, HE
JOINED THE NIH WHERE HE
COMPLETED FELLOWSHIPS ON
ONCOLOGY AT THE NATIONAL CANCER
INSTITUTE HE IS BOARD CERTIFIED
IN INTERNAL MEDICINE AND MEDICAL
ONCOLOGY.
DR. SHRINIVASAN, FOCUSED ON
INDIVIDUALIZED MECHANISM BASED
PROOF OF CONCEPT STUDIES.
AT THE NCI, THE DOCTOR PIONEERED
AN EVALUATION SYSTEM AND
TREATMENT STRATEGIES IN PATIENTS
WITH DISEASES AND CO-LED AN
INTERNATIONAL STUDY FOR THE
ALPHA HIP 2 INHIBITOR HAROLDING
A PARADIME SHIFT IN THE HL.
HE ALSO LED A NEW DEVELOPMENT OF
WORK FOR PATIENTS WITH
METASTATIC KIDNEY CANCER
ESTABLISHED WITH -- EXCUSE ME --
MILE MATOSEIS AND RENAL CELL
CANCER.
DR. SHRINIVASAN IS TARGETING NEW
AGENTS AS WELL AS NOVEL
IMMUNOTHERAPY APPROACHES IN CELL
AND KIDNEY CANCER, AS WELL AS
OTHER FORMS OF SPORADIC AND
KIDNEY HEREDITARY SYNDROMES.
AN INTERNATIONAL SPEAKER, THE
DOCTOR IS A AUTHOR AND CO AUTHOR
OF 100 PUBLICATIONS AND MORE
THAN 1 DOZEN BOOK CHAPTERS.
HIS WORK HAS BEEN RECOGNIZED AT
THE NCI DIRECTOR AWARD FOR
CLINICAL AND TRANSLATIONAL
SCIENCE LEADING TO PRACTICE
CHANGING TREATMENTS FOR PATIENTS
WITH KIDNEY CANCER.
HE'S ALSO A RECIPIENT OF THAL AN
S. RABSON AWARD WHICH RECOGNIZES
OUTSTANDING CLINICAL
INVESTIGATORS WHO DEMONSTRATED
EXCEPTIONAL COMMITMENT TO
PATIENTS AND THEIR FAMILIES.
THE TITLE OF HIS PRESENTATION
TODAY IS MECHANISM BASED
TREATMENT STRATEGIES IN KIDNEY
CANCER.
NOW PLEASE JOIN ME IN WELCOMING
OUR GRAND ROUNDS SPEAKER
DR. SHRINIVASAN.
[ APPLAUSE ]
>> THANK YOU DOCTOR FOR THAT
VERY KIND INTRODUCTION.
I AM GOING TO SAY HLRCC, INSTEAD
OF THE FULL NAME SO THAT ALL OF
YOU CAN FOLLOW IT.
IT'S MUCH EASIER THAN SAYING THE
LONG WORDS.
IT'S A GREAT PLEASURE FOR ME TO
BE HERE TODAY TO TELL YOU A
LITTLE BIT ABOUT THE WORK WE'VE
BEEN DOING AT THE NCI LEADING TO
SOME DISCOVERIES IN KIDNEY
CANCER AND HOW HE MANAGE KIDNEY
CANCER.
OVER THE NEXT 45-50 MINUTES OR
SO, I WILL LEAD YOU THROUGH SOME
ASPECTS OF WHAT WE'VE DONE AND
HOPEFULLY WE WILL HAVE QUESTIONS
FOR DISCUSSIONS AFTER THAT,
SOMETIMES FOR QUESTIONS FOR
DISCUSSION AFTER THAT.
SO IF YOU'RE LOOKING AT KIDNEY
CANCER IN THE 1980S, WHAT WE
KNEW ABOUT KIDNEY CANCER WAS
VERY LIMITED AND FROM A
CLASSIFICATION PERSPECTIVE,
CLASSIFICATION IS VERY, VERY
SIMPLE.
YOU HAD ADENOMAS OR YOU HAD
RENAL SUBCARCINOMAS, AND OTHER
CATEGORY WHICH RECOGNIZED THERE
WERE KIDNEY CANCERS THAT LOOK
DIFFERENT FROM THE MORE COMMON
CONVENTIONAL KIDNEY CANCERS BUT
NOT A LOT MORE WAS KNOWN ABOUT
IT.
OVER THE YEARS, OVER THE NEXT
DECADE OR DECADE AND A HALF,
PATHOLOGISTS MADE A LOT OF
STRIDES IN RECOGNIZING THAT
THERE WERE INDEED MANY DIFFERENT
HISTOLOGIC TYPES OF KIDNEY
CANCER.
THEY DEFINE CLEAR CELL KIDNEY
CANCER WHICH IS WHAT PEOPLE
TYPICALLY REFER TO AS KIDNEY
CANCER, THE MOST COMMON FORM
ACCOUNTING FOR 75% OF ALL KIDNEY
TUMORS.
AND THEN THIS APPLIED
ILLEGALSARY KIDNEY CANCER WHICH
IS THE WAY IT WAS CLASSIFIED
PREVIOUSLY THE MOST COMMON
KIDNEY MALIGNANCY AND
PATHOLOGISTS WERE FURTHER ABLE
TO DISTINGUISH BASED ON
HISTOLOGIC FEATURES, TYPES 1 AND
WHAT THE REST OF THE WORLD
CALLED TYPE 2 BUT WE CALL
NONTYPE 1 BECAUSE WE HAVE AN
OUTSTANDING KIDNEY CANCER
PATHOLOGIST, DR. MARINO, WHO
POINTED OUT VERY ASTUTELY AND
NOW WE KNOW IT'S ABSOLUTELY
TRUE, THAT WHILE TYPE 1 APPEARS
TO BE HOMOGEANOUS IN ITS
APPEARANCE AND CLINICAL
CHARACTERISTICS, TYPE 2 IS
REALLY A VERY HETEROGENEOUS
GROUP OF MALACY, SO WE USE THE
TERM NONTYPE 1 AND I WILL TELL
YOU IN A MINUTE OR 2 HOW THAT
EVOLVED WITH TIME AS WELL.
AND THEN THERE ARE OTHER FORMS
OF KIDNEY CANCER, CHROMA PHOBE,
AND OTHERS MEDULARY AND OTHERS
THAT MAKE UP THE REST.
BUT IT WAS WITH THE ADVENT OF
MORE EXTENSIVE GENETIC
EVALUATION AND GENETIC TESTING
THAT WE REALLY STARTED TO
UNDERSTAND HOW COMPLEX KIDNEY
CANCER WAS AND HOW IT WAS WE
USED A TERM TO DESCRIBE A
REALLY, REALLY DESPERATE
ENTITIES BECAUSE THEY ALL ARISE
IN THE KIDNEY.
HERE IS SHOWING THE
REPRESENTATION OF SOME FORM OF
THE CONDITIONS THAT WE RECOGNIZE
AND AS WELL AS THE FORMATIONS
THAT DRIVE THESE ENTITIES.
SO THESE DISCOVERIES NOW HAVE
REALLY LED TO A COMPLETE
RECLASSIFICATION OF KIDNEY
CANCER IN 2022, THE W. H. O.
RECOGNIZES, YOU KNOW A VARIETY
OF DIFFERENT FORMS OF KIDNEY
CANCER, SOME OF THEM STILL
CLASSIFIED HISTOLOGICALLY BUT
THERE IS A GREATER TENDENCY NOW
TO RECOGNIZE GENETICALLY AND
MOLECULARLY KIDNEY FORMS OF
CANCER AND MANY OF THE KIDNEY
CANCER ENTITIES, YOU SEE IN THIS
CLASSIFICATION ACTUALLY ARE
BASED ON MOLECULAR
CHARACTERIZATION.
SO WE KNOW NOW, IT'S BEEN WELL
ESTABLISHED THAT KIDNEY CANCER
IS NOT A SINGLE DEC BUT HOW CAN
WE DO WITH DIAGNOSING KIDNEY
CANCER, AND YOU DON'T TREAT ALL
THE LEUKEMIAS, THE WAY YOU HELP
THE 1 LEUKEMIA RIGHT, SO YOU
WOULD ASSUME THAT WOULD
TRANSLATE INTO KIDNEY CANCER AS
WELL.
UNFORTUNATELY, IT TAKES TIME FOR
US TO TAKE WHAT WE KNOW ABOUT
THESE TUMORS AND REALLY MAKE
MEANINGFUL IMPACTS AND
TREATMENTS.
SO FOR A LONG TIME AND THAT
TREND IS SLOWLY CHANGING NOW,
ALL APPROACHES THAT WE HAD WERE
REALLY DIRECTED TOWARDS THE MOST
COMMON FORM OF KIDNEY CANCER,
AND BECAUSE WE DIDN'T UNDERSTAND
OTHER FORMS AS WELL AS WE DID
CLEAR CELL KIDNEY CANCER, THE
TREATMENTS WE DEVELOPED FOR
CLEAR CELL WOULD BE TRY INDEED
OTHER FORMS OF KIDNEY CANCER,
OFTEN WITH VERY, VERY MODEST
OUTCOMES.
AN EXAMPLE IS THE VEGFRTKLs,
WHICH WAS IN 2005-2006.
AND A VARIETY OF DIFFERENT 1S,
ALL OF WHICH WERE QUITE ACTIVE
IN KIDNEY CLEAR CELL CANCER AND
WERE THE MAIN STAY OF TREATMENT
FOR THAT TYPE OF KIDNEY CANCER.
BUT WHEN YOU LOOK AT THOSE IN
THE ACTIVITY AND THE PATHWAY OF
KIDNEY CANCER, THE RESPONSES
WERE FAIRLY DISAPPOINTING.
