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>> OKAY, WE'LL GET STARTED.
NEXT MONDAY IS A HOLIDAY, SO WE
ACTUALLY HAVE CLASS ON TUESDAY
AFTERNOON.
AND THEN NEXT WEDNESDAY WE'LL
ACTUALLY BE MAKING UP ONE OF THE
CORE VISITS TO THE GENOMICS SO I
WILL BE SENDING OUT
ANNOUNCEMENTS LATER O OUR FIRST
SPEAKER IS JOHN SCHILLER.
HE GOT HIS BACHELOR'S DEGREE AT
THE UNIVERSITY OF WISCONSIN
MEDICINE PH.D. AT THE UNIVERSITY
OF WASHINGTON SEATTLE.
CAME TO NIH IN 86 AND
SUBSEQUENTLY BECAME A SENIOR
INVESTIGATOR.
IN 1999 HE BECAME CHIEF OF THE
NEO PLASTY.
>> THANKS.
SO A THE SYLLABUS IT SAYS I WILL
BE TALKING TO CERVICAL CANCER
AND I'VE TAKEN THE LIBERTY TO
EXPAND A LITTLE BIT.
I'M GOING TO TALK MORE GENERALLY
ABOUT HPV ASSOCIATED CANCER.
I'M NOT A CANCER BIOLOGY, I'M A
VIRILOLOGYIST.
HPV IS IMPORTANT FOR THE CAUSE
OF CANCER AND CANCER BIOLOGIST
SHOULD NO ABOUT HPV.
THE FIRST PART OF MY TALK I'LL
TALK A LITTLE BIT ABOUT THE
ASSOCIATION BETWEEN HPV AND
CERVICAL AND OTHER CANCERS AS
WELL A LITTLE BIT BUT MOSTLY
FOCUSING ON CERVICAL CANCER.
BUT THEN I'LL HOPEFULLY CONVINCE
YOU IT'S NOT ENOUGH TO KNOW
ABOUT A CAUSE OF CANCER, THE
ETIOLOGICAL AGENT THAT'S
OVERWHELMINGLY RESPONSIBLE FOR
CANCER.
YOU HAVE TO DO SOMETHING ABOUT
IT.
I'LL TELL YOU ABOUT DEVELOPING
THE HPV PROPHYLACTIC VACCINE
WHICH I'M SURE YOU ALL HEARD
ABOUT.
BUT THEN THE FINAL PART OF MY
TALK HOPEFULLY CONVINCE YOU IT'S
NOT ENOUGH TO HAVE A GOOD
INTERVENTION YOU HAVE TO GIVE TO
THE PEOPLE WHO NEED IT.
I'LL BE TALKING ABOUT SOME OF
THE IMPLEMENTATION ISSUES THAT
ARE ASSOCIATED WITH THE ROLLOUT
OF THESE VACCINES.
SO THE REASON WHEN WE THINK
ABOUT HPV AND CERVICAL CANCER
SHOULD BE OBVIOUS FROM THIS
SLIDE BOTH IN TERM OF THE TOTAL
NUMBER OF CASES WORLDWIDE IN THE
ETHOLOGICAL FRACTION.
CERVICAL CANCER REALLY DOMINATES
THE HPV ASSOCIATED CANCER SCENE.
BUT IT IS ASSOCIATED WITH THE
MAJORITY OF *** CANCERS,
CERVICAL *** CANCERS ABOUT
HALF, AND ALMOST HALF OF THE
ORAL PHARYNGEAL CANCERS.
HPV IS THOUGHT TO CAUSE ABOUT 5%
OF ALL CANCERS THAT WORLD.
THIS IS REALLY ONE OF THE MAJOR
CAUSES OF CANCER AS AN
INDIVIDUAL ETIOLOGICAL AGENT.
NOW, THERE'S A WHOLE LOT OF HPV
TYPE BUT FORTUNATELY FOR US
DEVELOPING VACCINES TWO TYPES
CAUSE THE MAJORITY OF CANCERS
WORLD WIDE.
16 AND 18.
DOESN'T MATTER WHAT PORTION OF
THE WORLD YOU LOOK AT.
AFTER THAT THE OTHER TYPES THAT
ARE TWO, THREE, FOUR, FIVE, SIX
SEVEN, TEND TO VARY A LITTLE BIT
BUT THERE'S A CERTAIN CLUSTER OF
ABOUT FIVE TYPES.
NOW OVERALL, HPV IS ASSOCIATED
WITH AROUND 16 OR 18 CAUSES
ABOUT 70% OF CERVICAL CANCER.
IT ALSO CAUSES MOST OF THE OTHER
HPV ASSOCIATED CANCERS, ABOUT
90%.
BUT WHAT THIS SLIDE MAINLY SHOWS
IS THE DISTRIBUTION OF CANCER
TYPES IN THE UNITED STATES IS
QUITE DIFFERENTLY SKEWED THAN IT
IS WORLDWIDE.
THERE'S TWO REASONS IN WHICH
YOU'LL NOTICE IS THAT IT'S NOT
SO DOMINATED BY CERVICAL CANCER.
IF YOU LOOK AT THE INCIDENCE OF
*** ***, VAGINAL AND ORAL
PHARYNGEAL TOGETHER IT'S EQUAL
TO THE LEVEL OF CERVICAL CANCER.
AND THAT A RELATIVELY LARGE
MINORITY ARE NOW UNDER -- IN MEN
AND NOT IN WOMEN.
THIS IS TWO-FOLD.
PAP SCREENING HAS REDUCED
CERVICAL CANCER BY 80% IN THE
UNITED STATES AND OTHER
COUNTRIES THAT HAVE
WELL-ORGANIZED PAP SCREENING
PROGRAM.
THIS ISN'T THE CASE IN THE
DEVELOPING WORD WHERE 85% OF
CERVICAL CANCERS OWE CAR.
SECONDLY THERE'S AN EPIDEMIC OF
ORAL PHARYNGEAL CANCER WITH MORE
THAN A TWO-FOLD INCREASE IN THE
LAST COUPLE DECADES.
FOR THESE TWO REASONS HPV
NON-CERVICAL CANCERS TEND TO BE
HIGHER AMOUNTS AND ALSO MORE IN
MEN THAN PREVIOUSLY THOUGHT.
THE IMPLICATIONS ULTIMATELY
ABOUT WHO YOU WANT TO VACCINATE.
NOW THE CANCER CAUSING TYPE JUST
HAPPEN TO CLUSTER IN ONE GENETIC
GROUP OVER HERE THAT ARE
SEPARATE FROM THE TYPES THAT
CAUSE GENTLE WARTS WHICH IS SIX
AND 11 AND SECOND ONE CALLED
HAND AND FOOT WARTS AND THERE'S
A WHOLE BUNCH OTHER GROUPS THAT
CAUSE ASYMPTOMATIC INFECTIONS.
ALL HPV IN ALL PAPILLOMA VIRUSES
HAVE A VERY CHARACTERISTIC
LIFE-STYLE.
THEY PRODUCTIVELY IN FACT ONLY
SCREEN FOR EPITHELIAL.
THIS IS THE ONLY TISSUE IN WHICH
THEY CAN REPLICATE.
THEY HAVE TO INFECT THE BASAL
EPITHELIUM DURING
DIFFERENTIATION THEY END UP
MAKING PROTEINS AND SETTLING THE
VIRUS ONLY IN DIFFERENTIATED
CELLS.
THE REASON THEY DO THIS IS TO
ESCAPE IN NERVATION.
THERE ARE PROTEINS OR THE
STRUCTURES ARE VERY IMMUNOGENIC.
BY EXPRESSING THEM IN THESE
TERMINALLY DIFFERENTIATED CELLS
THEY ARE NO LONGER UNDER
SURVEILLANCES.
THE INFECTION IS MAINTAINED IN
THESE BASAL CELLS DOWN AT THE
BOTTOM HERE WHICH ARE UNDER
IMMUNE SURVEILLANCE.
AND THEN YOU ONLY GET A CERTAIN
SUBSET OF GENES EXPRESSED AT
VERY LOW LEVELS.
THIS IS JUST AN EXAMPLE BOTH
MORPHOLOGICALLY AND HIS
THRAWJALLY AT HPV16 LESION THAT
COULD POTENTIALLY GO ON AND
CAUSE THE CANCER.
YOU CAN SEE IT'S VERY INAPPARENT
HERE, YOU BARELY WOULD NOTICE
THIS LESION.
IT'S NOT A BIG WART THAT YOU
WOULD SEE HERE.
HISTOLOGICALLY THIS IS THE
NORMAL TISSUE OVER HERE WHERE
YOU ONLY HAVE PROLIFERATION AS
DEMONSTRATED BY MCM WHICH IS
INDUCED BY E7 IN MARKER OF
PROLIFERATING CELLS DOWN HERE IN
THE BASAL LEVEL.
YOU GET PROLIFERATION OF SUPER
BASAL CELLS UP HERE AND THEN
EXPRESSION OF LATER PROTEINS
ONLY IN THESE TERMINALLY
DIFFERENTIATING CELLS WAY UP
HERE.
NOW WE CAN NOW UNDERSTAND
CERVICAL CARCINOGENESIS IN EACH
OF THE ASSOCIATED CARCINOGENESIS
BY OTHER TYPE FOR OTHER CANCERS
ALTHOUGH IT'S NOT QUITE AS WELL
UNDERSTOOD.
FROM THE POINT OF VIEW OF HPV
INFECTION.
SO IF YOU LOOK AT WHAT'S CALLED
MILD OR IN A PAP SMEAR
PSYCHOLOGY LOW GRADE SPLEENOUS
OR CERVICAL -- GRADE ONE, THESE
MILD DYSPLASIAS ARE
MANIFESTATION OF NORMAL HPV
INFECTION.
SOME YOU SEE, SOME YOU DON'T AND
MOST OF THEM JUST GO AWAY.
IF YOU HAVE PERSISTENT
INFECTION, YOU CAN GET
PROGRESSION INTERMEDIATE, MUD
RAT DYSPLASIA TO SEVERE
DYSPLASIA, CARCINOMA AND
EVENTUALLY CANCER IN THIS
PROCESS.
INTERESTING FEATURE IS THAT
THESE HIGHER GRADE LESIONS NO
LONGER PRODUCE VIRUSES BECAUSE
THEY DON'T HAVE THE SIGNAL TO
PRODUCE THE LAY PROTEINS.
AND SO THIS CARCINOGENIC
PROWTION -- PROGRESSION IS AS
MUCH A DEAD END.
THERE'S NO TUMOR VIRUS THAT
WANTS TO CAUSE CANCER.
IT'S NOT PART OF ANY NORMAL
VIRUS LIFE CYCLE IT'S ALWAYS AN
ABERRATION.
NOW TOGETHER WITH THE LACK OF --
PRODUCTION THERE'S A STAGE WHERE
YOU TEND TO GET HIGHER LEVELS OF
TWO OF THE VIRAL PROTEINS CALLED
E6 AND E7 WHICH ARE THE MAJOR UP
CO-PROTEINS THAT OFTEN TIMES
VIRAL INTEGRATION.
NOW THE WAY THESE TWO ONCOGENES
WORK IS THAT E7 IS MAINLY
RESPONSIBLE FOR INDUCING
PROLIFERATION.
PROLIFERATION OF THESE
TERMINALLY DIFFERENTIATING CELLS
THAT NORMALLY WOULDN'T BE MAKING
THEIR OWN DNA.
THIS PRO-LIFE RISK IS A PROBLEM
BECAUSE IT INDUCES APOPTOSIS.
SO THESE HAVE ANOTHER GENE
CALLED E6 WHICH BLOCKS THIS
APOPTOTIC PROCESSES AND LEADS
TO -- AND TOGETHER THEY
STABILIZE THE GENOME SO THAT
BOTH THE DIRECT ACTIVITIES OF E6
AND E7 WHICH I'LL DISCUSS IN A
MINUTE, THERE'S ALSO THIS
INDIRECT INDUCTION OF GENOMIC
INSTABILITY LEADS TO
TRANSFORMATION IN ONCOGENESIS.
WHY WOULD THESE HAVE THE ONCO.
THE VIRUSES LIKE OTHER ONCO
PROTEINS AS WELL HAVE THIS
ISSUE -- SO BY HAVING THESE
GENES, THEY TURN ON THE DNA
SYNTHESIS MACHINERY TO GET THEIR
OWN DNA GENOME SYNTHESIZED IN
CELLS THAT OTHERWISE WOULD NOT
DO IT.