SO THIS REALLY HIGHLIGHTS THE
FACT THAT YOU KNOW HAVING
RECOGNIZED THE HETEROGENEITY OF
KIDNEY CANCER, WE SHOULD BE
TRYING TO DEVISE TREATMENTS THAT
CLEARLY ACCOUNT FOR THESE
DIFFERENCES AND THAT'S REALLY A
LOT OF WHAT WE DO HERE AT THE
NCI.
WE HAVE USED INHERITED FORMS OF
KIDNEY CANCER AS A MODEL FOR
STUDYING NOT ONLY GENETICS AND
THE MOLECULAR CHANGES DRIVING
THESE TUMORS, BUT ALSO AS A
MODEL FOR EVALUATING TREATMENTS
THAT WE OFTEN THINK CAN THEN BE
APPLIED TO SPORADIC FORMS OF
KIDNEY CANCER THAT RESEMBLE SOME
OF THESE FAILURES.
WHY DO WE USE GENETIC FORMS OF
KIDNEY CANCER TO STUDY
TREATMENTS?
THEY'RE GENETICALLY WELL
DEFINED, MUCH MORE HOMOGENIUS
THAN SPORADIC POPULATIONS SO
IT'S VERY EASY TO TEST A
SPECIFIC HYPOTHESIS AT A
SPECIFIC TARGET IN THESE
POPULATIONS.
AT LEAST SCIENCE HAS MADE IT
VERY EASY.
GENETIC DRIVERS AND MOLECULAR
ALTERATIONS HAVE BEEN WELL
CHARACTERIZED IN MANY OF THESE
INHERITED FORMS OF KIDNEY CANCER
AND AS I POINTED OUT, THEY CAN
REALLY SHED LIGHT ON WHAT WE CAN
DO THEN WITH SPORADIC FORMS AND
COUNTERPARTS OF THESE FORMS OF
KIDNEY CANCERS.
A VARIETY OF INHERITED FORMS OF
KIDNEY CANCER HAVE BEEN DRIEBED
NOW, THIS IS LITERALLY BUT NOT
FULLY ALL ENCOMPASSING LIST OF
INHERITED FORMS OF DISEASE.
WHAT WE DO HERE AT THE NCI IS
TAKE A SYSTEMATIC APPROACH TO
CHARACTERIZATION OF THESE
TUMORS, AND USE THE INFORMATION
WE GET FROM THERE, TO REALLY
DEVELOP NOVEL TREATMENT
APPROACHES.
SO WE START OFF BY LOOKING AT
DISEASE CHARACTERIZATION AND
GENE DISCOVERY, FOLLOWED BY
MECHANISTIC STUDIES AND THEN TRY
TO TAKE THAT INFORMATION INTO
THE CLINIC.
OBVIOUSLY, YOU KNOW THIS IS NOT
A LINEAR PROCESS, THERE'S A LOT
OF CROSS TALK BETWEEN THE
VARIOUS GROUPS THAT ARE EXPERT
IN EACH OF THESE APPROACHES.
AND TODAY I'M GOING TO TRY AND
SHOW YOU THROUGH A COUPLE OF
EXAMPLES HOW THIS PROCESS WORKS
AND HOW IT HAS LED TO ADVANCES
IN HOW WE MANAGE CERTAIN GROUPS
OF PEOPLE WITH KIDNEY CANCER.
WE WILL START OFF WITH CLEAR
CELL AS I SAID, A LOT IS KNOWN
ABOUT THIS BUT I THINK IT'S VERY
INSTRUCTIVE TO GO OVER HOW
THISSENTITY CAME TO BE
RECOGNIZED, HOW THE GENETIC
UNDERPINNINGS OF THIS SUBTYPE
CAME TO BE UNDERSTOOD AND HOW
UNDERSTANDING THE BIOLOGY REALLY
LED TO SPECIFIC POSITION
TREATMENT APPROACHES.
STORY REALLY IN TRYING TO
UNDERSTAND CLEAR CELL KIDNEY
CANCER AT A DEEPER LEVEL
STARTING WITH AN INHIRITTED FORM
OF INHERITED KIDNEY DISEASE,
THIS IS A PREDISPOSITION FOR
DEVELOPING TUMORS IN A VARIETY
OF DIFFERENT ORGANS.
IT'S RARE, THE CONDITION,
ESTIMATED TO OCCUR IN
APPROXIMATELY 1 IN 35-40,000
LIVE BIRTHS IN THIS COUNTRY.
PEN TRANCE IS VERY HIGH, ALMOST
ALL PATIENTS BY THE AGE OF 60
WILL LIKELY HAVE 1 OR MORE
MANIFESTATIONS OF VHL.
SO WHAT ARE THE MANIFESTATIONS
OF VHL?
OBVIOUSLY KIDNEY CANCER, CLEAR
CELL KIDNEY CANCER, A BILATERAL
MULTIFOCAL FASHION, THESE
PATIENTS ALSO HAVE BILATERAL
RENAL CYSTS, TUMORS IN THE
PANCREAS, TUMORS OF A VERY
SPECIFIC SUBTYPE, CALLED NEURAL
PANCREATIC TUMORS, THEY DEVELOP
SIGNIFY TELOMERAS AND HEME ANGIO
BLASTOMAS, IN THE CENTRAL
NERVOUS SYSTEM AS WELL AS OTHER
TUMORS IN THE BROAD LIGAMENT
MELANOMAS AS WELL AS TUMORS IN
THE INNER EAR.
A LITTLE BIT OF HISTORY.
I'M A FAN OF HISTORY, SO I WILL
SPEND A COUPLE OF MINUTES
TALKING ABOUT A HISTORY OF VHL,
PROBABLY THE EARLIEST
DESCRIPTION WAS IN THE LATE
1890S, DR. COLLINS TALKED ABOUT
A PAIR OF SIBLING WHO IS HAD
ABNORMAL VASCULAR GROWTHS IN
THEIR EYES, OF COURSE AT THAT
POINT, THERE WASN'T A LINK TO
OTHER MANIFESTATIONS, NOR WAS
THISSENTITY CLEARLY CHARKTIZED,
AND AND WAS AN OBSERVATION AND
AN IMPORTANT 1 BUT AN
OBSERVATION AT THAT TIME.
IN THE 1920S, HIPPEL RECREATED
THIS FINDINGS IN PATIENTS HE WAS
SEEING WHO HAD OFTEN BILATERAL
HEME ANGIO BLASTOMAS THAT RAN IN
FAMILIES.
THIS OBSERVATION WAS
COMPLEMENTED A FEW YEARS LATER
BY ALBERT LINDAU WHO DESCRIBED
CNS BLASTOMA TUMORS.
OVER THE NEXT FEW YEARS, THE
ENTITY VHL CAME TO BE RECOGNIZED
AND IT WAS NAMED AFTER HIPPEL
AND LINDAU.
WE DON'T SEE A LOT IN THE
LITERATURE ABOUT VHL FOR THE
NEXT SEVERAL DECADES.
WHAT WE DO KNOW AND AS A GEANIAL
ONCOLOGIST, MY FOCUS IS ON
KIDNEY CANCER.
SO WHAT WE KNOW IS FOR THE
LONGEST PERIOD THESE PATIENTS
WERE MANAGED BECAUSE THEY HAVE
BILATERAL MULTIFOCAL TUMORS,
THEY COULD WITHOUT LIFE, IF YOU
TOOK TUMORS BACK, WITH NEW
TUMORS, WOULD FORM, SO TO COMBAT
THAT ISSUE, WHAT UROLOGISTS WERE
DOING UNTIL 1970S AND EARLY 80S
WAS DOING STAGED BILATERAL NEFF
RECTIFIED ME.
SO THEY WOULD TAKE A KIDNEY OUT.
GO BACK AND TAKE ANOTHER KIDNEY
OUT AND YOU KNOW LET THE PATIENT
SURVIVAL DIALYSIS THE REST OF
THEIR LIVES.
WHY WERE THEY DOING THIS WHY
WOULD THEY NEED TO REMOVE THIS?
BECAUSE THEY HAD MET STATIC
POTENTIAL.
IF YOU DID NOTHING, THEY WOULD
GROW, BECOME METASTATIC AND WE
HAD NO CURE FOR THE PATIENTS.
SO THIS WAS MEANT TO SAVE THE
PATIENTS BUT UNFORTUNATELY IT
LED TO REMOVAL OF BOTH KIDNEYS.
A PROGRAM TO STUDY THE VHL WAS
TEABED IN THE EARLY 1980S OF THE
NCI LED DOCTOR AND HIS
COLLEAGUES.
ONE OF THE THINGS THAT THE
PROGRAM ACHIEVED AND THERE ARE
SEVERAL OVER THE ACCOMPLISHMENTS
IN THE NEXT FEW MINUTES WAS TO
CHANGE THIS APPROACH AND THE
APPROACH THEY TOOK WAS TO ASK
THEMSELVES DO WE REALLY NEED TO
TAKE BOTH KIDNEYS OUT.
YES, WE UNDERSTAND THAT A
BILATERAL MULTIFOCAL TUMORS BUT
HOW CAN WE TRY AND SPARE THE
KIDNEYS WITHOUT ALLOWING THESE
TUMORS TO BECOME METASTATIC.
OVER THE YEARS THEY DEVELOPED A
SYSTEM WHEREBY THEY WOULD TAKE
TUMORS THAT WERE LARGE ENOUGH TO
CAUSE PROBLEMS, AND THAT SIZE
CAME TO BE DETERMINED TO BE
AROUND 3-CENTIMETERS OR SO,
THAT'S THE THRESHOLD BEYOND
WHICH THE RISK OF METASTASIS
CONTINUES TO BUILD.
SO THEY WOULD TAKE OUT TUMORS
THAT WERE APPROACHES
3-CENTIMETERS, AND THEY WOULD
TAKE OUT ONLY THE TUMORS.
NOT THE WHOLE KIDNEY.
SO THEY WERE ABLE TO GO IN VERY
SELECTIVELY, REMOVE THE TUMORS,
WITH A LOT OF NORMAL NEPHRONS,
AND THIS GAME STUDIED AND HAS
BOTTOM AN ACCEPTED PRACTICE IN
THE MANAGEMENT OF THESE
PATIENTS.
UNTIL RECENTLY, VHL WAS
ESSENTIALLY A DISEASE MANAGED BY
SURMINGICAL AND LOCAL THERAPIES.
-- SURGICAL AND LOCAL THERAPIES.
WHAT WAS THE GOAL IN KIDNEY
CANCER?
THE GOAL IS TO PREVENT
METASTATIC DISEASE AND AS I ALSO
POINTED OUT TO MINIMIZE THE RISK
OF METASTATIC DISEASE, TUMORS
WOULD GET TAKEN OUT BEFORE THEY
REACHED 3-CENTIMETERS OR AS THEY
WERE REACHING 3-CENTIMETERS.
NOT ALL TUMORS ASSOCIATED WITH
VHL HAVE METASTATIC POTENTIAL.
NONETHELESS, THEY ALL CAN CAUSE
PROBLEMS.
FOR INSTANCE CNS, AND THE
BLASTOMAS, DON'T METASTASIZE,
BUT BECAUSE OF THEIR LOCATION
THEY CAN CAUSE SIGNIFICANT
FUNCTIONAL IMPAIRMENT AND THE
GOAL IN THOSE TUMORS IS TO TRY
AND REGAIN FUNCTION AND AGAIN,
LOCAL APPROACHES WERE REALLY ALL
THAT WERE AVAILABLE TO US UNTIL
RECENTLY.
SO WHILE THESE PROTESTS WERE
EFFECTIVE IN MANAGING THESE
PATIENTS, THEY CAME AT A COST,
LIKE MANY OF THESE PATIENTS
NEEDED SURGERIES IN MULTIPLE
ORGANS, SOMETIMES REPEATED
SEVERAL TIMES DURING THEIR
LIFETIME AND THIS REALLY BECAME
A VERY BURDENSOME AFFAIR.
SURE, WITH CAREFUL SURVEILLANCE
AND ALL OF THESE TUMORS YOU
COULD REGAIN FUNCTION TO A
SIGNIFICANT DEGREE IN SOME OF
THESE PATIENTS, YOU COULD
MINIMIZE THE RISK OF METASTATIC
DEC BUT IT CAME AT A -- THE
PATIENT'S PAID A PRICE FOR IT.
WHEN I CAME INTO THE NCI, 1 OF
THE GOALS HIWAS TO TRY AND FIND
-- I HAD WAS TO TRY AND FIND A
SYSTEMIC OPTION THAT COULD WORK
IN CONJUNCTION WITH ESTABLISHED
PRACTICES, OBVIOUSLY THE NEED
FOR SURGERY OR MINIMIZE THE NEED
FOR SURGERY.
SO HOW DO YOU EVEN GO ABOUT
DEVISING SYSTEM AND TREATMENT.
THERE WERE NO SYSTEM AND
TREATMENTS OTHER THAN CYTOKINE
THERAPY WHICH IS EFFECTIVE IN
PROPULSION OF METASTATIC CANCER
UNTIL THE EARLY 2000S.
BUT THE INITIAL STEPS REALLY
THAT REALLY BROUGHT US TO A
POINT WHERE WE COULD DEVISE
THESE TREATMENTS, TOOK SHAPE
AGAIN IN THE EARLY 80S AND
MARSTON LINEHAN JOINED STEVE'S
GROUP HERE AT THE NCI, HE TOOK
IT UPON HIMSELF TO STUDY VHL AND
WAS CONVINCED BY STUDYING THESE
PATIENTS WITH VHL, THESE
FAMILIES WITH VHL, HE WOULD BE
ABLE TO IDENTIFY THE GENETIC
CAUSE OF THE DISEASE.
SO THAT WAS A GENETIC DEFECT
THAT LED TO THESE TUMORS.
AND ALSO BY UNDERSTANDING VHL,
HE COULD ALSO SHED LIGHT ON HOW
PATIENTS WITH SPORADIC KIDNEY
CANCERS AND GUARD AGAINST THOSE
CANCERS.
LONG STORY SHORT.
TOOK AROUND 10 YEARS, LINEHAN
AND ZBAR, ALONG WITH OTHER
INVESTIGATORS WERE ABLE TO
IDENTIFY THE JEERN THAT CAUSED
VHL.
AND WERE ABLE TO IDENTIFY ON
CHROMOSOME 3, THE ABLE TO DEFECT
AND FURTHER LOCALIZE THE GENE,
NOW WHICH WE CALL THE VHL YEEN
THAT WAS ACTIVATING MUTATIONS IN
THE GERM LINE.
AND THIS WAS THEN SHOWN TO BE
THE CAUSE FOR VHL DISEASE.
THE VERY SAME GENE AND VERY
SIMILAR MUTATIONS ALSO OCCUR IN
THE SPORADIC VARIANT OF KIDNEY
CELL CANCER.
MUCH MORE THAN THE GENETIC FORM,
THE DIFFERENCE BEING IN VHL
DISEASE, 1 IS THE PRESENT GERM
LINE AND THE SECOND IN THE
SOMATIC TISSUE WHILE BOTH ARE
SOMATIC IN THE SPORADIC VERSION
OF CLEAR CELL RCC.
VHL DOES HAVE A CLASSIC GENE
THAT REQUIRES TO HITS FOR FULL
MANIFESTATION.
SO NOW WE KNOW THERE'S A GENE
THAT CAUSES THIS DISEASE EMPLOY
THE NEXT QUESTION OF COURSE THAT
FACED IN A SCIENTISTS IN THE
1990S WAS HOW DOES LOSING VHL
FUNCTION LEAD TO KIDNEY CANCER.
ONE OF THE EARLIEST CLUES REALLY
CAME FROM STUDIES THAT WERE BONE
BY FORMER NCI DIRECTOR CLAUSEN,
AS WELL AS A LAB IN HARBOR,
THERE'S LOTS OF STORIES THAT I
DON'T HAVE TIME TO GO INTO
TODAY, BUT WHAT BOTH GROUPS
IDENTIFIED WAS THAT VHL WAS
ASSOCIATED WITH B& C WHICH IS
WHERE TRANSCRIPTION OF FACTORS
BUT ALSO HAD LONG FUNCTION.
THIS VERY, VERY CRITICAL FINDING
WAS THEN FOLLOWED BY OBSERVATION
THAT ELONGINS IN TURN COMPLEXED
WITH RBX 1 WAS -- THIS REALLY
PAVED THE WAY FOR US TO
UNDERSTAND 1 OF THE MANY
FUNCTIONS OF VHL WAS THAT IT
ACTS AS A COMPLEMENT OF E-3
LIAISON GAS WHICH REGULATES
MULTIPLE CELLULAR PROTEINS.
OVER THE NEXT SEVERAL YEARS, IT
BECAME A PATTERN THAT 1 OF THE
KEY PROTEINS THAT WAS REGULATED
WAS A GROUP OF TRANSCRIPTION
FACTORS CALLED HYPOXIA AND
FACTORS 1 AND 2 BEING THE 2, IN
THE MOST WELL RECOGNIZED
VERSIONS OF THIS, YOU HAVE THIS
GROUP OF TRANSCRIPTION FACTORS.
AND IT BECAME A MODEL IS
PROPOSED WHEREBY IN NORMAL CELLS
WITH INTACT VHL, THE LEVEL OF
THESE LEVELS WILL BE TIGHTLY
REGULATED BASED ON THE LEVELS OF
AMBIENT OXYGEN.
IF THERE WAS ENOUGH AMBIENT
OXYGEN, VHL WOULD BIND TO AND
LEAD TO DEGRADATION OF THESE
FACTORS.
ON THE OTHER HAND, POST
TRANSLATIONAL CLINICAL
MODIFICATION OF THESE FACT FACS
WHICH WAS NECESSARY BY THE VHL
WOULD NOT THERE, AND THEREFORE
THESE FACTORS WOULD ACCUMULATE
IN A BIT OF REVERSE, THE
CONSEQUENCES OF HYPOXIA.
IN PATIENTS IN INACTIVE VHL, THE
SYSTEMS ON ALL THE TIME.
VHL IS UNABLE TO RECOGNIZE HIF,
REGARDLESS OF AMBIENT OXYGEN
RETENTION AND THEREFORE
UPREGULATION OF THE SYSTEM AND
DOWN STREAM CONQUENCES.
IN FACT, IT WAS UNDERSTANDING
THIS PATHWAY WHICH BY THE WAY
WAS CRITICAL IN TRIBUTING IN
2019 THAT 3 INVESTIGATORS
RECEIVED, ALLEN, AND RATLIFF AND
COLLEAGUES, IT'S UNDERSTANDING
THAT A LOT OF THE TREATMENTS WE
HAD, AT LEAST THE TARGETED
TREATMENTS WE'VE HAD FOR
PATIENTS WITH CLEAR CELL KIDNEY
CANCER WERE DEVISED.
MOST OF THESE TREATMENTS AS
SHOWN HERE, TARGETED DOWN STREAM
CONSEQUENCES OF HIF REGULATION,
SUCH AS VEG-F, PDFR AND
PROLIFERATION.
THE FIELD HAS LONG THIRSTED
HOWEVER TO TRY AND TARGET THIS
PATHWAY APPROXIMATELY 3 AS A
LEVEL OF HIH, THIS PROVED TO BE
A BIGGER CHALLENGE THAN WE WOULD
HAVE LIKED.
THESE TRANSCRIPTION FACTORS AND
THORSITORIOUSLY DIFFICULT TO
TARGET, BUT WE THOUGHT IN THE
EARLY 2000S THAT WE MAY BE ABLE
TO DO JUST THAT.