UP JUST TO GIVE YOU A SUMMARY,
THIS IS A COMPLICATED SLIDE.
E6 AND E7 INTERACT WITH A NUMBER
OF DIFFERENT CELLULAR PARTNERS.
THE MOST IMPORTANT ONE AND THE
ONE THAT'S IN BEST STUDY IS
INTERACTION WITH P53.
INTERACTION WITH P53 IN THE --
WHICH LEADS TO DEPENDENT
DEGRADATION.
IT INTERACTS WITH P300.
AND BY INTERACTING WITH THE
TRANSCRIPTION COMPLEX -- IT
ACTUAL ME CAN CONTRIBUTE TO A
MORTALLIZATION.
IT INDUCES THIS CATALYTIC
PORTION.
IT ALSO INTERACTS WITH APOPTOTIC
FACTORS LIKE BACKS AND IRF3 --
AND ALSO SOLID ADHESION PROTEINS
TO KINASE.
E7 AS I MENTIONED IS THE MAIN
PROTEIN THAT INDILUTIONS THE
CELL PROLIFERATION.
IT DOES PRIMARILY BY INTERACTING
WITH P53 OR THESE OTHER POCKET
PROTEINS P107 AND B130.
BY DOING THIS BY JUST THE
INTERACTION ALSO REDUCES SOME
DEGRADATION OF THESE PROTEINS.
FREEZE UP E2F WHICH IS THE MAJOR
TRANSCRIPTION FACTOR THAT LEADS
TO EXPRESSION OF CYCLIN A AND
LEADS TO -- SO THOSE ARE THE
MAJOR FUNCTIONS.
WHEN THIS SORT OF THING GOES
AWRY IS WHEN WE GET CANCERS.
NOW ONE OF THE INTERESTING
FEATURES ABOUT CERVICAL CANCER
IS WHERE IT ARISES.
SO THESE INFECTION OCCUR
THROUGHOUT THE GENTLE TRACT BOTH
IN THE VAGINAL TRACT AND VARIOUS
PORTIONS OF THE ***.
ALMOST ALL THE CANCERS ARISE AT
ONE POINT WHICH IS CALLED A
TRANSFORMATION ZONE WHICH IS THE
SITE WHERE YOU GO FROM THE
STRATIFIED SQUAMOUS EPITHELIAL
TO THE COLUMNAR EPITHELIAL IN
THE ***.
THIS IS A VERY INTERESTING
PORTION BECAUSE THIS ONE LITTLE
PORTION HERE HAS NOW GOT MARKERS
IT'S ACTUALLY ONE OF THE
MARKERS -- AND THESE CELLS, YOU
SEE HUH THIS IS STRAIGHT
SQUAMOUS AND THIS IS COLUMNAR,
IT REMAINS IN THIS STATE.
THERE'S A REASON WE DON'T
UNDERSTAND YET BUT EIGHTS VERY
IMPORTANT CELL BIOLOGICAL
QUESTIONS.
THESE CELLS ARE SUSCEPTIBLE TO
CARCINOGENIC PROGRESSION BY
HPD E6 AND E7.
IF YOU GET INFECTED IN ANY OTHER
PLACE THAN THE *** OR VAGINAL
TRACK THAT GOING ON TO CANCER IS
QUITE LOW.
THIS IS ONE OF THE REASON WHY IN
TREATMENT YOU REMOVE THESE
TRANSFORMATION ZONES.
THESE CELLS DON'T REPOPULATE.
THEY'RE GONE.
THAT'S WHY IF YOU DO A BLADE OF
THERAPY OF AN HPD LESION, YOU
DRAFSALLY REDUCE A WOMAN'S RISK
OF GETTING CERVICAL CANCER EVEN
BY A NEW TYPE.
SO INTERESTINGLY *** CARCINOMA
ALSO OCCUR AT THE TRANSFORMATION
ZONE.
BUT HPV INFECTION OF THE ***
AND VAGINAL AS I MENTIONED ARE
VERY COMMON BUT CANCERS AT THESE
SITES ARE RELATIVELY RARE.
WE THINK IT'S RARE BECAUSE THESE
TISSUES FORTUNATELY DON'T HAVE
TRANSFORMATION ZONES.
THAT'S WHY *** CANCER IS LESS
THAN CERVICAL CONNORS.
IT'S NOT THAT IT'S RARER THAN
CERVICAL CANCERS IT'S NOT THE
CASE.
THIS IS TO SHOW YOU
HISTOLOGICALLY WHAT THIS LOOKS
LIKE.
THE TRANSFORMATION ZONE IS WHERE
YOU GO FROM RED TO THIS, AND
THIS AIR IMRAW THAT LOOKS
WHITISH STAINED WITH ACETIC
ACTION IS WHERE IT IS OCCURRING
AND WHERE THE CANCER EVENTUALLY
DEVELOPS.
NOW THE TIME COURSE OF HPV IN
ASSOCIATION WITH CANCER IS VERY
CHARACTERISTIC AND THAT HPV
INFECTION IS VERY COMMON IN
YOUNG PEOPLE.
AND MOST OF THE INFECTIONS ARE
CLEARED SPONTANEOUSLY BY
IMMUNOLOGICAL, THEY THINK THAT T
CELL IS NAMELY RESPONSIBLE FOR
CLEARING LESIONS ONCE THEY
DEVELOP.
IN THE LIFETIME INCIDENCES IS
VERY HIGH PROBABLY MORE THAN 80%
OF WOMEN GET SOME SORT OF
CERVICAL HPV INFECTION DURING
THEIR LIFETIME.
BUT AS I SAID, THESE
SPONTANEOUSLY GO AWAY.
AND THEN THIS ELIMINATES THE
RISK FOR INFECTION.
IT'S PERSISTENT INFECTION THAT'S
AT RISK.
THE INFECTION THAT GOES AWAY IS
NOT A RISK FOR CERVICAL CANCER.
IN A SMALL PROPORTION YOU GET
PERSISTENT INFECTION AND
ESPECIALLY THE 16 AND 18.
THIS IS BY FAR THE SINGLE MOST
IMPORTANT RISK FACTOR FOR
PROGRESSION TO PRE CANCER AND
CANCER.
CERVICAL CANCER WITHOUT HPV
INFECTION IS VERY VERY RARE.
SO MOVING ON TO THE VACCINE.
NOW WE HAVE THE SITUATION WHERE
WE HAVE AROUND THAT'S CAUSED BY
A PARTICULAR SUBSET OF VIRUSES.
THE OBVIOUS THING TO DO IF YOU
WANT TO PREVENT THAT CANCER IS
TO PREVENT THE INITIAL INFECTION
THAT HAVE A CHANCE OF GOING ON
AND CAUSING THAT.
AND THE SOLUTION IS SOMETHING
THAT WE STARTED WORKING ON BACK
IN THE EARLY 90'S, 1991, 92.
AND WHAT WE FOUND IS THAT IF YOU
TAKE A SINGLE PROTEIN FROM THIS
VIRUS THAT'S CALLED L1, IT'S THE
MAJOR CLASS OF PROTEIN.
IN THIS CASE WE EXPRESSED IT IN
INSECT CELLS THAT IT SPONTANEOUS
ASSEMBLES INTO WHAT WE CALL
VIRUS-LIKE PARTICLES.
WHICH ESSENTIALLY IS THE OUTER
SHELL OF THE VIRUS.
THEY DON'T HAVE THE VIRAL BUT
THE ONLY PROTEIN EXPRESSED IN
THIS SYSTEM IS THIS ONE VARIANT
PROTEIN.
NONE OF THE TRANSFORMING
PROTEINS.
AND SO THESE STRUCTURES FOUGHT
ONLY LOOK LIKE VIRUS BUT MOST
IMPORTANTLY, IF YOU INITIALLY
INJECTED THEM INTO ANIMALS, AND
THE SERUM THAT CAME OUT OF THE
ANIMALS HAD SKY HIGH ACTIVITY OF
PREVENTING INFECTION BY THE
VIRUS OF TISSUE CULTURE CELLS.
SO WE THOUGHT THIS WOULD BE A
GOOD VACCINE BUT IT WAS NOT
INFECTIOUS OR NON-ONCOGENIC AND
ANTI-BODIES PREVENT INFECTION IN
TISSUE CULTURE CELLS.
THE KEY TO DEVELOPING THESE
VACCINES WAS AN OBSERVATION.
IF YOU DO INTRAMUSCULAR
INJECTIONS -- YOU GET VERY
STRONG PROTECTION FROM
EXPERIMENTAL INFECTION OF THE
SKIN IN ANIMAL MODELS.
IF YOU DENATURE L OR USE L1
PEPTIDE YOU GET NO PROTECTION.
YOU NEED TO GENERATE IMMUNOGEN
CELLS TO NEUTRALIZE THE BANT
STUDIES.
THAT TURNED OUT TO BE THE CASE.
BASED UPON THESE FINDINGS IT
TOOK TWO COMPANIES TO DEVELOP
THE HPV VOX SCENES.
THIS IS IN ABOUT THE MID 90'S.
AND THEY ARE NOW ON THE MARKET,
TWO DIFFERENT VACCINES WHICH ARE
BASED ON THE SAME CONCEPT OF
THESE VIRUS-LIKE PARTICLES.
BUT THE SPECIFICS OF THE
VACCINES ARE SOMEWHAT VARIED.
SO GOLDMAN
SOD IN -- GLAXOSMITHCLINE --
THIS CALL IT ASL4 WHICH CONTAINS
A SIMPLE IN SOMETHING CALLED
MONO iTHIS IS QUITE A
MILESTONE BECAUSE IT'S THE FIRST
CASE WHERE A TLR -- HAD BEEN
LICENSED FOR PROPHYLACTIC
VACCINE IN THE UNITED STATES.
PROFESSION TO THIS THE VACCINES
HAD NOTHING OR SIMPLE ALUMINUM
SALTS.
THIS IS A BREAK THROUGH IN THE
REGULATORY INDUSTRY THAT WE'RE
ABLE TO USE IT IN VACCINES.
GUARD SILL CONTAINS THE SAME TWO
HIGH RISK TYPES, 16 AND 18 BUT
ALSO SIX AND 11 WHICH CAUSE
ABOUT 90% OF GENTLE WARTS.
THIS HAS GOT A SIMPLE SALT --
WHICH IS DIFFERENT THAN THE ONE
USED HERE.
IT'S MADE IN YEAST PRESUMABLY
BECAUSE MERCK HAD MADE THEIR
HEPATITIS B VACCINES IN THE
STRAIN BEFORE THAT.
THEY KNEW HOW TO MAKE PROTEINS
IN YEAST.
THE VACCINES ARE INJECTED OVER
THREE MONTHS BY INTRAMUSCULAR
INJECTION.
THIS SHOWS THE TIME LINE OF THE
DEVELOPMENT OF THE VACCINE.
AND THE PARALLEL DEVELOPMENT OF
OUR UNDERSTANDING THAT THE VIRUS
WAS RESPONSIBLE FOR CERVICAL
CANCER.
THE VACCINE, THE VIRUS WAS FIRST
DISCOVERED BY HAROLD WHO LATER
GOT THE NOBEL PRIZE A FEW YEARS
AGO FOR THIS DISCOVERY BACK IN
1992.
ABOUT A DECADE LATER WE STARTED,
WE SHOW THAT THE BLT'S TO BE
INTRODUCED INTO NEUTRALIZING
ANTI-BODIES.
IT TOOK ANOTHER SEVEN YEARS FOR
THE FIRST CLINICAL TRIALS WHICH
CORRESPONDED TO THE FIRST
PUBLICATION THAT SAID HPV IS THE
NECESSARY CAUSE OF CERVICAL
CANCER.
THE FIRST TIME THE AGENT HAS
BEEN NAMED ACTUALLY ESSENTIAL
FOR GETTING A PARTICULAR CANCER.
IT WAS ACTUALLY ALMOST 15 YEARS
FROM THE TIME WE DISCOVERED THE
VLT'S BEFORE THE VACCINE WAS
LICENSED FIRST IN FEMALES AND
THEN THREE YEARS LATER IN MALES.
IT WAS CRITICAL TO ESTABLISH THE
PRE MALIGNANT DISEASE ASSOCIATED
WITH CERVICAL CANCER THAT'S HPV
ASSOCIATED BECAUSE WE COULD
NEVER HAVE RUN A TRIAL IN WHICH
CANCER WAS THE PRIMARY END POINT
OF THE TRIAL.