LYNN NECKERS AND POST DOC AT THE
TIME WERE STUDYING A GROUP OF
MOLECULES AND LYNN'S AN EXPERT
ON P90 AND THEY STARTED A GROUP
OF P90 AND SHOWED THAT THESE
MOLECULES IN PROTOTYPIC TRIALS
WERE ABLE TO DOWN REGULATE HIF.
THIS WAS VERY EXCITING FINDING
FOR US.
AT THAT TIME, WE KNEW THAT THESE
DRUGS DOWN REGULATED HIF 1,
BECAUSE IT'S A CLIENT PROTEIN
FOR THE HSP90 SYSTEM.
WE WERE NOT ABLE TO STUDY HIF2
AS WELL AS WE WOULD LIKE BECAUSE
WE DIDN'T HAVE AN ANTIBODIES
THAT WERE GOOD ENOUGH BUT THERE
WERE INDICATIONS FROM OTHER
GROUPS INCLUDING BILL'S GROUP
THAT HIF2 MIGHT ALSO BE A CLIENT
FOR HSP90 AND MIGHT BE DOWN
REGULATED SO WE HAD SOME
INFORMATION ABOUT WHAT THESE
DRUGS DID FOR THE HIF AXIS BUT
THERE WAS CLEARLY SOME
INFORMATION MISSING BUT WE
THOUGHT THIS WAS EXCITING ENOUGH
THAT THIS WAS AN APPROACH THAT
COULD POTENTIALLY BE TESTED IN
THE CLINIC.
AND SO WE UNDERTOOK THE FIRST
EVER CLINICAL TRIAL OF A
SYSTEMIC AGENT IN THE PATIENTS
WITH VHL, THIS WAS AS I SAID A
AGENT AND INTRANSLATIONAL
RESEARCH VENOUS AGENT AND WE
ALSO ASKED VERY SIMPLE
QUESTIONS, FIRST , THE SPECIFIC
ISSUES KEEPING IN MIND WHEN
TREATING THESE PATIENTS.
THE DESIGN WE HAD TO TAKE
PATIENTS THAT WERE GOING TO
SURGERY, THEY HAD TUMORS THAT
WERE APPROACHING 3-CENTIMETERS
AND THE PHYSICIANS THOUGHT THEY
SHOULD HAVE THESE TUMORS REMOVED
AND ADMINISTERED THIS DRULG FOR
A PERIOD OF TIME, IF THE
PATIENTS RESPONDED WE WOULD
CONTINUE TREATMENT, IF THEY
DIDN'T RESPOND WE WOULD TAKE
THEM TO SURGERY, COLLECT THE
TISSUE TO SEE IF THE PATHWAY WE
THOUGHT WOULD BE IMPACTED WAS
IMPACTED BY THIS DRUG.
THIS IS AN EXCEEDINGLY DIFFICULT
STUDY TO CONDUCT BECAUSE OF THE
DRUG PARTLY BUT ALSO BECAUSE AT
THAT POINT WE FAILED TO
RECOGNIZE HOW DIFFICULT IT WAS
TO BRING THESE PATIENTS IN AND
HAVE THEM UNDERGO A STUDY THAT
WAS FAIRLY COMPLEX.
BUT A LOT OF LESSONS TO LEARN
FROM THIS AND 1 OF THOSE THAT
WAS THAT YES, WE COULD DO THE
STUDIES IN VHL PATIENTS AND IT
ALSO IDENTIFIED FOR SEVERAL
FACTORS, WE NEEDED TO TAKE INTO
ACCOUNT, TO IMPROVE STRATEGIES
WITH FUTURE TRIALS.
THE TRIAL ITSELF WAS NOT
CLINICALLY VERY PROMISING.
WE SAW NO RESPONSES, WE DID SEE
A LOT OF STABLE DISEASE BUT OVER
4 MONTHS, STABLE DISEASE IS THE
NORM IN PATIENTS WITH VHL, EVEN
IF YOU DIDN'T TREAT THEM.
OVER THE SUCCEEDING YEARS AND
THIS WAS AROUND THE TIME WHEN
VEG F TARGETS BECAME AVAILABLE
FOR CLINICAL USE AND WAS SHOWN
TO BE EFFECTIVE IN THE SPORADIC
FORM OF CLEAR CELL RCC, AND WE
AND OTHER INVESTIGATORS ASKED IF
THESE VEG F TARGETED 18thS
TYROSEEN INHIBITORS WOULD HAVE
CLINICAL UTILITY IN PATIENTS
WITH VHL.
I'LL SUMMARIZE THE DATA FROM
THOSE STUDIES IN A COUPLE OF
SLIDES.
WHAT WE LEARNED THEN WAS THAT
YES, THERE'S SOME ACTIVITY
ASSOCIATED WITH THESE AGENTS,
I'M SHOWING 2 STUDIES WITH 1
CALLED VANDETANIB, AND ALSO
SUNITINIKB SIN, STUDIED AT MD
ANDERSON.
WE DID SEE A LOT OF ACTIVITY IN
THE OTHER MANIFESTATIONS,
CERTAINLY NOT THE OTHER
BLASTOMAS THAT ARE ASSOCIATE
WIDE VHL.
BUT KIDNEY CANCERS DID SEEM TO
REGRESS AT LEAST IN THE
PROPORTION OF PATIENTS.
THE MAJOR PROBLEM AND THE SECOND
LESSON WE LEARNED IN TREATING
THESE VHL PATIENTS WAS THAT A
LOT OF THESE PATIENTS DIDN'T
LIKE THESE DRUGS.
PATIENTS WITH METASTATIC KIDNEY
CANCER WHO HAVE NO OTHER
TREATMENT OPTIONS AND ARE GOING
TO DIE IF THEY DON'T GET THIS
TREATMENT ARE WILLING TO ACCEPT
A LOT OF TOXICITY THAT WHAT USED
TO BE CHARACTERIZED AS WELL
TOLERATED KINASE INHIBITORS.
THESE PATIENT WHO IS HAD
LOCALIZED DISEASE WHO HAD
SURGICAL OPTIONS, NOT A WALK IN
THE PARK THEMSELVES BUT THEY HAD
OTHER OPTIONS AND THEY WERE NOT
STARING IMMINENT DEATH IN THE
FACE IF THEY DIDN'T TAKE THIS
DRUG.
THEY HAD A VERY LEVEL OF
ACCEPTANCE FOR THESE SIDE CENTER
FOR EXCELLENCE ON AGINGS, MEDIAN
TIME WITH THESE STUDIES WAS ON
DRUG IN NEEZ STUDIES WAS LESS
THAN 6 MONTHS WITH THE VAST
MAIORITY OF PATIENTS CONTINUING
-- CONTINUING TREATMENT FOR
TOXICITY.
SO SECOND IMPORTANT LESSON
LEARNED IF YOU WANT TO DEVICE
EFFECTIVE TREATMENT STRATEGY FOR
THESE PATIENTS ISSUES THE TARGET
ON THE VHL TUMORS, WE NEED TO
DEVISE DRUGS THAT ARE WELL
TOLERATED AND REALLY WELL
TOLERATED.
I UNDERSTAND EARLY 2000S WORK IN
LINEHAN'S LAB AT NCI AND ANOTHER
COLLEAGUE'S LAB AT HARVARD,
DEMONSTRATE THAD HIF1 AND 2, HIF
2 SEEMED TO BE THE MORE
ONCOGENIC DRIVER OF THESE
TUMORS.
HIF1 IN THIS CONTEXT CONFERS AT
LEAST TO SOME EXTENT A TUMOR
EFFECT.
SO, EFFORTS THEN WERE DIRECTED
AT TRYING TO FIND AN AGENT OR
AGENTS THAT SPECIFICALLY TARGET
HIF2 BECAUSE IT COULD BE ARGUED
THAT TARGETING HIF1 MIGHT BE
DELETERIOUS.
AS I SAID, TARGETS TRANSCRIPTION
FACTORS IS NOT EASY AND IT
WASN'T IN THIS CASE, SO IT TOOK
SEVERAL YEARS BEFORE A BREAK
THROUGH CAME AND THE BREAK
THROUGH CAME FROM DR. BRUIC AND
GARDENER'S LAB AT UT
SOUTHWESTERN EMPLOY TO
UNDERSTAND HOW THEY DEVELOPED
THIS DRUG, IT'S IMPORTANT TO
SPEND A MINUTEOT HIF FUNCTION,
BOTH HIF1 AND 2 FUNCTION AS A
HETERODIMER.
SO HIF1 AND 2 ARE 2 DISTINCT
ALPHA SUBUNITS BUT THEY'RE A
HETERODIMIC PARTNER, IS COMMON.
SO THEY HAD TO DEVISE A METHOD
THAT WOULD SELECTIVELY KNOCK
DOWN HIF2 BUT NOT HIF1.
AND IN EVALUATING THESE
MOLECULES THEY WERE ABLE TO
IDENTIFY A PAST B DOMAINOIN IN
HIF-2 FROM WHAT WAS EXISTED IN
FIH1, AND DEVELOP A GROUP OF
DRUGS THAT SPECIFICALLY FIT IN
THIS DOMAIN AND AS
HETERODIMMERAISATION, IF YOU
DON'T HAVE THE FACTORS, THESE
TRANSCRIPTIONS ARE NOT
ACTIVATING.
THEY SYNTHESIZED AND RELATED
CHEMICALLY TO 1 ANOTHER, AND
EARLY COMPOUNDS WERE SHOWN TO BE
VERY EFFECTIVE.
INHIBITORS OF HIF2 ALPHA AS WELL
AS INDUCING REGRESSION IN VHL
HIF TUMORS BY THE EVANS GROUP AT
HARVARD AS WELL AS JIM'S GROUP
AT UT SOUTHWESTERN.