ONE, IT WOULD HAVE TAKEN US
DECADES AND DECADES BECAUSE IT
TAKE DECADES FOR PRIMARY
INFECTION TO GO ON TO CAUSE
CERVICAL CANCER.
AND SECONDLY ACTIVE FOLLOW UP
STUDIES YOU IDENTIFIED PRIMA LEG
NUBILITY LESIONS AND ITALLY YOU
HAVE TO REMOVE THEM.
YOU CAN'T LET ANYBODY GO ON AND
GET CANCER.
SO WE COULD NEVER HAVE
DEMONSTRATED PROTECTION DIRECTLY
FROM CERVICAL CANCER.
SO WHAT THE REGULATORS ALLOWED
US TO DO IS TO USE PREVENTION OF
MODERATE AND SEVERE DYSPLASIA AS
A PRIMARY END POINT TO GET
CANCER AS AN INDICATION ON THE
LABEL.
IF WE UNDERSTOOD SO WELL APART
THERE PAP SMEAR TESTING IF YOU
REMOVE THESE LESIONS, WOMEN
DON'T GET CANCER.
WE ALSO BIOLOGICALLY UNDERSTOOD
IT AND COULD REPRODUCIBLY
IDENTIFY THESE LESIONS.
AND BECAUSE WE COULD UNDERSTAND,
WE UNDERSTOOD THE NATURAL
HISTORY OF THE DISEASE WELL
ENOUGH WE'RE ABLE TO GO AHEAD
WITH THE CLINICAL TRIALS AND NOW
IT'S AN END POINTED.
WHEN THE RESULTS OF THESE TRIALS
FINALLY CAME THROUGH, WE WERE
ALL REMARKABLY SURPRISED AND
GRATIFIED AT HOW WELL THESE
WORKED.
YOU HAVE TO UNDERSTAND THAT IN
THE CONTEXT OF DOING THESE
TRIALS, A LOT OF PEOPLE HAD
TRIED TO DEVELOP VASCULAR TEENS
SINCE SEXUALLY TRANSMITTED
DISEASES.
AT THAT POINT, EVEN TODAY THE
SUCCESS WAS ZERO ESSENTIALLY.
AND SO I HAVE TO TELL YOU WHEN
WE WENT AROUND TO THE COMPANIES
TO SAY WHY DON'T YOU DEVELOP
THIS, WE'VE GOT ALL THIS GREAT
ANIMAL DATA, ALL THIS GREAT IN
VITRO DATA THEY SAID THAT'S
REALLY GOOD BUT SEXUALLY
TRANSMITTED DISEASES DON'T WORK.
THEY CAN'T ONLY WORK BUT THEY
CAN WORK REALLY GREAT.
SO THIS IS JUST A SUMMARY OF
SOME OF THE DATA.
SO IF YOU LOOK AT THE IMMEDIATE
CANCER END POINT THAT'S A HIGH
GRADE -- IMMEDIATE PREVERSER OF
CERVICAL CANCER PROTECTION WAS A
HUNDRED PERCENT IN WOMEN WHO
DIDN'T HAVE EXPOSURE TO THOSE
VIRUSES BEFORE THEY GOT BACK.
THAT'S A VERY IMPORTANT POINT,
OKAY.
I'LL FALK ABOUT WOMEN WHO HAVE
BEEN EXPOSED IN A MINUTE BUT
THESE ARE WOMEN WHO ARE NAIVE TO
THE VACCINE SITES.
AGAIN THIS IS THE PROPHYLACTIC.
IT'S MEANT TO VACCINATE GIRLS.
GENTLE WARTS WASN'T TOO BAD
EITHER.
IT WAS 96.4%.
SO THIS IS WAY BETTER THAN ANY
OF US HAD EVER HOPED.
I HAVE ANOTHER LECTURE WHERE I
JUST BASICALLY GO OVER AND TRY
TO EXPLAIN WHY THE VACCINE WORKS
SO WELL.
IT'S SOMETHING OUR LAB HAS BEEN
TRYING TO FIGURE OUT WHY THIS
VASCULAR SEEN WORKS WELL IN ALL
OTHER SEXUALLY TRANSMITTED
VACCINES ARE TERRIBLE BUT THAT'S
ANOTHER LECTURE.
I WON'T GO INTO THAT TOO MUCH AT
THIS TIME.
SO IN TERMS OF PRENEO PLASTY
DISEASE THE SUMMARY WE'VE SHOWN
THAT THE HPV VACCINES ARE VERY
GOOD AT PREVENTING INFECTIONS
AND INTEREPITHELIAL PLASIA FOR
*** IN THE *** IT'S ALSO
*** VAGINAL.
FOR THE *** IT'S BEEN SHOWN IS
IT PREVENTS INFECTION BUT NOT
DISEASE BUT THE REASON IS ***
DISEASE RELATIVELY UNCOMMON.
BOTH THE INFECTION DON'T LEAD TO
VISIBLE LESIONS UNTIL THIS HAS
ACTUALLY BEEN FORMALLY
DEMONSTRATED.
THERE'S BEEN TREND BUT NOT
ENOUGH CASES TO FORMALLY DREAM
IT.
ORAL PHARYNGEAL THIS MEASURING
ON THE SAME CAUSAL PATHWAY AS
THE INFECTIONS THAT CAUSE THE
PHARYNGEAL CANCERS WHICH OCCUR
DEPARTMENT IN THE CRYPT FOR THE
MOST PART, OKAY.
AND BECAUSE THE PRIMA
PRE MALIGNANT -- THAT ARE THE
PRECURSORS OF ORAL PHARYNGEAL
CANCER.
UNLESS A LOT HAPPENS PROBABLY
NEVER REALLY KNOW WHETHER THE
VACCINE PREVENTS ORAL PHARYNGEAL
CANCER UNTIL 20 YEARS FROM NOW
WE SEE A DROP IN THE PEOPLE WHO
HAVE GOTTEN VACCINATED.
SHE'S -- WHAT'S SHOWN HERE -- EITHER
CLOSELY RELATED TO 16 OR 18.
BUT PROTECTION AGAINST THESE
OTHER HIGH RISK TYPES.
OVERALL IF YOU TAKE ALL THE HIGH
RISK TYPES THAT CAUSE INFECTION
IN THIS STUDY, IF YOU TAKE OUT
16 AND 18 AND ONLY PROTECTED
AGAINST 12% OF THOSE.
LET'S A LITTLE BIT OF CROSS
PROTECTION BUT PROTECTION IS
TIGHTLY RESTRICTED.
YOU CAN'T COUNT ON GETTING A LOT
OF PROTECTION ON THE TYPES THAT
AREN'T TARGETED SPECIFICALLY BY
THE VACCINES.
AND SO AGAIN, THIS IS A BIT OF
AN ISSUE BECAUSE NOW 16 AND 18
CAUSE ABOUT 70% OF CANCERS
WORLDWIDE.
AFTER THAT THERE'S NO TYPE THAT
CAUSES MORE THAN ABOUT 4%, OKAY.
HOW DO YOU DEAL WITH THOSE IT
JUST SHOWS IN UNITED STATES
15-18 CAUSES 7% OF CERVICAL
CANCER BUT AS YOU MOVE INTO
LOWER GRADE DISEASES THE
PROPORTION GOES DOWN SO IT'S
ONLY ABOUT 50PERCENT OF HIGH
GRADE -- A LOT OF WOMEN WILL
STILL BE GETTING PAP SMEAR
ABNORMALITIES WHICH ISN'T
NECESSARILY LIKELY TO GO ON TO
CANCER BUT THEY'RE NOT CAUSED BY
16 AND 18.
THIS SHOWS ACTUALLY THE
PROTECTION THAT WAS IN THE
CLINICAL TRIALS WHICH WAS
SOMEWHAT HIGHER AND THE REASON
FOR THIS IS WE'VE GOT SOME CROSS
PROTECTION.
IN 2, 16 AND 18 LESIONS TEND TO
PROGRESS MORE RAPIDLY OVER TIME
THAN BY OTHER QUOTE ONCOGENIC
TYPES.
SO IN A SHORT TRIAL OF FOUR TO
SIX YEARS YOU SEE BETTER
PROTECTION AGAINST 16 AND 18
THAN THE OTHER TYPE.
SO WE'RE DEVELOPING A VACCINE
THAT INCLUDES ONLY 16 AND 18 BUT
THE NEXT MOST COMMON TYPE.
I CAN TELL YOU TODAY FOR THE
FIRST TIME THE RESULTS OF THAT
STUDY BECAUSE THEY JUST
ANNOUNCED IT TODAY.
I'VE ACTUALLY KNOWN IT FOR A
WHILE BUT IT'S THE FIRST DAY
I'VE ACTUALLY BEEN ABLE TO TALK
ABOUT IT.
THEY MADE AN ANNOUNCEMENT ABOUT
A WEEK AGO THAT PIVOTAL HE FA
SEE TRIAL IS COMPLETE AND
PRIMARY END POINT HAS THE NUT.
BUT JUST TODAY THEY ACTUALLY
ANNOUNCED THAT SO WHAT THE TRIAL
WAS, IT WAS COMPARING GUARD SILL
TO WHAT'S CALLED THE NON---
THERE'S ABOUT A HUNDRED PERCENT
PROTECTION FOR BOTH OF THEM THAT
LOOK AT IMMUNOGENICITY E
DEVELOPMENT.
COMPARED TO THE GUARD SYM THEY
FOUND 98% EFFICACY AGAINST THESE
FIVE ADDITION AL TYPES.
SO THEY HAVEN'T GONE TO THE FDA
YET BUT LOOKING AT THIS AD IT'S
QUITE LIKELY THEY'RE GOING TO
SAY GO AHEAD AND START GIVING IT
TO THIS GIRL.
THIS IS REALLY GOING TO HELP GET
PROTECTION AGAINST THESE OTHER
TYPES THAT AREN'T IN THE
ORIGINAL VACCINE.
OF COURSE ONE OF THE QUESTIONS
IS ALL OF YOU HAVE ALREADY
GOTTEN THE VACCINE WHAT ARE YOU
GOING TO DO.
ARE YOU GOING TO TAKE THE NEW
VACCINE OR ARE YOU GOING TO BE
SATISFIED WITH WHAT YOU GOT.
SO IT'S GOING TO BE KIND OF AN
INTERESTING ISSUE TO SEE WHAT
HAPPENS WITH THAT.
I DON'T THINK THEY'RE GOING TO
SELL THE VACCINE THAT JUST HAS
THE FIVE NEW TYPES WITHOUT THE
OTHER TYPES IN IT.
IF YOU HAVE THE SAFETY STUDIES
WHERE IT'S SAFE IN WOMEN WHO
HAVE GOTTEN THE PREVIOUS
VACCINE.
SO YOU WANT TO SPEND YOUR MONEY
TO GET THE NEW VACCINE YOUR
INSURANCE MIGHT NOT COVER IT BUT
YOU MIGHT BE ABLE TO GET IT.
THEY THINK THE VACCINE IS
PROTECTING FROM INITIAL
INFECTION BECAUSE MOST VACCINES
NEVER TEST POSITIVE.
WE DON'T THINK THEY'RE GETTING
LESIONS MAKING THEM GO AWAY.
WE THINK IT'S NOT INFECTING
ATAL.
WE DO SEE BREAK THROUGH IN
QUOTES INFECTIONS, THEY TEND TO
APPEAR EARLY DURING THE TRIALS.
BUT THE PROTECTION'S BETTER IN
YEAR FOUR FIVE SIX THAN IT IS IN
YEAR ONE.
WHY IS THAT?
THE ANTI-BODY-IF YOU HAVE THE
INFECTION WE HAVEN'T BEEN ABLE
TO DETECT IT AT THE TIME OF
VACCINATION MOST WOMEN HAVE
STERILIZED IMMUNITIES WHICH IS
PRETTY AMAZING.
ANTI-BODIES ARE MEDIATORS OF
PROTECTIONS FOR SEVERAL REASONS.
THERE'S HIGH LEVELS OF VIRUS --
ROUTINELY GENERATED AND CROSS
PROTECTION IN CLINICAL TRIALS --
IN VITRO MAYBE MOST IMPORTANTLY
IN ANIMAL STUDIES, WE CAN SEE
COMPLETE PROTECTION BYPASSIVE
TRANSFER OF SERUM FROM A
VACCINATED TO NAIVE ANIMAL,
OKAY.
AND THE NEUTRALIZING ANTI-BODIES
RECOGNIZE THESE VARIABLES --
AGAIN PERHAPS MORE IMPORTANTLY
L1 IS NOT DETECTABLY EXPRESSED
IN THE BASAL CELLS.
IF YOU LOOK AGAIN AT A VIRUS
THAT'S, VIRUS PRODUCING LESIONS
L 1-S ONLY MADE IN THESE
TERMINALLY DIFFERENTIATED CELLS
WHEREAS THE INFECTION IS BEING
MAINTAINED DOWN HERE WHERE
THERE'S NO L1.
IT'S LARD TO -- HARD TO IMAGINE
IF YOU GOT T CELLS UP HERE IT
WILL ELIMINATE THESE CELLS.
YOU GET LESS AND LESS AND TO THE
POINT OF NO L1 EXPRESSION THIS
HIGH GRADE PRE MALIGNANT
LESIONS.
THIS IS JUST SOME DATA FROM THE
TRIAL THAT WAS SPONSORED BY THE
NCI.
SIX MONTHS OR 12 MONTHS TIME TO
ALREADY HAVE INFECTION AND YOU
ASK WHAT PERCENTAGE IS CLEAR IT
DOESN'T MATTER WHETHER YOU LOOK
AT THE CONTROLS WHETHER THE
CLEARANCE IS THE SAME.
IN 12 MONTHS HALF OF THEM HAVE
CLEARANCE.
OKAY.
THEY THINK THIS VACCINE IS
WORKING BY A MEDIATED MECHANISM.
T CELLS HELP TO GENERATE THE
ANTI-BODIES YOIPPED WE DON'T
THINK THERE ARE THE EFFECT
PACIFIC MECHANISMS INVOLVED.
THE VACCINE IF IT HAD GREAT
EFFICACY PROBABLY IN PART
BECAUSE IT'S GOT GRADE -- THIS
IS THE PERCENT CONVERSION WHICH
IS BASICALLY 100%.
THE RESPONSES ARE VERY DURABLE.
THIS IS FROM GUARD SILL -- YOU
CAN SEE THAT AFTER SIX YEARS
EVERYBODY IS STILL ZERO
POSITIVE.
YOU'VE HAD AFTER THE FIRST YEAR
AND-A-HALF OR TWO YEARS THERE'S
A PLATEAU AND THERE'S NO CHANGE
IN THE ONES GO OUT WHICH IS TRUE
FOR FINE YEARS.
A YEAR AND-A-HALF TO NINE YEARS
WE HAVE DATA THAT ABSOLUTELY
STABILIZES THE TITERS.
AND THESE LEVELS ARE HIGHER AT
LEAST A LOG HIGHER THAN THE
LEVELS GENERATED BY NATURAL
INFECTION.
SO ALTHOUGH WE DON'T KNOW HOW
LONG THE VACCINE'S GOING TO
LAST, YOU KNOW, 2006 WAS THE
FIRST DATA.
WE THINK THAT THERE'S BEEN
STRONG PROTECTION FOR EIGHT
YEARS WITH NO INCREASE IN THE
NUMBER OF BREAK THROUGH
INFECTION OVER TIME.
AS I MENTIONED MOST OF THE BREAK
THROUGH INFECTIONS OCCURRED
EARLY NOT LATE.
SO GIVEN THE FACT THAT THE
ANTI-BODY TITERS AREN'T GOING
ON, WE'RE OPTIMISTIC FOR LONG
TERM PROTECTION FOR THESE
VACCINES.
THE DATA ACTUALLY WAS JUST
ANNOUNCED TODAY OR YESTERDAY,
PRETTY GOOD DATA TO BE HERE FOR
THIS LECTURE, A LOT OF GOOD
DATA.
THIS IS SOMETHING THAT A PAPER
FROM THE NCI THAT WE'RE INVOLVED
WITH.
SO IN THIS STUDY THERE WAS SOME
WOMEN, A SUBSET WHO GOT ONLY ONE
DOSE OR TWO DOSES.
AND WE CONTINUED TO FOLLOW THEM
AND LOOKED AT THEIR ANTI-BODY
RESPONSES.
WE LOOKED TO SEE IF THEY WERE
GOING TO GET 16 AND 18
INFECTIONS.
AND THE REMARKABLE THING IS THAT
THE WOMEN WHO ONLY GOT ONE DOSE
ENDED UP WITH STABILIZING
ANTIBODY TITERS.
ONLY FIVE FOLD LESS THAN THE
TITER AFTER THREE DOSES OUT AT
FOUR YEARS.
AND PROTECTION WAS A HUNDRED
PERCENT IN THOSE WOMEN.
NOW, YOU KNOW, THIS IS A REALLY
ENCOURAGING FINDING BUT I, TO
QUALIFY THIS, THIS WAS NOT A
CONTROLLED TRIAL.
IN OTHER WORDS THE WOMEN WERE
NOT RANDOMIZED ONE, TWO OR THREE
DOSES.
WE TRIED TO LOOK TO SEE IF THERE
WAS ANYTHING DIFFERENT BETWEEN
WOMEN WHO HAD ONE DOSE OR
MULTIPLE DOSES.
THERE WASN'T ANYTHING DIFFERENT
IN TERMS OF RISK FACTORS BUT WE
HAVE RANDOMIZED TRIALS OF ONE,
TWO AND THREE DOSES TO SEE IF WE
GET COMPLETE PROTECTION WITH ONE
DOSE.
THIS IS SURPRISING NOBODY SEEN
STABILIZING ANTI-BODY TITERS
AFTER ONE DOSE OF THE UNIT
VACCINES.
THIS IS SOMETHING AFTER A LIVE
VIRUS VACCINE BUT NOT
SUBVACCINES.
WE REALLY THINK IT'S THE DISPLAY
OF THESE REPETITIVE EVEN TODAYS
THAT SEND A VERY STRONG SIGNAL
TO THE B CELLS TO SURVIVE AND
KEEP PUMPING OUT ANTI-BODIES THE
REST OF YOUR LIFE.
AND SO WE'RE ACTUALLY, I
ACTUALLY OPTIMISTIC THAT THIS IS
A ONE DOSE VACCINE.
DON'T TELL ANY OF YOUR FRIEND
JUST TO GET ONE DOSE.
IF I HAD KIDS RIGHT NOW THEY
WOULD GET TWO DOSES AND A LOT OF
THE WORLD MANY COUNTRIES IN THE
WORLD ARE MOVING TO TWO DOSES
NOW.
BECAUSE TWO DOSES ALSO GIVES NO
DIFFERENCE.
SMATTER IF YOU GIVE TWO DOSES TO
YOUNG GIRLS, THEY GET AS HIGH AN
ANTI-BODY RESPONSE AS THREE
DOSES OF YOUNG ADULT WOMEN WHERE
THE EFFICACY WAS SO HIGH.
SO BECAUSE OF THIS FOR YOUNGER
KIDS THAT RESPONDENT BETTER TO
SUBUNIT VACCINES, MANY COUNTRIES
LOOK LIKE THEY'RE GOING TO MOVE
TO A TWO DOSE TRIAL.
>> [INDISCERNIBLE]
>> YES, THAT'S A GOOD QUESTION.
WE'VE SHOWN THIS WITH GUARD
SILL.
IT'S UNCLEAR WHETHER THIS IS
GOING TO BE GOOD.
IT'S A REALLY GOOD QUESTION.
ONE OF THE THINGS WE WANT TO DO
IS RUN A CONTROL TRIAL TO
COMPARE THE TWO VACCINES OR RUN
NO VACCINE.
IT'S A VERY IMPORTANT THING TO
DETERMINE SCIENTIFICALLY FOR A
NEW VACCINE IS WHETHER VIRUS
LIKE DISPLAYS TO GET PERSISTENT
ANTI-BODY LEVELS YOU NEED TO
HAVE A TLR AGONIST OR WHETHER
YOU CAN GET AWAY WITHOUT IT.
THE FUTURE -- IF WE HAVE TETANUS
OR ANYTHING ELSE, YOU CAN DO
VIRUS-LIKE DISPLAYS YOU PROBABLY
WOULDN'T NEED TO REVACCINATE.
THE QUESTION IS WOULD YOU NEED A
TLRA, GREAT QUESTION.
SO ONE OF THE QUESTIONS THAT
COMES UP IS HOW DO THE
ANTI-BODIES THAT WE THINK ARE
PROTECTING THE INFECTION GET TO
THE ***.
IF YOU DO SYSTEMIC IMMUNIZATION
IT'S REALLY GOOD AT MAKING IS
SYSTEMIC IGG OR REALLY LOUSY AT
MAKING SECRETORY IGA.
THIS IS A VIRUS INFECT A PLEU
COASTAL SITE.
MOST PEOPLE WHEN YOU THINK OF
MUCOSAL SITES YOU THINK OF
THE -- YOU GOT ALMOST ALL YOUR
ANTI-BODIES ARE IGA THAT ARE
SECRETED THERE.
WE CAUGHT A BREAK BECAUSE AT THE
*** HALF OF THE ANTI-BODIES
ARE IGG.
IT COMES OUT BY THE NEO NATAL FC
RECEPTOR.
SO WE CAN GET BY WITH
ANTI-BODIES THAT ARE SYSTEMIC
ANTI-BODIES WAS THEY'RE
ELABORATED ON THE *** QUITE
READILY BY THIS MECHANISM.
AND PERHAPS MORE IMPORTANTLY,
WE'VE DONE TOWARDS IN ORDER FOR
THE SUPERVISOR TO INFECT YOU
NEED THE MEMBRANE THAT SEPARATES
THE DERMIS FROM THE EPIDERMIS.
YOU CAN IMAGINE IF YOU HAVE A
MICRO ABRASION THAT LEADS TO
EXPOSURE OF THE BASEMENT
MEMBRANE YOU'RE GOING TO HAVE
INTERSTITIAL ANTI-BODIES FLOWING
OUT OF HERE.
SO THE VIRUS WILL BE TRYING TO
INFECT AGAINST A GRADIENT OF
ANTI-BODIES.
OKAY.
AND WE THINK THAT THIS IS THE
MAJOR INCOMISM OF PROTECTION
BECAUSE WE GET SO GOOD
PROTECTION AGAINST GENTLE
WARTS
NOT BY MUCOUS -- SO WE THINK
THIS MAY BE THE MAIN MECHANISM
OF PROTECTION.
SO CONCLUSION IS THE VLP
VACCINES ARE HIGHLY EFFECTIVE
AGAINST *** GENERAL SULT END
POINT AND INFECTION TO HIGH
GRADE PRECANCER.
GUARD CIVIL IS PROTECTIVE
AGAINST GENERAL CULL WARTS IN
BOTH MEN AND WOMEN.
PROTECTION IS RESTRICTED BECAUSE
THE PROTECTION IS BEING
ANTI-BODY MEDIATED.
ALTHOUGH THE DURATION OF
PROTECTION IS STILL UNKNOWN AS
IT WOULD BE FOR ANY VACCINE
THAT'S RECENTLY INTRODUCED.
THE STRONG PROTECTION OF EIGHT
YEARS AFTER ANTI-BODY LEVELS
HAVE STABILIZED MAKES US VERY
ENCOURAGED FOR LONG LIVED
PROTECTION.
FLOWRVE SO NOW I'M GOING TO TURN
A LITTLE BIT MORE TO THE
IMPLEMENTATION.
SO I THINK IN A RELATIVELY SHORT
NUMBER OF YEARS I THINK WE CAN
NOW CONSIDER THESE ESTABLISHED
PRODUCTS THEY'VE BEEN LICENSED
WORLDWIDE FOR PROVENTION OF
CERVICAL CANCER.
THERE'S NEO PLASIA.
THERE'S BEEN MILLIONS OF DOSES
SOLD AROUND THE WORLD.
SAFETY ISSUES ALTHOUGH PEOPLE
CONTINUE TO RAISE AND SO FAR
THERE'S NO SIGNAL THAT EVEN WITH
THIS NUMBER OF DOSES
ADMINISTERED THEY HAVE ANY
SERIOUS ADVERSE EVENTS THAT ARE
ASSOCIATED WITH THEM.