SO AT LONG LOST, WE HAD DRUGGED
THAT WE COULD TARGET, WE COULD
USE TO TARGET HIF2 ALPHA.
SO HOW DO WE REALLY THEN
EVALUATE THESE DRUGS.
IN CANCER MOST DRUGS ARE
EVALUATED FIRST IN PATIENTS WHO
HAVE NO OTHER OPTIONS, TYPICALLY
IN THE METASTATIC SETTING WHERE
OTHER OPTIONS HAVE BEEN
EXHAUSTED OR THERE ARE NO OTHER
TREATMENTS FOR GIVEN SETTING.
HOWEVER, I THINK PEOPLE WHO MADE
THIS DRUG COMPANY, CALLED
PELATTA AT THE TIME, RECOGNIZED
THAT THE MODEL, BUT NOT A
TYPICAL APPROACH MIGHT ACTUALLY
PROVIDE A GOOD ANSWER TO AS TO
WHETHER OR NOT A DRUG AS
SPECIFIC AS THIS TARGETS HIF2,
HAS ACTIVITY IN HIF2 AND TUMORS,
SO THEY CAME TO US AND APPROACH
US AND SAY, DO YOU THINK A STUDY
IN VHL PATIENT SYSTEM FEASIBLE
EMPLOY THEY HAD GONE THROUGH THE
PHASE 1 STUDY AT THE TIME AND 1
OF THE FIRST QUESTIONS I HAD FOR
THEM WAS HOW WELL TOLERATED IS
THIS DRUG IN AND IT DID SEEM TO
HAVE AN EXCELLENT TOLERANCE.
THERE WAS NO DOUBT IN OUR MINDS
THAT TO EVALUATE A POSITION DRUG
SUCH AS THE 1S THAT DEVELOP,
CLEAN LITERALLY HOMOGENOUS MODEL
THAT WAS CLEARLY DRIVEN BY THE
TARGET OF THEIR DRUG WOULD
PROBABLY BE THE BEST MODEL FOR
LOOKING AT PROOF OF PRINCIPLE
THAT THIS PATHWAY CAN BE
SUCCESSFULLY INTERDICTED TO
REALLY DEVELOP -- TO DELIVER
CLINICAL EFFICACY.
SO WE UNDERTOOK A STUDY AT THE
NCI IN 2017 OF THE FIRST AGENT
IN THIS GROUP TO GET TO THE
CLINIC WAS A DRUG CALLED PD2085.
IT WAS A SINGLE SET STUDY AND
VERY SOON AFTER THE FIRST
PATIENT WAS TREATED WE KNEW THIS
WAS ANYTHING TO BE A VERY
EFFECTIVE CLASS OF DRUGS.
WE SAW A CLEAR REDUCTION IN THE
SIZE OF THE RENAL TUMORS.
DR. CHU AND DR. WILEY, THEY HAD
THE FIRST EVALUATION OF THE
PATIENTOT DRUG, CAME RUNNING
DOWN TO THE CLINIC AND SAID YOU
HAVE TO SEE THESE TUMORS AND THE
SIZE AND THE PROGRESS.
WE TRIED TO FOR YEARS TO DO ALL
KINDS OF THING BUSINESS SYSTEMIC
THERAPY, NOTHING AFFECTED THESE
TUMORS SO FAR BUT THIS DRUG HAS.
WE UNFORTUNATELY WERE ABLE TO
TREAT ONLY 4 PATIENTS ON THIS
STUDY AND THIS WAS LARGELY
BECAUSE EVEN THOUGH THIS DRUG
WAS EFFECTIVE, THERE WAS SOME
FORMULATION ISSUES, THERE WERE
PK VARIABLES BETWEEN PATIENTS
AND SO WE ACTUALLY DISCONTINUED
THE STUDY IN FAVOR OF A SECOND
STUDY WITH A DRUG THAT TRIED TO
OVERCOME THESE ISSUES, A DRUG
THAT WAS CALLED PD2977 OR
MK6482, NOW KNOWN AS
BELZIDIFIDE.
THIS STUDY WAS AN INTERNATIONAL
MULTICENTER STUDY THAT WE HELPED
LEAD THAT LOOKED AT BELZIDIFIAN
THAT LOOKED AT TAKING IT ONCE A
DAY IN PEASHTS WHO HAD VHL
DISEASE, DID NOT RECEIVE PRIOR
TREATMENT AND DID NOT HAVE MATTA
STATIC DISEASE, SO WE WERE
TREATING PATIENTS WITH LOCALIZED
DISEASE, THE PRIMARY END POINT
WAS TO LOOK AT RESPONSE IN VHL
ASSOCIATED KIDNEY TUMORS BUT
ALSO LOOKING AT TUMORS IN ALL
THE OTHER ORGANS AS WELL AS
STARTING THERAPY.
THE DATA WAS PUBLISHED IN 2021,
I'M SURE YOU RECOGNIZE 1 PERSON
IN THIS COLLAGE OF PHOTOGRAPHS,
THE DOCTOR AT VANDERBILT AT THE
TIME AND PRESENTED WITH THE
STUDY.
DATA WERE FURTHER UPDATED AND
ACL LAST YEAR, SO I WILL PROVIDE
A SUMMARY OF THE DATA FROM A
YEAR OR SO AGO OF THE 61
PATIENTS TREATED, AT THE TIME OF
THIS ANALYSIS WHICH WAS
APPROXIMATELY A MEDIAN FOLLOW UP
OF 4 YEARS, 36 REMAINED ON
STUDY.
PATIENTS WENT OFF STUDY FOR A
VARIETY OF REASONS, MOST OF THEM
BECAUSE THEY CHOSE TO GO OFF
STUDY OR BECAUSE AFTER FDA
APPROVED THIS DRUG, THEY COULD
GET THIS DRUG LOCALLY AND THEY
SAW NO REASON TO REMAIN ON THE
STUDY.
BUT THE PATIENTS THAT PROGRESSED
IN THE STUDY, WENT OFF FOR THOSE
REASONS.
THE HIGHLY EFFECTIVE DRUG,
ALMOST 90 + PATIENTS HAD SOME
LEVEL OF TUMOR REGRESSION, WITH
AFTER OVERALL RESPONSE RATE OF
67% AND A COMPLETE RESPONSE RATE
OF AROUND 11%.
WHAT KIND OF RESPONSES ARE WE
SEEING IN THESE PATIENTS IN I
WILL SHOW YOU EXAMPLES OF TUMOR
REGRESSIONS IN VARIOUS ORGANS.
THIS FIRST CASE IS A 45 YEAR-OLD
WOMAN WHO CAME TO US HAVING
PREVIOUSLY BEEN DIAGNOSE TD
EARLIER WITH VHL.
HAD UNDER GONE A PARTIAL NEFF
RECTIFIED ME, AND SOME CNS
BLASTIO ANG I DON'T MEANAS, SHE
WAS VERY MUCH DESIRING MORE
SURGERY IF SHE COULD AND WE HAD
AN OPENING AND WE PUT HER ON THE
STUDY.
ON THE LEFT YOU SEE THE PATIENT
HAS BILATERAL FAIRLY LARGE
TUMORS, APPROACHING SURGICAL
SIZE, SO SHE WOULD HAVE GONE TO
SURGERY NOT SOON AFTER BUT THE
DRUG WAS REALLY ABLE TO INDUCE
REGRESSION OF THESE TUMORS.
YOU CAN SEE THE RIGHT SIDE OF
TUMORS IS BADLY VISIBLE AND YOU
CAN SEE A BIT OF THE LEFT SIDE
OF THE TUMORS.
WE KNOW THIS DRUG CAUSES
REGRESSION OF RENAL TUMORS, I
ALSO TOLD YOU THAT SOME OF THE
VEG F TARGETED AGENTS WERE
EFFECTIVE IN KIDNEY CANCER AND
NOT EFFECTIVE IN OTHER AGENTS SO
WE WERE VERY, VERY INTERESTED IN
SEEING WHAT HAPPENS IN OTHER
TUMORS HERE AND WE SAW THAT
THERE WAS ACTIVITY ACROSS THE
SPECTRUM OF VHL MANIFESTATIONS.
PANCREATIC NEUROENDOCRINE
TUMORS, ALTHOUGH LIMITED IN
NUMBER, ONLY 22 OF THESE PATE
WHO IS HAD KIDNEY TUMORS ALSO
HAD A PANCREATIC ENDOCRINE
TUMOR.
POST OF THEM HAD A RESPONSE TO
THIS DRUG AAS DID PATIENTS WITH
THE CNS HEME ANGIO BLASTOMAS.
THIS IS A CASE I WILL SHOW YOU
OF A 30 YEAR-OLD MAN DIAGNOSED
WITH VHL AT 12.
BETWEEN 12 AND 30 HE HAD
MULTIPLE SURGERIES, HE HAD AN A,
QUIRED PHENOTYPE WITH MULTIPLE
SURGERIES LEAVING HIM WITH
DEFINITES FROM THE SURGERY BUT
SOME OF THE PREVIOUS TUMORS THAT
HADN'T BEEN REMOVED WERE
STARTING TO GO.
WE ALSO HAD OTHER MANIFESTATIONS
OF KIDNEY CANCER OF RCC.
THIS IS THE SPINAL HEME ANCHLIO
BLASTOMA THAT I SHOW YOU ON THE
RIGHT, AND THE LEFT HEME ANGIO
BLASTOMA, AND THE STAGE AFTER
THERAPY, AS YOU KNOW,
NEUROSURGEONS WERE CLOSELY
INVOLVED WITH THESE STUDIES AND
ALL THE DECISIONS MADE ON THESE
THERAPIES, WHO TO TAKE TO
SURGERY, WHO TO TAKE FOR THE
STUDIES.
THESE WERE PUBLISHED EARLIER IN
2024.
I TOLD YOU ANN ECTOMYOSIN
DETOMORROW NATION ABOUT A
PATIENT WITH RETINAL HEME ANGIO
BLASTOMAS WHO EXPERIENCED TUMOR
REGRESSION, WE HAD A TOTAL OF 12
PATIENTS WITH 16 AFFECTED ON THE
STUDY, AND THEN CLOSELY LOOKING
AT THESE PATIENTS WITH OUR
OPHTHALMOLOGIST, WE WERE ABLE TO
FIND THAT IN EVERY SINGLE
PATIENT, WE EITHER ARRESTED THE
GROWTH OF THE TUMORS OR INDUCED
REGRESSION.
AND THESE DATA BEEN DETAIL
INDEED A RECENT PUBLICATION FROM
OUR GROUP.
I SPENT A LITTLE TIME TALKING
ABOUT THE IMPORTANCE OF SIDE
EFFECTS.
THIS IS AS I SAID A WELL
TOLERATED DRUG EMPLOY THE MAJOR
SIDE EFFECT OF THIS DRUG IS
ANEMIA WHICH IS AN ON-TARGET
SIDE EFFECT EMPLOY THE POINT IN
THIS TRANSCRIPTIONALLY REGULATED
SO IF YOU ADD IT SHOULD GO DOWN
AND THEN IT TELLS US THE DRUG IS
HITTING THE TARGET AT LEAST TO
SOME EXTENT.
THIS IS SO FAIRLY EASILY MANAGED
SIDE EFFECT ALTHOUGH IN A FEW
PATIENTS IT CAN BE CHALLENGING
TO MANAGE.
FATIGUE, HEADACHES, DIZZINESS
AND A HOST OF OTHER SYMPTOMS
WERE SEEN IN A PROPORTION OF
PATIENTS TREATED.
I WILL FOCUS ON 2 SIDE EFFECTS
WHICH I THINK ARE THE MOST
CLINICALLY RELEVANT IN THESE
PATIENTS, ANEMIA AS I SAID, ON
TARGET SIDE CENTER FOR
EXCELLENCE ON AGINGS SEEN IN 90%
BUT LOW GRADE IN MOST PATIENTS.
MOST PATIENTS ARE MANAGED WITH
DOSE REDUCTIONS AND TRANSFUSIONS
IN A FEW PATIENTS.
WE HAVE SUCCESSFULLY USED ESAs
IN THESE PATIENTS TO RESCUE
THEIR ANEMIA.
A MORE CONCERNING SIDE EFFECT IS
HYPOXIA, A MECHANISM FOR THIS
REMAINS UNCLEAR ALTHOUGH WE HAVE
THEORIES.
ON OUR STUDY, ONLY 1 PATIENT HAD
HYPOXIA, OUT OF THE 61,
ALTHOUGH, IN A PARALLEL STUDY,
PHASE 2 STUDY ACTUALLY OF
BLEZIDIFAN, THE PATIENTS'
INCIDENCE WAS MUCH HIGHER.
THERE ARE SERL REASONS FOR THIS,
1 PATIENT MIGHT BE THE PATIENTS
ARE YOUNGER, AND WITH THE
METASTATIC OCCURRENCES, THE
PATIENTS WERE OLDER AND THEY MAY
HAVE HAD MORE CO-MORBIDITIES
THAT MAY HAVE CONTRIBUTED TO
THIS.
THE WAY WE MANAGE THIS IS TO
RECOGNIZE IT AS AN EVENT.
USE CERTAINTIED MEASURES, DOSING
AND DISRUPTION IF NEEDED.
SO NOW WE HAD THE DATA AND NEXT
QUESTION WE HAD TO ASK OURSELVES
WAS CAN WE USE THIS DATA TO
BENEFIT PATIENTS AT LARGE WITH
VHL AND IN OTHER WORDS IS THERE
A PATH FOR REGULATORY APPROVAL.
WE ALREADY KNOW, AND KNEW AT
THAT POINT THAT A RANDOMIZED
STUDY COULD BE DONE WITH THE
DISEASE, WITH DIFFICULT END
POINTS, WE COULDN'T USE THE
USUAL SURVIVAL END POINTS THAT 1
USES IN PATIENTS AND METASTATIC
CANCER.
SO THEN WE ASKED OURSELVES HOW
CAN WE UTILIZE STUDIES FROM A
NONRANDOMMIZED NONCONTROLLED
SINGLE ARM INTERVENTION?
THE FDA PREVIOUSLY PROVIDED
AROUND THAT TIME GUIDANCE THAT
SUGGESTED THAT IN THESE KINDS OF
CIRCUMSTANCES, NATURAL HISTORY
STUDIES, WELL CHARACTERIZED
NATURAL HISTORY STUDIES COULD BE
USED AS AN EXTERNAL OPERATOR TO
TRY TO DETERMINE THE BENEFIT OF
AN INTERVENTION IN THE STUDY OF
THIS KIND.
SINCE THE EARLY 80S ON A NATURAL
HISTORY STUDY OF VHL, THE
ONCOLOGY BRANCH HAD BEEN
COLLECTING DATA ON THE GROWTH
CHARACTERISTICS OF TUMORS IN
VHL, AND IN THIS PUBLICATION,
AND IN THE MAYBE NOT 5 OR 6
YEARS AGO, CAREFULLY
CHARACTERIZED THE GROWTH
CHARACTERISTICS OF VHL
ASSOCIATED RENAL TUMORS AND A
SIMILAR PATTERN ACTUALLY OBTAINS
FOR OTHER MEN FESTATIONS AS WELL
AND WHAT THEY WERE FINDING IS
THEY WERE STUDYING 400 FAMILIES
OVER 30 YEARS WAS AN ABSENCE OF
INTERVENTION OF
INEXPECTATIONSONNABLE GROWTH OF
RENAL TUMORS RENAL AND
OTHERWISE.
AND THE AVERAGE GROWTH WAS
AROUND 3.5-MILLIMETERS IN THE
STUDY.
SO WE LOOKED TO SEE WHAT
HAPPENED IN OUR STUDY BECAUSE WE
HAD CAREFULLY COLLECTED DATA
FROM ALL ENTRANCE AS PART OF THE
STUDY AND POINT, WE KNEW WHAT
THE GROWTH TRAJECTORY WAS BEFORE
THEY STARTED TREATMENT.
AND IT SORT OF PARALLELLED WHAT
WE SAW IN THE NATURAL HISTORY
STUDY.
ALL THESE TUMORS GREW BUT A
SIGNIFICANT CHANGE IN THE
TRAJECTORY WAS SEWN ONCE THE
INTERVENTION BELZUTIFAN WAS
APPLIED.
WE WANTED TO SEE IF IF THERE WAS
A MORE QUANTIFIABLE BENEFIT TO
THIS DRUG.
ONE WAY TO WAS TO SEE IF THE
NUMBER OF THE ISHT VENTIONS,
SURGICAL INTERVENTIONS CHANGE
WIDE THE DRUG.
AND INDEED WE FOUND THERE WAS A
SIGNIFICANT DROP IN THE SURGICAL
INTERVENTIONS, 1 PATIENT SPENT
ON THE STUDY, USING THEIR OWN
PREVIOUS HISTORY AS AN INTERNAL
CONTROL.
SO BASED ON THESE DATA, THE FDA
APPROVED THE USE OF BELZUTIFAN,
FOR THE USE OF COMBATING TUMORS.
I WANT TO EMPHASIZE, THAT IT IS
AND CAN BE USED AS AN ADJUNCT,
NOT AS A SUBSTITUTE FOR SURGERY
BECAUSE I THINK THERE'S STILL A
LOT WE DON'T UNDERSTAND ABOUT
BELZUTIFAN, AND WE DON'T KNOW IF
-- I'M NOT CONFIDENT WE CAN
COMPLETELY DO AWAY WITH SURGERY
BUT I THINK WE CAN SIGNIFICANTLY
IN WELL SELECTED PATIENTS REDUCE
THE NEED FOR SURGERY.
I WILL SKIP A COUPLE SLIDES AND
POINT OUT THAT FOLLOWING THIS
STUDY, THIS DRUG HAS ALSO BEEN
APPROVED BASED ON THIS
RANDOMIZED PHASE 3 STUDY FOR
PATIENT WHO IS ARE PREVIOUSLY
PROGRESSED AND STANDARD
TREATMENT OPTIONS WITH
METASTATIC CLEAR CELL KIDNEY
CANCER.
THIS IS A LARGE PHASE 3 STUDY
THAT WE DIDN'T PARTICIPATE IN
WHERE, THE INVESTIGATOR SHOWED
THAT COMPARED TO EVEROLIMUS,
BETZUTIFAN WAS IMPROVED MUCH
MORE.
FDA APPROVED IT FOR USING IT IN
PEASHS.
I WANT TO SUMMARIZE THIS PART F
THE TALK BY WORKING ON THE VHL,
WE WERE ABLE TO DEVISE TARGETED
EFFECTIVE STRATEGIES THAT WERE
SPORADIC AND INHERITED FORMS OF
CLEAR CELL RCC.
I WILL SPEND THE NEXT FEW MINUES
TALKING ABOUT 1 FORM OF KIDNEY
CANCER, HLRCC.
WE'VE DONE SINCE THE 1990S THAT
THERE IS A GROUP OF TUMORS WHICH
HAVE PATHWAY FEATURES AND 1
HISTOLOGIC EVALUATION AND OVER
THE YEARS AS A SAD PATHOLOGIST
TRIED TO CLASSIFY IT INTO TYPE 1
OR TYPE 2 AND NONTYPE 1.