AND JUST TO POINT OUT GUARD SILL
WAS APPROVED FOR GENTLE WARTS IN
MEN IN 2009.
AND FOR *** CANCER IN 2010 FOR
BOTH SEXES.
ALTHOUGH THE TRIAL'S ARE
INTERESTING, THEY WERE ONLY DONE
IN MEN.
THIS IS AN EXAMPLE OF GLOBALLY
WHERE THE VACCINES ARE
LICENSED -- INCIDENTALLY IT
INTERESTINGLY IT HASN'T BEEN
LICENSED IN CHINA YET.
THEY ARE TRYING TO DEVELOP IN
HOUSE THEIR OWN VACCINE BUT SO
ARE FAR THEY HAVEN'T ACCEPTED
APPROVAL OF EITHER GUARD SILL OR
CERVICALIX.
WHO TO VACCINATE.
WELL CLEARLY GIRLS BEFORE THEY
BECOME SEXUALLY ACTIVE ARE THE
MAIN TARGETS FOR THIS VACCINE.
AT LEAST WORLDWIDE BECAUSE THEY
BEAR, BECAUSE WOMEN BEAR THE
MAJORITY OF THE BURDEN OF HPV
INFECTION.
WHICH IS CERVICAL CANCER.
BUT THEN YOUNG WOMEN MIGHT
BENEFIT IF THEY HAVEN'T BEEN
EXPOSED TO 16 OR 18.
JUST BECAUSE YOU'RE SEXUALLY
ACTIVE DOESN'T MEAN YOU
ABSOLUTELY MEAN YOU'VE BEEN
EXPOSED TO 16 AND 18.
BUT IT COMES TO DIMINISHING
RETURNS AS YOU GET OLDER AND
HAVE MORE *** PARTNERS.
ALSO BOYS, CERTAINLY DO GET
HPV-ASSOCIATED CANCERS AND THEY
ARE VECTORS FOR INFECTING THE
WOMEN.
SO ONE COULD IMAGINE HER
IMMUNITY DEVELOPING FASTER IF
YOU HAVE BOYS EVEN IF YOUR MAIN
GOAL IS TO PREVENT CERVICAL
CANCER.
OLDER MEN IS PROBABLY LESS
ADVANTAGEOUS THAN THE BOYS.
IN THIS SLIDE JUST SHOWS WHY WE
HAVE TO VACCINATE YOUNGER GIRLS.
BECAUSE THIS IS DATA FROM THE
U.S. AND GREAT BRITAIN WITHIN
FOUR MONTHS OF BECOMING SEXUALLY
ACTIVE 20% HAVE HPV INFECTION BY
TWO YEARS IT'S ALMOST 50%.
IF YOU WAIT UNTIL YOUR DAUGHTERS
ARE ALREADY SEXUALLY ACTIVE,
THERE'S A REASONABLE CHANCE THAT
YOU MIGHT MISS THE OPPORTUNITY
TO PROTECT THEM.
AS I MENTIONED, ONCE THEY HAVE
THE INFECTION THE VACCINE'S NOT
GOING TO DO ANYTHING FOR THEM AT
ALL.
SO IT'S INTERESTING THAT THE CDC
WHO DETERMINED THE VACCINE
POLICY IN THE UNITED STATES,
INITIALLY RECOMMENDED, THE
RECOMMENDATION FOR BOYS WAS
PERMISSIVE.
BUT IN OCTOBER 2011, THEY
ACTUALLY WENT ON AND RECOMMENDED
THAT YOU HAVE ROUTINE
VACCINATIONS OF 11 AND 12 AND
CATCH UP VACCINATION OVER 25M
THE CHANGE IN RECOMMENDATION WAS
BASED ON TWO THINGS.
ONE BASED ON THE POOR UPTAKE OF
GIRLS.
IF YOU DO MODELY OF HER IMMUNITY
AND YOU GET STRONG PROTECTION IN
ONE, YOU ALMOST DON'T NEED THE
VACCINE FOR THE OTHER.
I'LL SHOW YOU SOME DATA IN A
MINUTE.
IF YOU GET POOR UPTAKE OF AN
INTERVENTION THAT PREVENTS
INFECTION THEN ACTUALLY YOU GET
MORE HURT IMMUNITY BENEFITS OUT
OF THAT IN THE OTHER SECRETARY
AS WELL.
THE OTHER THING THAT PROMPTED
THEM TO DO THIS.
WHEN GUARD SILL WAS LABELED FOR
*** CANCER FDA APPROVED IT FOR
THAT IT'S HARD TO PREVENT A
BENIGN INTERVENTION FROM
SOMEBODY WHO IS GETTING CANCER
AND THEY JUST COULDN'T DO THAT.
EVEN THOUGH THE COST BENEFIT
RATIOS ARE NOT AS HIGH AS
PREVENTING INFECTION IN WOMEN.
ANOTHER ISSUE IS THE DELIVERY OF
THREE DOSES TO EARLY
ADOLESCENCE.
THIS IS ACTUALLY NOT ROCKET
SCIENCE.
IF YOU WANT TO GET HIGH COVERAGE
YOU VACCINATE IN SCHOOL.
IN SCOTLAND AND ENGLAND THEY
VACCINATED 12 AND 13 YEARS OLDS
IN SCHOOLS AND GOT VERY HIGH
COVERAGE.
FOR SOME REASON I DON'T
UNDERSTAND THE POLICIES.
THEY VACCINATED TO DO A CATCH UP
VACCINATIONS IN SCHOOLS FOR 17
AND 18 YEARS OLD THEY GOT HIGH
COVERAGE.
ENGLAND DECIDED THEY WOULD DO IT
IN CLINICS AND THEY GOT 30%.
AUSTRALIA IS ABOVE 80% IN A
SCHOOL-BASED VACCINATION AND
WE'RE AT ABOUT 30% THREE DOSE
COVERAGE FOR 13-17 YEAR OLDS.
WHICH I WOULD KINDLY CALL OUR
SYSTEM DISORGANIZED.
YOU MAY HAVE WORST TERMS FOR IT
THAN THAT.
I WORK FOR THE GOVERNMENT, I
CAN'T SAY TOO MUCH.
ANYWAY, LET'S CALL IT
DISORGANIZED.
NOW IT'S ACTUALLY POSSIBLE.
YOU CAN GET GOOD COVERAGE AND
THIS CAN BE DONE IN DENMARK.
BUT THEY DID A REMARKABLE JOB OF
BEFORE THEY INTRODUCED THIS TO
EDUCATE THE PARENTS BUT MORE
IMPORTANTLY EDUCATED THE
PEDIATRICIAN AS THE VALUE OF THE
VACCINE AND GOT THEM ON BOARD.
WE HAVEN'T REALLY DONE A GOOD
JOB OF EITHER.
BUT THIS JUST SHOWS WHAT COULD
HAPPEN IF YOU DO GET DO COVERAGE
OF A VACCINE.
IN AUSTRALIA IF YOU LOOK AT CIN2
PLUS IS CERVICAL DYSPLASIA
THERE'S A DROP IN INCIDENTS IN
18 YEAR OLDS AND SOME INCIDENCE
OF A DROP IN 178-20 YEAR OLDS
BUT NO DROP IN THE WOMEN WHO
WEREN'T PART OF THE VACCINATION
PROGRAM.
GENTLE WARTS IS A EARLY
MANIFESTATION OF INFECTION THAN
CIN23.
ON AVERAGE FOR A VERY SHORT
POAFERRED TIME FOR THE INITIAL
INFECTIONS TO MANIFEST
THEMSELVES AS GENTLE WARTS.
YOU CAN SEE THAT IN THE
VACCINATION COHORTS ESPECIALLY
THE UNDER 21 THERE'S BEEN A
REMARKABLE 92% REDUCTION GENTLE
WARTS BASED UPON THIS PROGRAM.
IN OLDER WOMEN IT'S REDUCED BY
72%.
EVEN MORE RACKABLE IF YOU LOOK
AT THE RATE OF GENTLE WARTS IN
HETEROSEXUAL MEN, YOU DON'T NEED
A STATISTICIAN TO SEE THIS IS
PRETTY MUCH DROPPING OFF THE
TABLE.
THE BOYS WERE NOT PART OF THE
VACCINATION PROGRAM.
THEY HAD JUST STARTED
VACCINATING BOYS KIND OF WONDER
WELL WHY ARE THEY DOING IT
WITHOUT GETTING THE 82%
REDUCTION.
BUT THERE'S NO SIGNIFICANT
VACCINATION IN THE OLDER GUYS,
OKAY, REDUCTION.
AND SO THIS IS REALLY DUE TO
HURT IMMUNITY.
IT'S ALSO NO REDUCTION IN MSM,
OKAY.
SO REALLY IS THAT, THE WOMEN ARE
BEING VACCINATED FOR PREVENTING
THE INFECTION IN MEN.
SO I THINK THIS BODES VERY WELL
EVEN IF YOU DON'T GET COMPLETE
VACCINATION COVERAGE, YOU CAN
REALLY CONTROL THE DISEASE BY,
IF YOU CAN GET THE MAJORITY OF
PEOPLE VACCINATED.
THERE'S VACCINATED AND
UNVACCINATED COHORTS IN ACCEPT
GROUPS.
THIS IS SOME DATA FROM THE
UNITED STATES WHERE WE'RE
ACTUALLY NOT DOING VERY GOOD
WITH HPV IN COMPARISON TO TWO
OTHER VACCINES.
THE TETANUS -- VACCINE THAT'S
DELIVERED A ALSO TO ADOLESCENCE.
THIS IS DATA FROM 2010.
YOU CAN SEE IT'S 49% AT LEAST
ONE DOSE AND 32% HAVING ALL
THREE DOSES.
AND MALE VACCINATIONS ABOUT
1.4%.
SO THIS IS JUST ABOUT THE TIME
THAT WE GOT VOX NATION
RECOMMENDATION, STRONG
RECOMMENDATION FROM THE CDC FOR
BOYS.
INSURANCE COMPANIES ARE NOW
COVERING IT SO MAYBE WE'LL START
TO SEE SOMEWHAT OF AN INCREASE
IN VACCINATION OF BOYS.
THIS IS AN UPDATE THAT JUST
APPEARED A COUPLE DAYS AGO.
SO ADOLESCENCE GIRLS 13-17 IN
THE UNITED STATES, 33% HAVE HAD
ALL DOSES.
IT'S BASICALLY WAS GOING UP IN
THE LAST FEW YEARS IT'S JUST
GONE FLAT.
AND 54% HAVE AT LEAST ONE DOSE.
IF YOU LOOK AT THE ONE DOSE DATA
THAT I SHOWED YOU IN ANOTHER
SLIDE WHERE WE GET A HUNDRED
PERCENT PROTECTION AND NO CHANGE
IN THE ANTI-BODY TITERS.
WE'RE LOOKING TER ONE DOSE DATA
A LITTLE BIT DIFFERENTLY THAN WE
DID BEFORE.
WE MAY NOT CONSIDER THIS AS MUCH
A FAILURE AS WE DID BEFORE.
CONSISTENT WITH THIS, IF YOU
LOOK AT THE REDUCTION IN THE
PACK SEAT TARGETED TYPE IN 14
AND 19 YEAR OLDS OVER THE PERIOD
WHERE WE'VE DONE VACCINATIONS
HAS DROPPED BY 50%.
THAT'S VERY SIGNIFIENT.
IT'S ACTUALLY CLOSER TO THIS
NUMBER THAN THIS NUMBER.
SO PART OF THAT MAY BE DUE TO
HURT IMMUNITY AND HEART IS THE
FACT THAT EVEN THESE PEOPLE ARE
SUCCESSES.
AGAIN, DON'T RECOMMEND PEOPLE
JUST GET ONE DOSE.
THAT'S NOT THE TAKE HOW MANY
LESSON HERE.
THERE REALLY IS A LOT OF MISSED
OPPORTUNITY.
THEY CALCULATED THAT.
IF ALL THE GIRLS CAME INTO
CLINIC IN WHICH THEY HAD AN
OPPORTUNITY TO HAVE A PHYSICIAN
OR A NURSE GIVE THEM A VACCINE,
WHAT WOULD THE COVERAGE RATES
BE?
IT WOULD BE 93%.
A LOT OF THE PROBLEMS IS THAT
PHYSICIANS ARE NOT STRONGLY
RECOMMENDING THE VACCINES AND
SOME PEOPLE'S PARENTS ARE OPTING
OUT OF IT.