DR. MARINO IN THE AUDIENCE TODAY
WAS INSTRUMENTAL IN HELPING NOT
ONLY RECOGNIZE MANY OF THESE
ENTITIES THAT ALSO POINTING
THERE'S SIGNIFICANT
HETEROGENEITY WITHIN THE TUMORS
WE CALL PAPILLARY, WITHIN THE
PAPILLARY GROUP.
THE HETEROGENEITY WAS MADE EVEN
MORE APPARENT AND CONFIRMED WHEN
WE DID A BROAD BASED MOLECULAR
ANALYSIS UNDER THE AUSPICES OF
STGA, WHICH SHOWED AT A IN
LECULAR LEVEL AT LEAST 4
DISTINCT FORMS OF PAPILLARY
TUMORS, I THINK THE STORY'S MORE
COMPLICATED BUT WE WERE ABLE TO
SHOW UNDER STUDY THAT THERE WERE
AT LEAST MORE THAN 2.
I WILL FOCUS TODAY ON HLRCC,
FAMILIARIAL SYNDROME, IT'S A
VERY AGGRESSIVE OF KIDNEY CANCER
WITH PAPILLARY FEATURES.
PATIENTS ALSO DEVELOP SKIN AND
MYELOMAS AS PART OF THE
MANIFESTATION.
UNTIL RECENTLY AGAIN THERE WERE
NO EFFECTIVE TREATMENT OPTIONS
FOR THESE PATIENTS.
TREATMENT OPTIONS THAT WORK WELL
IN CLEAR CELL KIDNEY CANCER WERE
MODEST USE IN THESE PATIENTS.
THEY DID WORK IN SOME PATIENTS
BUT THE RESPONSES WERE FEW.
SO THE FIRST QUESTION WE ASKED
OURSELVES IS WHAT CAUSED THIS
CANCER?
THAL INSTANCE IT IS GERM LINE
ALTERATION AND A KREBS CYCLE
DESIGN.
THE NEXT QUESTION OF COURSE,
LOGICAL QUESTION TO ASK WAS HOW
DOES LOSS OF KREBS CYCLE ENZYME
LEAD TO KIDNEY CANCER?
I DON'T THINK WE HAVE ALL THE
ANSWERS YET BUT I THINK WE HAVE
AN UNDERSTANDING SEVERAL
MECHANISMS THAT COULD GO BIG
CELL WHICH WAS DEFECTIVE HIDE
RATAISS--SYNTH AND MAKE A CELL
WITH KIDNEY CANCER.
ONE OF THE CONSEQUENCES OF
FUMARATE HYDRATASE, AND THAT HAS
MULTIPLE CONSEQUENCES IN THE
CELL.
ONE OF THESE IS -- SEE THOSE
POST TRANSLATION MODIIVESS AND
VARIETY OF INTRACELLULAR
PROTEINS PROCESSED ON SUCK
SINNATION, IT ENDS UP ACTIVATING
THE PROTEINS THAT ARE THUS
MODIFIED IN A STUDY THAT CAME
OUT OF THE ULB, AND NICHD LED BY
2 GROUPS, IT WAS SHOWN THAT 1 OF
THE PROTEINS THAT IS ENACTIVATED
BY SUCKINNATION, WHICH IS
CRITICAL IN MAINTAINING
MITOCHONDRIA AND DNA
REPRECATION. REP RE--
REPLICATION.
ON THE PATIENTS WITH TUMORS
LOSS, THERE WAS LESS DNA AND THE
MITOCHONDRIA DNA THAT DID EXIST
WAS SEVERELY DAMAGED.
THESE CELLS CONSEQUENTLY HAVE NO
ABILITY TO PERFORM
MITOCHONDRIA ASPECTS OF
RESPIRATION, SO NO
PHOSPHORYLATION, FORCING THEM TO
RELY ON A MORE PRIMITIVE FORM OF
ENERGY GENERATION, GLYCOLYSIS,
EVEN UNDER AEROBIC PROCESS.
TO TRY AND TARGET THIS GROUP OF
TUMORS, WE CHOSE TO EVALUATE VEG
F TARGETED AGENT BETUZAM, AND IN
PATIENTS WITH METASTATIC HLRCC.
THE STUDY DESIGN WE UNDERTOOK
WAS FAIRLY SIMPLE.
WE HAD 2 COHORTS OF PATIENTS,
INDEPENDENT COHORTS, 1 WAS A
PATIENT OF METASTATIC HLRCC, AND
THERE WAS A GROUP OF SPORADIC
HLRCC TUMORS, SOME OF WHOM WE
KNEW AT THE TIME HAD SOME
OVERLAPPING CHARACTERISTICS WITH
PATIENTS WITH HLRCC.
AND WE HAVE A MUCH BEATER
UNDERSTANDING OF THESE TUMORS
NOW THAN WE DID AT THAT POINT.
PATIENTS RECEIVE A STANDARD DOSE
OF BETAZUMAB, PLUS ERLOTINIB,
AND SHOWING HERE, IT'S IMPORTANT
TO NOTE, THAT MANY OF THESE
PATIENTS HAD PREVIOUSLY RECEIVED
THERAPY.
THIS IS NOT A TREATMENT NAIVE
GROUP OF PATIENTS.
OVERALL RESPONSE RETINAL
LOCATION IN THE HLRCC GROUP WAS
72% FOR A DISEASE WHERE NOTHING
REALLY WORKED.
THIS WAS A VERY, VERY YOU KNOW
SATISFYING EXPERIENCE.
A LOT OF THESE PATIENTS DID
EXTREMELY WELL AND I WILL SHOW
MORE ABOUT THE DURATION OF THESE
AND RESPONSES IN A SECOND.
MOST OF THESE RESPONSES ARE
PARTIAL RESPONSES BUT NOT
SUSTAINED COMPLETE RESPONSES.
THE MEDIAN PFS WAS ALMOST 2
YEARS SO THE RESPONSES WERE VERY
DURABLE.
WE ALSO LOOKED TO SEE WHAT
HAPPENED IN THE SPORADIC
POPULATION, SURPRISINGLY THE
SPORADIC POPULATIONS, THERE WAS
NOT A LOT WITH THESE GROUP OF
PATIENTS, SOME OF THEM SEEMED TO
RESPOND.
THIS WAS LOWER.
THIS WAS AN UNSELECTED GROUP OF
PATES UNLIKE THE 1S WITH HLRCC,
BUT WE SAW A LEVEL OF RESPONSE
OF 35% OR SO.
THE MEDIAN PF WAS NOT AS GOOD AT
8 MONTHS, NOT AS GOOD AS HLRCC,
BUT BETTER OR COMPARABLE THAT
EXISTED FOR TREATING PATIENTS
WITH THE PAPILLARY RCC.
SO WE HAD THEN A GROUP, AN
INTERVENTION THAT RESULTED IN
HIGH RESPONSE RATES PARTICULARLY
IN PATIENTS WITH THE DEFICIENT
RCC.
BUT WAWE ALSO KNEW WAS THAT MOST
PATIENTS EVENTUALLY PROGRESSED
AND DIE FRIDAY THEIR DISEASE.
OUR NEXT EFFORTS THEN WERE
FOCUSED ON CAN WE IMPROVE ON
THIS, CAN WE TAKE SOME OF THESE
PATIENTS FOR HAVING PARTIAL
RESPONSES AND EVENTUALLY DYING
FROM THE CANCER, CAN TAKE SOME
OF THEM AT LEAST PROPORTION OF
THEM AND TURN THEM INTO MORE
DURABLE SPONSORS BUT WE ALSO
RECOGNIZE THERE'S A NEED TO FIND
ADDITIONAL STRATEGIES FOR
PATIENTS WHO ACTUALLY PROGRESS
ON THIS APPROACH.
I SPENT A COUPLE OF MINUTES
TALKING ABOUT HOW WE ARE
TACKLING THE FIRST ISSUE.
AS YOU KNOW IN THE MITSD OF THE
LAST DECADE, IMMUNE CHECK POINT
WAS TARGETED CTLA-4 AND THE PD1
AXIS AND BECAME WIDELY USE
INDEED CANCER AND WE WERE
INTERESTED IN SEEING IF THEY
HAVE ACTIVITY IN THIS GROUP OF
TUMORS.
THAT DR. MARINO LOOKEDDA LOOKEA
LARGE NUMBER OF PATIENTS THAT
HAD TUMORS THAT INCLUDED VHL,
AND RCC, AND FOUND THAT UNLIKE
MANY FORMS OF RCC, THERE WERE A
LOT OF PATIENTS, ALMOST 60% OF
THE PATIENTS WITH FH-DEFICIENT
TUMORS WHO HAD HIGH LEVELS OF
PDL1, AND DENSE INFILTRATES.
IN KIDNEY CANCER, EXPRESSION OF
PD1 OR PDL1 DOESN'T NECESSARILY
CORRELATE THE RESPONSE, BUT WE
HAVE A COUPLE OF ANECDOTES OF
THIS KIND THAT ACTUALLY
ENCOURAGE US TO LOOK INTO THIS
GROUP OF AGENTS A BIT MORE IN
THESE TUMORS, THIS IS A PATIENT
WHO HAD RECEIVED, RESPONDED WELL
TO ZELATINIB, AND WE PUT THIS
PATIENT ON NIVOLUMAB, AND SAW
GRATIFYINGLY COMPLETE RESPONSE
DEVELOPING WITHIN A FEW MONTHS
THAT WAS SUSTAINED FOR MANY,
MANY YEARS.
ON WITH THE PRECLINICAL DATA AND
WITH ANECDOTA CLINICAL DATA WE
THEN TOOK THE STEP TO DEVISE A
NEXT CLINICAL TODAY WHICH WAS A
COMBINATION OF A CHECK POINT
INHIBITOR TARGETS PDL, AND
TARGETING NIVOLUMAB, AND THIS IS
A STUDY THAT'S ONGOING IN THE
NEXT YEAR OR 2 TO DISCUSS DATA
FROM THE STUDY.
I CANNOT END THIS TALK WITHOUT
REALLY TELLING THE AUDIENCE
ABOUT THE STRONG AND LONG
ASSOCIATION BETWEEN
INVESTIGATORS OF THE NIH AND KID
NO CANCER.
I THINK WE HAVE A VERY, VERY
RICH LEGACY STARTING WITH
DEVELOPMENT OF CYTOKINE
THERAPIES BY STEVE ROSENBERG AND
HIS COLLEAGUES IN PATIENTS WITH
KIDNEY CANCER WHICH I SAID FOR
MORE THAN A COUPLE OF DECADES
WAS THE ONLY ACTIVE GROUP OF
AGENTS IN THESE TUMORS.
FIRST IDENTIFICATION OF A KIDNEY
CANCER GENE, DETAILED DEFINITION
OF GENETIC HISTOLOGIC AND
CLINICAL HETEROGENEITY OF KIDNEY
CANCER.
THE FIRST VEG F TARGETED AGENT,
CELLULAR THERAPIES AND ON TO THE
CURRENT ERA WHERE WE ARE IN THE
PROCESS OF IDENTIFYING AND
EVALUATING THE EFFICACY OF
TARGET AS WELL AS IMMUNO
THERAPEUTIC APPROACHES.
WE HAVE A LONG WAY TO GO BUT I'M
VERY OPTIMISTIC THAT WE'RE WELL
ON OUR WAY TO EVENTUALLY
INSURING THAT EVERY SINGLE
PATIENT WITH KIDNEY CANCER HAS A
VIABLE TREATMENT OPTION AND
HOPEFULLY 1 THAT WILL LEAD
EEIVETTUALLY TO ERADICATION AND
CURE OF THIS DISEASE.
I WILL STOP THERE, TAKE A MEMORY
CLONE TONIGHT ACKNOWLEDGE ALL
THE PATIENTS AND THE FAMILIES
WHO HAVE BEEN WILLING
PARTICIPANTS AND PARTNERS IN THE
ALL RESEARCH WE'VE DONE HERE
WITHOUT THEM NONE OF THIS WORK
WOULD BE POSSIBLE.
I ALSO WANT TO TAKE A MOMENT TO
ACKNOWLEDGE THE WONDERFUL GROUP
OF PEOPLE THAT WE HAVE HERE AT
THE NIH AND THIS IS NOT JUST CCR
OR NCI, AS YOU CAN SEE, THE
EFFORT IS TRANS-NIH AND OFTEN
INVOLVES COLLABORATORS OUTSIDE
THE NIESH H AS WELL AS FAR MORE
COLLABORATORS.
WITHOUT THIS INCREDIBLY
COMMITTED AND DEDICATED SMART
GROUP OF WORK WITH THESE PEOPLE
NONE OF THIS WORK WOULD BE
POSSIBLE.
I WILL STOP THERE AND TAKE ANY
QUESTIONS YOU MAY HAVE.
KD--SALLY ARK PLAWZ
[ APPLAUSE ]
>> THANK YOU THAT WAS A
WONDERFUL PRESENTATION,
APPRECIATE YOU CLARIFYING A VERY
RICH FIELD AND THANK YOU FOR
YOUR CONTRIBUTIONS FOR A VERY
IMPORTANT.
ARE THERE ANY QUESTIONS, WE
PROBABLY HAVE TIME FOR 1
QUESTION.
ONE QUESTION, I DO HAVE AND IT'S
NOT REALLY TREATMENT, IT'S MORE
ABOUT THE TREATMENT EVALUATION,
SO IF YOU HAVE A PATIENT WITH
RENAL CELL CARCINOMA, VHL, IF I
RECALL THE VHL, INHERITANCE IS
LIKE 50%, IT'S LIKE AUTOSOMAL
DOMINANT.
>> IT'S AUTOSOMAL DOMINANT, YES.
>> SO IF YOU HAVE THE INDEX CASE
HOW DO YOU EVALUATE AND MANAGE
THE FAMILIES?
>> RIGHT.
SO ONCE WE KNOW WHICH SIDE OF
THE FAMILY IS EFFECTED, WE
RECOMMEND ALL OF THEM GET
GENETICALLY SCREENED, ANYBODY
WHO HAS THE GENE UNDERGOES
CAREFUL SURVEILLANCE, THERE'S A
SCHEME OF SURVEILLANCE THAT WE
PRACTICE, THERE'S VHL LINES THAT
AM CAN UP WITH RECOMMENDATIONS
ON HOW TO SCREEN PATIENTS AS YOU
CAN IMAGINE, THE SCREENING FOR
DIFFERENT MANNESTATION WILL BE
DIFFERENT.
SOME OF THESE MANIFESTATIONS
LIKE RETINAL HEME ANGIO BLASTOMA
WILL BE DONE VERY, VERY EARLY.
YOU HAVE 1 YEAR-OLD CHILDREN
WITH THESE MANIFESTATIONS.
SO THE SCREENING FOR THAT WILL
BE DIFFERENT FOR KIDNEY CANCER
WHICH CAN AFFECT SLIGHTLY OLDER
INDIVIDUALS.
BUT FOR EACH OF THESE
MANIFESTATIONS, THERE'S A
PRESCRIBED SCREENING OF
SURVEILLANCE IN A SCHEMATIC THAT
WE FOLLOW AND USING THIS
APPROACH, I THINK IF THE IDEA TO
THIS APPROACH, WE ARE ABLE TO
HEAD OFF A LOT OF THE BAD
CONSEQUENCES BUT AS A -- THAT'S
WHY I THINK THESE NEW TREATMENT
OPTIONS ARE GOING TO PLAY A
SIGNIFICANT ROLE IN THE
MANAGEMENT OF THESE VHL PATIENTS
NWHEN YOU HAVE --
>> WHEN YOU HAVE A PATIENT WITH
RENAL CELL VHL POSITIVE, DO YOU
SEE IT IN THE CHILDREN AS WELL,
SAME TYPE OF TUMOR OR ANY TYPE
OF TUMOR?
>> SO PATIENT FIST VHL, THE
RENAL TUMORS ARE ALWAYS CLEAR
CELL, THEY'RE ALWAYS CLEAR CELL,
BUT I DON'T KNOW IF I GOT YOUR
QUESTION CORRECT.
>> LIKE DO THEY GET PNET OR
RETINAL TUMORS?
>> YES, ANYBODY WITH VHL CAN GET
ANY OF THESE TUMORS AND MANY OF
THEM GET MULTIPLE FORMS OF
TUMORS.
THERE ARE SOME GENETIC PHENOTYPE
CORRELATIONS WHICH THERE ARE
GROUPS THAT WON'T GET OR HAVE A
LOW RISK OF GETTING SITELOMERAS,
AND THERE ARE GROUPS THAT HAVE
MORE, BUT THOSE EXCEPTIONS
APART, MOST OF THESE PEOPLE WILL
GET FORMS OF V, -- VHL TUMORS.
THE KIDNEY CANCER MAY BE PRENT
IN THE 3 OR 4 GROUPS?
, WE HAVE A QUESTION THERE.
>> HI, REALLY COOL TALK, I HAD A
QUESTION REGARDING, I GUESS AT
THE END OF THE TALK WHERE YOU'RE
GOING OVER DRUG TREATMENT FOR
HLRCC, I WAS CURIOUS DO WE HAVE
ANY INKLING TO KNOW WHY THE
TREATMENT SEEMS TO WORK SO MUCH
BETTER IN THE HEREDITARY CASE
RATHER THAN IN THE SPORADIC
CASE?
>> YEAH, FIRST OF ALL I THINK
THERE ARE A FEW FACTORS TO
CONSIDER.
WE DESIGN THIS TREATMENT TO BE
EFFECTIVE, BASED ON OUR
UNDERSTANDING OF THE BIOLOGY OF
THE HEREDITY FORM OF DEC TO BE
EFFECTIVE IN THAT PARTICULAR
POPULATION.
IT'S ALSO A MUCH MORE HOMOGENOUS
POPULATION.
IN THE SPORADIC POPULATION WE
HAVE NO IDEA A PRIORI WHO THOSE
PATES ARE.
WE KNOW NOW AFTER HAVING TREATED
THEM AND STUDIED THEM, DONE SOME
BACKGROUND GENETIC AND OTHER
ANALYSIS WHO EACH OF THOSE
PATIENTS IS, BUT IT IS A VERY
DESPERATE GROUP OF PEOPLE.
SOME OF THOSE PATIENT ANDS THEIR
TUMORS WERE NOT DRIVEN BY THE
SAME FACTORS THAT DROVE HLRCCOR
THAT DRIVE HLRCC TUMORS SO IT'S
NOT SURPRISING THOSE PATIENTS
DIDN'T RESPOND.
THOSE ARE THE REASONS FOR THE
DISPARITY IN RESPONSES.
AGAIN, WE WERE NOT SURPRISED, WE
WERE ACTUALLY HAPPY THAT WE GOT
SOME RESPONSES ON THIS, AND WE
ARE TRYING TO NAIL DOWN WHO
THOSE PATIENTS WITH HRLCCR, DO
RESPOND, THOSE PATIENTS THATY
BEHAVE AND RESPOND JUST LIKE
HLRCC PATIENTS, IF THEY DO, IT'S
DOABLE, AND IT'S PFS WILL BE
SIMILAR TO WHAT WE SEE IN
HLRCC PATIENTS SO IT'S MORE A
QUESTION OF IDENTIFYING THE
RIGHT TUMORRINGS THAN ANYTHING
ELSE.
>> THANK YOU.
>> THANK YOU AGAIN AND THANK YOU
FOR JOINING -- IF YOU HAVE ANY
QUESTIONS CAN YOU COME ON DOWN.
>> YEAH, WE CAN CATCH UP LATER.
>> THANK YOU.