SO ONE OF THE ISSUES WE HAVE TO
CONTEND WITH IS THE EFFECTIVE
VACCINE ON CERVICAL CANCER
SCREENING RECOMMENDATION AND
COMPLIANCE.
WE CLEARLY CAN'T GIVE UP
SCREENING BECAUSE THE VACCINE
WON'T HELP WITH ESTABLISHING
INFECTIONS, I SHOWED YOU THAT
DATA.
AND SINCE THE VACCINE IS TIGHT
RESTRICTED IT WON'T PROTECT
AGAINST 20-30% OF CERVICAL
CANCERS.
20% IS BEING GENEROUS AS THERE'S
SOME COST PROTECTION.
YOU REALLY NEED TO CONVINCE
VACCINATED WOMEN THAT YOU NEED
TO COMPLY WITH SCREENING
PROGRAMS.
AND IT WOULD BE TOO BAD IF WE
CAN'T CHANGE SCREENING PROGRAMS
EVENTUALLY IN VACCINATED WOMEN
ESPECIALLY THE WOMEN WHEN THEY
START GETTING TO KNOW THE
VACCINE WILL THEY GET COVERAGE
FOR DIFFERENT TYPES.
PART IS THE CONVENIENCE AND PART
IS WE JUST SPENT A TON OF MONEY
ON SCREENING.
IF YOU LOOK AT THE ANNUAL DIRECT
MEDICAL COSTS FOR ALL THE BURDEN
OF PREVENTING AND TREATING
HPV-ASSOCIATED DISEASE, OVER 82%
IS SPENT ON SCREENING.
SO WE REALLY WOULD HOPE THAT IN
THE LONG RUN, WE WOULD BE ABLE
TO DO SOMETHING ABOUT SCREENING
IN THE VACCINEES.
THE OVERALL ALL IDEA ALTHOUGH
THE SPECIFICS ARE NOT CLEAR WE
HAVE TO DO A LOT MORE RESEARCH
AND EVALUATIONS TO KNOW HOW AND
WHEN WE CAN EVENTUALLY CHANGE
SCREENING RECOMMENDATIONS.
BUT THE IDEA IS TO GO FROM THE
PAP SMEAR, WHICH IS RELATIVELY
INSENSITIVE.
IN OTHER WORDS, YOU CAN BE PAP
SMEAR NEGATIVE AND STILL HAVE A
REASONABLE CHANCE OF DEVELOPING
CERVICAL CANCER IN THE NEXT TEN
YEARS BECAUSE A LOT OF LESIONS
ARE LISTED.
HPV TESTING IS MUCH MORE
SENSITIVE.
SO IF YOU ARE HPVDNA NEGATIVE
THE CHANCE OF GETTING CERVICAL
CANCER IN TEN YEARS ARE REALLY
REALLY LOW.
SO WHAT WE WOULD DO IS SWITCH TO
AN HPV BASE CERVICAL PREVENTION
STRATEGY BUT WE WERE VACCINATED
EARLY TO REDUCE THIS PEAK EARLY
ON AND THEN THE INIF IN--
INFECTIONS -- AFTER AGE 30, BUT
DO THIS RELATIVELY INFREQUENTLY.
THEN MODELING DOING THIS TYPE OF
THING COULD NOT ONLY PREVENT
MORE CANCERS BUT DO IT AT A
LOWER COST THAN THE CURRENT PAP
SMEAR TECHNOLOGY WHICH IS
REALLY DEPENDENT UPON REPEATED
REPEATED SCREENING.
BECAUSE OF THIS LOW SENSITIVITY
OF RELATIVELY LOW SENSITIVITY.
IT'S NOT TO SAY IT DOESN'T WORK,
IT WORKS WE REDUCED CERVICAL
CANCER BY 80% IT'S JUST
EXPENSIVE AND YOU NEED A LOT OF
DIFFERENT SCREENS TO HAVE IT
WORK PROPERLY.
AND FINALLY HOW TO DELIVER THE
VACCINES TO ECONOMICALLY
DISADVANTAGED INDIVIDUALS WHERE
85% OF CERVICAL CANCERS OCCUR IN
DEVELOPING CURRENT TREES.
THIS HAS GOT TO BE A
MULTIPRONGED APPROACH.
THIS IS ONE SIZE FITS ALL.
IT'S ENCOURAGING THAT RECENTLY
BOTH COMPANIES HAVE COMMITTED
DETAILS THAT BUYS BACK -- LESS
THAN $5 A DOSE.
THIS IS STILL PRETTY EXPENSIVE
FOR A VACCINE.
A LOT OF VACCINES COST A NICKEL.
ANOTHER THING THAT WE'RE WORKING
WITH IS COMPANIES IN EMERGING
COUNTRIES THAT HAVE THE VACCINE
MANUFACTURED THERE.
FOR INSTANCE IN INDIA AND CHINA,
BRAZIL, OTHER COUNTRIES LIKE
THAT, THAT COULD MANUFACTURE THE
VACCINE AT A LOWER PRICE.
THIS IS REALLY, HEPATITIS B
VACCINE GOING FOR ALMOST $100 A
DOSE BUT UNICEF BUYS THE VACCINE
FOR $.20 A DOSE.
IT TOOK 20 YEARS TO GET IT THERE
AND WE SO MANY -- HOPE TO GET
THE TIME LINE SHRUNKEN.
IT DOESN'T A STATISTICIAN --
EVEN I CAN UNDERSTAND.
AND THE LAST THING I WOANLTS GO
INTO BUT WE'RE WORKING ON SECOND
GENERATION VACCINE THAT COULD BE
MANUFACTURED DELIVERED AT LOWER
COSTS.
ONE OF THE REALLY COOL IDEAS IS
MAKING THE MEASLES VACCINES.
IT DOESN'T COMPROMISE MEASLES
IMMUNITY AND WE GET A HIGH DOSE
OF ANTIBODY RESPONSE FROM ONE
DOSE TO THE MEESEAL VASCULAR
SEANTZ AND THREE DOSES ON THE --
IMAGINE THIS YOU GET HPV FOR
NOTHING.
THAT WOULD BE A VACCINE THAT
WOULD BE CHEAPER THAN VACCINE
AND DELIVER BECAUSE MEASLES IS
STANDARDIZED.
YOU CAN'T COMPROMISE THESALS
OTHERWISE YOU'RE SUBSTITUTING
ONE BAD THING FOR ANOTHER.
I'M GOING TO STOP THERE IN CASE
THERE'S A FEW QUESTIONS.
I WANT TO ACKNOWLEDGE THE PEOPLE
IN MY LAB, PARTICULARLY DOUG
LOWY WHO IS THE CO-RESEARCHER IN
OUR LABORATORY, SOME GOOD
ACADEMIC OUTSIDE RESEARCHERS.
BUT WE HAVE TO GIVE A SHOUT OUT
TO THE PEOPLE IN THE COMPANIES
WHO REALLY SPEND AN AWFUL LOT OF
TIME AND EFFORT AND MONEY AND
RESOURCES TO BRING THESE
VACCINES TO MARKET.
IT DOESN'T JUST TAKE THE
ACADEMIC ON THE FRONT END OF
STUFF BUT IT TAKES GOOD PEOPLE
IN THE CORPORATE WORLD TO BRING
A GOOD INTERVENTION TO PEOPLE
AND HOPEFULLY PREVENT CERVICAL
CANCER.
SO WITH THAT, I'LL STOP AND TAKE
ANY QUESTIONS.
[APPLAUSE]
YES.
>> [INDISCERNIBLE].
>> THERE'S STUDIES IN ***
POSITIVE CHILDREN AND ALSO
ADULTS.
I HAVE TO SAY THESE ARE PEOPLE
THAT ARE ON -- THEY HAVE
REASONABLE T CELL COUNTS.
AND RESPONSIBILITIES ARE
SIGNIFICANTLY LOWER BUT STILL
STRONG, OKAY.
SO ONE OF THE POSSIBILITIES
WOULD BE FOR INSTANCE THEY GET
AN EXTRA DOSE OR SOMETHING LIKE
THAT.
BUT LOOKING AT THE LEVELS THAT
THEY GET MY PREDICTION WOULD BE
THAT THEY GET PROTECTED.
CERTAINLY I THINK IT'S ALREADY
RECOMMENDED THAT *** POSITIVE
CHILDREN, BECAUSE PEOPLE WITH
*** COULD HAVE SIGNIFICANT AND
MUCH GREATER PROBLEM WITH
INFECTION THAN NON-*** PEOPLE,
THAT THERE'S SPECIAL EMPHASIS TO
MAKE WHO ARE THEY GET
VACCINATED.
MY GUESS IS THEY'LL PROBABLY
WORK AND THEY MAY HAVE TO BE
REVACCINATED WHERE OTHER PEOPLE
WOULDN'T.
THE RESPONSE IS PRETTY GOOD.
THESE PARTICLES, AN EXAMPLE OF
WHAT'S CALLED A T INDEPENDENT
VACCINE BECAUSE THEY HAVE
MULTIVALENT COMPONENTS.
THEY ACTUALLY CAN GENERATE
REASONABLE RESPONSES LIKE FOR
INSTANCE IN MICE THAT HAVE NO T
CELLS LEFT WHATSOEVER.
>> [INDISCERNIBLE]
>> FOR THE PEOPLE BACK HOME, THE
QUESTION WAS WAS THERE --
CHALLENGE BECAUSE OF
IMMUNOGENICITY.
THERE WAS NO COMPETITION.
FIRST OF ALL NONE OF THIS IS
PUBLISHED SO I CAN'T SAY A WHOLE
LOT ABOUT THIS.
BUT FROM A REGULATORY POINT OF
VIEW WE HAD TO SHOW
NON-INFERIORITY.
YOU HAVE OTHER TYPES.
IT STILL MAY BE WAY OVER WHAT WE
NEED FOR PROTECTION BUT BECAUSE
IT'S GONE DOWN A LITTLE BIT THE
REGULATORS ARE GOING I DON'T
KNOW.
SO THAT PART WAS CHALLENGE.
IT WASN'T CHALLENGING TO GET
GOOD RESPONSES ALL THE TIME BUT
TO ACTUALLY SHOW NON-INFERIORITY
THAT IT WASN'T EVEN A LITTLE BIT
LOWER, OKAY.
THAT WAS THE CHALLENGE, YOU
KNOW.
SO BEYOND ANY SHADOW OF A DOUBT
THAT IMMUNOGENICITY.
THERE DOESN'T SEEM TO BE LIKE A
WHOLE LOT OF COMPETITION BETWEEN
THE TYPES BETWEEN ANTI-BODIES.
>> [INDISCERNIBLE]
>> THE ANTI-BODIES IS DIFFERENT.
DO YOU MEAN THE ACTUAL
INFECTION?
>> [INDISCERNIBLE].
>> WE DON'T HAVE, THE QUESTION
IS WHETHER THE PROTECTION,
WHETHER THE PROTECTION IN ORAL
WOULD BE ANY DIFFERENT BECAUSE
OF THE TRANSDATION OF
ANTI-BODIES.
AGAIN, WE THINK THAT PROTECTORS
MAINLY DUE TO EXUDATION OF SITES
OF TRAUMA.
BUT THE ORAL CASE IS REALLY
INTERESTING BECAUSE WE THINK
THAT THE VIRUS HAS TO BIND THE
BASEMENT MEMBRANE.
ANATOMICALLY THE TONSILLAR CRYPT
IS EXPOSED.
IF IT'S EXPOSED IT SHOULD BE
EXPOSED TO ANTI-BODIES MOVING
OUT.
THESE ARE IMIMMUNOLOGICAL SO MY
GET IS THE PROTECTION IS STRONG
THERE AS WELL.
SO FAR THE DATA WE LOOKED AT IS
KIND OF PRELIMINARY DATA.
AND AGAIN WE DON'T KNOW -- IT
LOOKS LIKE THEY HAVE SIMILAR
LEVELS OF PROTECTION.
JUST IN TERMS OF WE DON'T HAVE
ANY DATA BUT IF I WOULD HAVE TO
PREDICT BASED UPON WHAT I KNOW
ABOUT THE BIOLOGY I WOULD
PREDICT THAT WE WOULD GET
PROTECTION.
AGAIN, NOT BASED UPON ANY DATA.
THE VACCINES ARE NOT LICENSED
FOR PROTECTION AGAINST ORAL
PHARYNGEAL CANCER.
WE CAN'T USE IT IN ANY OF THE
COST EFFECTIVENESS MODELING OR
ANYTHING.
IT'S NOT LICENSED FOR THAT
INDICATION.
DO I THINK IT'S ACTUALLY GOING
TO BE A BENEFIT OF THE VACCINE?
YES.
BECAUSE ONE IMPORTANT POINT IS
THAT IT WASN'T CLEAR BEFORE.
IT'S POSSIBLY ORAL PHARYNGEAL
INFECTIONS FOR INSTANCE ACQUIRED
DURING BIRTH FROM A MOTHER THEY
JUST SAT THERE FOR A LONG TIME
AND E VERY MUCHLY GOT INFECTION.
THEY WEREN'T SEXUALLY
TRANSMITTED.
WE THINK THEY WERE SEXUALLY
TRANSMITTED NOW LOOKING AT THE
EPIDEMIOLOGY FOR THE MOST PART.
EVEN IF THEY DON'T PROTECT FROM
THE INFECTION PROCESS ITSELF, IF
THE VACCINE OVERALL'S PREVENTING
GENTLE EXPOSURE THE CAVITY IS
DIMINISHED AND INDIRECTLY IT
WILL PROTECT AGAINST THOSE
INFECTIONS.
IT MAY TAKE LONGER TO SEE THE
PROTECTION.
I THINK IT COULD WORK ONE WAY OR
ANOTHER DIRECTLY OR INDIRECTLY.
OKAY.
>> OUR NEXT SPEAKER IS -- VERMA.
HE GOT HIS PH.D. IN INDIA.
SUBSEQUENTLY HE WAS AT THE BIO
CHEMISTRY DEPARTMENT AT GEORGE
WASHINGTON UNIVERSITY.
CAME TO NCI IN 2006.
HE'S IN THE EPIDEMIOLOGY
RESEARCH IN THE METHODS AND
TECHNOLOGY BRANCH.
AND THE TITLE OF HIS TALK,
CANCER EPIGENETICS.
>> THANK YOU FOR THIS
OPPORTUNITY TO DISCUSS A CANCER
EPIGENETICS.
THIS IS -- HOW YOU COMPARE
GENETICS WITH EPIGENETICS.
I'M -- WITH THIS PROBLEM AS YOU
SEE, MOSTLY IN MEN THAN WOMEN --
AND CARDIOVASCULAR DISEASE IN
TERMS OF -- IN 2010 THERE WERE
ESTIMATELY 13 MILLION CANCER
SURVIVORS IN THE UNITED
STATES -- HAVE ACHIEVED BUT --
THIS PROBLEM.
IN CANCERS LIKE BREAST, ***,
COLON, PROSTATE AND LUNG IT
TAKES MANY YEARS TO DEVELOP --
IDENTIFY SUCH MARKERS --
FOLLOWING OUR PROGRAM OUR
PROGRAM IS EPIDEMIOLOGY --
FOLLOW UP AFTER TREATMENT ALSO.
WE DO [INDISCERNIBLE] TO SEE
THIS ONE ARE GETTING RESPONSE
AND WHICH TREATMENT IS GOOD FOR
THE TRIALS.
SO WE KEEP TRACK OF -- TO
IMPROVE THE QUALITY OF LIFE.
OUR MAIN FOCUS IS TO DETECT
EARLY, WHAT ARE THE MARKERS SO
THAT WE CAN USE IN COMBINATION.
GENETIC MARKERS -- AS YOU SEE
HERE A DIFFERENT THIRD GROUP,
DIFFERENT KIND OF MARKER STILL
THERE ON THE LEFT.
DEVELOPMENT OF -- IN SOME CASES,
IN SOME CANCERS THOSE MUTANTS
ARE GENE IDENTIFIED BUT IN SOME
OTHER CANCERS WE DO NOT KNOW.
SO IN GENOMICS -- USUALLY ONE OR
TWO WERE THERE -- IN WHICH
CHROMOSOME GENES ARE AND GREW
VERY RAPIDLY BECAUSE OF THE
TECHNOLOGY DEVELOPMENT.
AND BY NOW WE HAVE SO MANY
CHROMOSOMES WHICH WE HAVE
IDENTIFIED.
140 -- AND THESE ARE THE ONES
THAT HAVE BEEN SHOWN TO US.
NOW IF YOU SEE ABOUT THIS CANCER
HOW THE DISTRIBUTION OF THE
TRANSMUTATIONS IS THERE.
IN CHILDREN THE MUTATIONS ARE
DIFFERENT THAN IN ADULTS.
BUT THESE ARE THE FREQUENCIES.
AND AFTER -- COME UP WITH A
MODEL THAT BASICALLY --
MUTATIONS ARE ABOUT IN THE 40'S.
AND THERE ARE OTHER -- THOSE ARE
THE KEY COMMON TO MOST OF THE
CANCERS.
EPIGENETICS IS GOING TO SEE -- I
TELL YOU WHAT YOU ACTUALLY WILL
SEE.
IN CANCER, INITIALLY IT WAS A
JOY IT IS I'M GENETICS DISEASE.
IT MAKES YOU MORE PRONE TO
CANCER [INDISCERNIBLE] WITH EPI
GENIC -- FOR DISTINGUISHED
GENETICS -- AND THEN THIS WAS
STUDIED -- WHETHER IT IS IN
CARDIOVASCULAR DISEASE -- SO
THAT GAVE THE IDEA THERE IS
SOMETHING ELSE ALSO.
AND FROM THAT ONCOGENOMIC -- AND
ENVIRONMENT OF THE -- THIS
AFFECT THE GENESIS AND
EPIGENESIS.
GENOME IS EFFECTED -- DO DEVELOPMENT.
IT CHANGES WITH THE TIME.
IF YOU WANT TO FIND OUT EPI
GENOME SYSTEMS -- AT THE SAME
TIME IN SOME DISEASES LIKE
NEUROLOGICAL DISORDERS -- CANCER
AND OTHER DISEASES IT IS EVEN
JEAN SUS-- WHICH HAS BEEN DONE.
AND SOME COHORTS -- IN THESE
STUDIES ARE BEING CARRIED OUT --
ANOTHER POINT I WOULD LIKE TO
MAKE THAT EXTRA-THINGS LIKE
TRANSCRIPTION -- THEY ARE WHICH
WILL HAPPEN.
AND THEN CHANGES -- FOR A LONG
TIME THEN ONLY BENEFITS SOME.
IT IS BETTER TO FOCUS -- IN FEW
CANCERS THOSE CHANGES HAVE
BEEN -- TRANSLOCATIONS AND
AMPLIFICATIONS -- HAS BEEN DONE
IN GENESIS.
NOW EPIGENESIS HAS BEEN DONE --
CHANGES ARE THERE THAT ARE
IMPORTANT AND THEN -- INITIALLY
THESE ARE IMPORTANT AND EXTERNAL
FACTORS DO CONTRIBUTE TO THE
DISEASE.
BUT IN THE ADULT LIFE IT IS
MORE -- TO STUDY EPIGENETICS,
YOU CAN COLLECT THE SAMPLES AND
FOLLOW UP.
SO IF YOU SEE -- NOT ONLY HER
LIFE -- ARE AFFECTED.
AND -- GENERATION.
AND WHEN -- CHANGES IN
MUTATION -- THE NUMBER OF
EPIGENESIS IS MUCH MORE THAN --
ENVIRONMENT WE ARE THE DIFFERENT
AGENT WHICH AFFECT EPI
GENOME -- CHROMIUM, NICKEL --
AND IN THIS INITIAL MECHANISM IT
IS NOT MUTAGENIC SO IN THIS --
AND THEN THESE WERE IDENTIFIED
WHICH WERE -- ESPECIALLY IN --
AND BEARS ON THAT CONDITION FOR
COUNT WHICH WAS CONCLUDED THAT
IN -- AS YOU KNOW -- NEUTRALIZES
THE CHARGE -- AND EPIGENESIS
THESE ARE STABILIZERS BUT
THERE'S NO CHANGES IN THE
SEQUENCE -- BUT NOW THIS
METHYLATION HAVE BEEN ACCEPTED.
SO WHAT GENESIS PROVIDES US,
THAT TELLS US WHAT CAN BE DONE.
THESE ARE THE BLUEPRINTS -- BUT
WHEN IT SHOULD BE DONE, HOW LONG
IT SHOULD BE DONE, WHEN IT
SHOULD BE STOPPED.
AS I MENTIONED THE COMPONENTS OF
EPI GENOME.
THEY ARE THERE DNA, ALONG WITH
THAT WE HAVE MICRO RNA THAT ARE
PART OF THE EPIGENESIS
RESOLUTIONS.
IN THE CHROMOSOME -- EXPRESSION
OF THE GENE IS EFFECTED.
ALONG WITH THAT -- THEY ARE ALSO
IMPORTANT WHICH ARE ENROLLED IN
CHROMATIN.
AND HISTONE GETS MODIFIED AND
THE MODIFICATION ARE THERE.
ALONG WITH ALL THESE THINGS IN
GENOME STUDY -- THEY ARE
ENROLLED IN -- EPI GENOME, A LOT
OF THE STUDIES HAVE BEEN DONE TO
SHOW THE IMPORTANCE OF THIS
SEQUENCE.
EPIGENESIS -- ANY KIND OF
GENETIC -- IT HAPPENS BY
METHYLATION -- IDENTIFIED THE
METHYLATION -- IN HISTONE
DEFENSE MODIFICATIONS HAVE BEEN
IDENTIFIED AND THE
NON-COATING -- ALL THESE THINGS
WORK TOGETHER.
THE IDEA IS THAT WHENEVER THESE
KIND OF STUDIES ARE DONE --
WHENEVER YOU SEE THESE
SEQUENCES -- 60 SECONDS OR 70
SECONDS -- THEY ARE NOT
METHYLATED BUT IN TUMOR
SUPPRESSOR GENES THEY ARE
METHYLATED CALLED HYPER
METHYLATION -- AT THE SAME
TIME -- ONCOGENE.
SO IT DEPENDS WHICH GENE YOU ARE
STUDYING.
HAVE BEEN THE PRIMARY WORKER IN
EPIGENESIS AND THEY ARE
INDICATED THAT IN -- HISTONE
IS -- AND METHYLATION OF
LYSINE -- TRANSFERASE ALSO.
IF YOU SEE AT THE TIME WHEN --
THESE CHROMOSOMES ARE --
GRADUALLY HYPER METHYLATION
STARTS -- THE DOSE FACTORS WHICH
ARE IMMEDIATE FOR GENE
EXPRESSION -- MORE COMPLEX.
THESE HAVE BEEN IDENTIFIED IN
DIFFERENT PROTEINS HAVE BEEN
IDENTIFIED.
DURING MOST OF THE -- GLOBALLY
ALL DNA HYPER METHYLATED BUT IN
GENE -- HYPER METHYLATION --
AND -- AND NORMAL INCREASE,
DECREASE AND NO CHANGE.
THE METHYLATION OF ONE ONLY OR
ONE ALLELE AND ANOTHER IS -- IT
CAN HAPPEN WHEN ABNORMAL IS
THERE THEN ONCOGENE
ACTIVATION -- ESPECIALLY IN GENE
THERAPY THAT WAS STARTED IN
EARLY 90 WHEN THOSE -- GENETIC
PHENOMENON.
THEY DID NOT MOVE AND WHAT WAS
THE REASON.
THAT WAS THERE AND INCREASE THE
DNA AND POSSIBLY -- IF NO CHANGE
IS DONE -- BOTH CAN HAPPEN.
NOW -- FURTHER IDENTIFIED AND
WHAT I HAVE SHOWN IS -- NETWORK.
USE TO STUDY ONE OR TWO -- THE
PATHWAY IS POSSIBLE, AND
SIMILARLY A LOT OF -- MICRO RNAS
ARE STUDIED.
EITHER MICRO RNA CAN TELL
WHETHER SOMEBODY IS AT HIGH RISK
OF THE CANCER OR NOT.
OR THE MICRO RNA THAT HAD SOME
CHANGES -- METHYLATED OR
NON-METHYLATED AND DECIDE
WHETHER MICRO RNA WILL BE ACTIVE
OR NOT.
SO TRANSCRIPTION ALSO -- IN
HISTONES AS I MENTIONED, THESE
ARE THE MODIFICATIONS WHICH HAVE
BEEN IDENTIFIED -- AT NIS WE
INITIATED ONE PROGRAM CALLED
HUMAN EPI GENOME -- MATURATION
PROFILE OR HISTONE PROFILING OF
CHROMATIN -- SHOULD BE DONE.
SO DURING THAT TIME --
MODIFICATION, HIGH QUALITY
MONO -- ARE NEEDED.
THE PROGRAM WE HAD MADE AND WE
DISTRIBUTE TODAY.
HISTONES ALSO -- DEFENSE
LOCATION WHEN SOMETHING IS
CHANGED, THE HISTONE
MODIFICATIONS ARE THERE -- AND
THIS IS -- HISTONE MODIFICATION
LIKE CROSS LINKING DNA COMPLEX
AND THEN IMMUNOCLASSIFY CASE.
DNA IS HYPER SENSITIVE.
-- RICH CHROMATIN -- SO IN PAST
FEW YEARS BECAUSE OF THE
EPIGENESIS -- AND LAST YEAR
REPRESENTATIVE WE ARE MOW
EMPHASIS ON EPIDEMIOLOGY.
AND THIS I DID A FEW YEARS
AGO -- ABOUT MODIFIER FACTOR AND
HOW THEY ARE CORRELATED
GENETICALLY OR EPI
GENETICALLY -- THE BIO MARKERS
WE HAVE EMPHASIZED WE ISOLATE --
AND TWO TIMES I HAVE
INTERVIEWED -- I EMPHASIZE IN
ONE INTERVIEW THAT IF YOU
COMPARE GENETICS OR EPI
GENETICS -- SO YOU CAN USE -- IF
YOU HAVE MUTATIONS OR ANYTHING
YOU CAN JUST USE WHAT IS FOLLOW
UP BUT EPI GENETICS YOU HAVE
ADVANTAGED AND MANY COMPANIES --
THEY ARE INVESTING BY JOHNSON
AND JOHNSON -- ALL THOSE HAVE
PROGRAMS ABOUT HISTONE REGARDING
METHYLATION.
ALL THOSE PROGRAMS ARE HIGH
NUMBER.
FOR NOW METHYLATION -- AND THE
DEFENSE IS -- AND FOR
METHYLATION -- WHICH CAN
DISTINGUISH METHYLATED DNA FROM
UNMETHYLATED DNA.
AFTER THIS TREATMENT -- AND THIS
IS SHOWN THIS TREATMENT CAN
CHANGE METHYLATED VERSUS
NON-METHYLATED.
AND DEPENDING ON YOUR PROJECT --
OR YOU CAN USE METHYLATION -- OR
IF YOU WANT TO DO REAL TIME --
DEFENSE TECHNOLOGIES HAVE
DIFFERENT OBJECTIVES.
AT THE SAME TIME WHEN YOU DO
METHYLATION ANALYSIS, YOU DO --
YOU HAVE TO KNOW HOW MUCH IS THE
TOTAL METHYLATION -- HOW MUCH
WAS THE -- OR GROUP OF GENE WHAT
WAS THERE AND PROFILE OF
METHYLATION [INDISCERNIBLE] HOW
MANY NUMBER OF GENES ARE
INFECTED.
THIS WE PLAN BEFORE SO THAT WE
HAVE -- RESULTS.
IN BOTH PROTEINS WHICH ARE EPI
GENETICALLY REGULATED -- FROM
JOHNS HOPKINS, AND HE HAS
IDENTIFIED WHICH -- AND HE HAS
DONE SOME CLINICAL TRIALS.
DEPENDING ON THE LOCATION --
WHICH IS THE EFFECT, WHICH
MODIFICATION WILL AFFECT -- A
LOT OF THIS HAS BEEN DONE.
AND CANCER DEVELOPMENT IS
DIFFERENT -- ARE SHARED FROM
TUMOR.
AND THEY ARE FOR METHYLATION
ITSELF -- YOU CAN COLLECT
SOMETHING AT DIFFERENT TIMES.
THIS IS A LIST WHERE THE -- MANY
CANCERS -- AND IN DEFENSE
CATEGORIES YOU WANT TO SEE --
TRANSFERASE -- WHICH HAVE BEEN
IDENTIFIED IN CANCERS THAT ARE
AFFECTED.
AS I MENTIONED, THAT THESE EPI
GENETIC EXCHANGE CAN REVERSE --
SO SOME OF THESE ARE SHOWN
HERE -- AND GENES THAT ARE -- SO
THESE ARE FOR THE -- OR HISTONE
IN BOOKS THAT HAVE BEEN DONE.
THEY HAVE BEEN DISCOVERED AS
ANOTHER -- SOME KIND OF SIDE
EFFECTS AS WITH HAPPENS -- AND
TO CATEGORIZE IN DEFENSE --
HISTONE TRANSFERASE OR --
INHIBITOR OF THOSE AGENTS WHICH
ARE EITHER IN CHARGE OR HAVE
BEEN -- OR THEY HAVE BEEN
MODIFIED.
IN DIFFERENT CATEGORIES THEY ARE
IDENTIFIED VERY VERY WELL.
AND THEY BELONG TO DEFENSE
CATEGORIES LIKE -- LIKE YOU WANT
TO USE THE SMALL -- THAT HAS
BEEN DONE.
AND THEN THIS KIND OF -- ONLY
ONE TIME AND NOW WE HAVE -- 11.
THEY ARE TRYING TO FIND OUT HOW
THEY CAN -- SO THESE ARE --
WHICH ARE ANOTHER KIND OF -- AND
MANY TIMES THEY WORK IN
COMBINATION ESPECIALLY WITH PARP
INHIBITOR AND THEY WORK --
PROCESS.
NOW I WILL GIVE YOU FEW
EXAMPLES.
THIS IS A CLINICAL -- WITH EPI
GENETIC MODULATION WITH --
THEN -- SIGNIFICANT IMPROVEMENT
AND THESE WERE SUCH A GROUP --
THERE ARE OTHER TREATMENTS WERE
NOT WORKING.
IN ANOTHER ONE, COMBINATION
OF -- RECOGNIZE -- IN
COMBINATION THAN IT WAS TESTED.
THEN PATIENTS STARTED GIVING
RESPONSE.
IF YOU SEE OR IF YOU WANT TO
CHECK HOW MANY TRIALS ARE GOING
ON OR NIH CLINICAL TRIALS
ESPECIALLY AT NIH -- HISTONE
INHIBITORS HAVE BEEN USED --
LYMPHOME, LEUKEMIA, BREAST
CANCER -- SOME ARE COMPLETELY
AND SOME STILL ARE -- AND THEY
ARE BEING FOLLOWED.
THIS IS ABOUT -- AND COHORTS
ARE -- BUT WE ENROLL IN --
IDENTIFIED THE -- MULTIETHNIC --
WE IDENTIFIED SOME MARKER NOW
SINCE WE HAVE SAMPLES BEFORE YOU
CAN GO BACK AND SEE THEM.
THESE ARE FOR HISTONES AND THESE
ARE FOR MATURATION INHIBITORS.
YOU CAN SEE IN -- THEY HAVE
INTEREST IN THAT.
IN TREATMENTS -- YOU CAN SEE
THAT REPRESENTATIVE -- KIND OF
SEQUENCE WE DO -- GENETIC
CHANGES ARE THERE -- CHANGES
ARE -- BUT IN TERMS OF TREATMENT
EPI GENETIC -- AND THESE ARE
BOTH THAT WHICH HAVE BEEN
APPROVED -- METHYLATION -- THIS
IS NOT ONLY IN THEORY BUT IT
IS -- FOR EXAMPLE THIS WAS SMALL
LUNG CANCER WHERE EPIGENETICS
WAS SUCCESSFUL -- THIS ONE WAS
FOR -- THE NOW A FEW EXAMPLES I
WILL GIVE LIKE COLON CANCER.
THESE ARE SHOWN WHICH ARE -- TO
EXPLOIT THAT AND IN THIS ALSO,
IN LAB -- WAS IDENTIFIED IN
COLON CANCER ESPECIALLY WHICH IS
CALLED -- MET LATER PHENOTYPE --
MANY TIMES PEOPLE DID NOT KNOW
WHICH IS THE HIGHEST OR THE
LOWEST AND -- NOT DISTINGUISH
BUT THEN SINCE THE PHENOTYPE WAS
DISTINGUISHED -- INTEGRATION OF
EPIGENETICS -- ALL YOU SEE HERE
THE MUTATION IS VERY COMMON IN
COLON CANCER -- ALONG WITH THAT
MICRO -- ARE THESE FOR
METHYLATION, HYPER METHYLATION.
FIRST COMBINATION WAS USED AND
THEN -- CAN BE IDENTIFIED.
SOMEONE IS -- OR IT HAS THE
MUTATION AND HYPER METHYLATION
AND PHENOTYPES THEN THEY ARE AT
VERY HIGH COLON CANCER.
IN IML -- IMMEDIATE LATION
PROFILING, BOTH POPULATIONS
COULD BE IDENTIFIED AS -- IN THE
LUNG CANCER GENES ARE REGULATED
BY METHYLATION.
ALONG WITH THAT IF YOU
INCLUDE -- OR SOME GENOMIC
MARKERS THEN YOU GET
SENSITIVITY -- SCREENING OR
FOLLOW UP OF TREATMENT.
AND HERE IS THE MARKER.
NOW, I MENTIONED ABOUT -- A
NUMBER OF -- BE FOLLOWED FOR
METHYLATION PROFILING.
NOW COMES INTERFEBRILE CANCER --
SO IN THE SAME PATIENT THIS --
BUT THIS CAN BE QUANTITATED ALSO
METHYLATED G1, YOU CAN
CALCULATE.
AND SOMETIMES THAT MATURATION
PROFILING YOU CAN CORRELATE WITH
SURVIVAL ALSO -- THIS CANCER AND
OVARIAN CANCER THIS IS SUCH
INCIDENCE AND EQUIVALENTS -- BY
THE TIME YOU DETECT IN ONE OR
TWO IT'S TWO LATE.
SO EARLY MARKERS ARE NOT THERE.
THE CANCER IS -- SOMEBODY'S
ALCOHOLIC, LONG -- THEN 216 AND
214 IF THEY ARE METHYLATED --
LIKELY TO CANCER.
THAT ALSO IMPLIES THAT WHENEVER
THE PATIENT -- THEN WE TAKE
PATIENTS AND -- BACKGROUND AND
ALL THAT IS VERY USEFUL.
-- LIKE ALCOHOLISM OR DIABETES
OR OTHER DISEASES -- IN BREAST
CANCER ALSO A LOT OF PEOPLE WERE
FOLLOWED SIMULTANEOUSLY.
AND IN THAT TREATMENT -- ALONG
WITH METHYLATION PROFILING.
IN BREAST CANCER, THERE ARE
LEVELS OF METHYLATION
PROFILING -- CAN DISTINGUISH
HIGHEST POPULATION --
POPULATION.
YOU HEARD ABOUT -- CANCER BEFORE
SOME TIME.
WE HAVE 15-20% CANCER -- OR HHV8
SARCOMA, HEPATITIS B, LIVER
CANCER.
SO THOSE ARE THERE AND
ESPECIALLY ASSOCIATED NUCLEAR --
EPSTEIN BARR VIRUS -- THOSE WERE
IDENTIFIED WHICH WAS -- AND
THOSE WERE THE VIEWS WHICH
TYPICALLY THEY HELPED IN GETTING
INTEGRATED VIRUS.
TIMES WHENEVER VIRAL LOAD --
INTEGRATED BUT BOTH SHOULD BE
DONE.
AND IN MANY CASES, IT HAS BEEN
OBSERVED THAT THESE VIRUSES ARE
AFFECTING -- LUNG, AND PROSTATE,
MANY PLACES.
IN LAST FEW YEARS COMPLETE OF
HPV -- THAT HAVE BEEN DONE BY --
AND WHY YOU NEED THIS KIND OF
STUDIES, BECAUSE WHEN THERE
ARE -- THEN ALSO WE CAN TELL
WHO -- OR NOT.
THOSE KIND OF APPROACHES -- WITH
THOSE KIND OF -- CAN BE DONE.
AND HERE THIS IS SHOWN THAT LIKE
EARLY -- ALLEGING HOW MUCH
METHYLATION IS THERE, ALL THOSE
THINGS WE KNOW ABOUT -- ON HOW
MUCH METHYLATION -- THOSE ARE
VERY VERY -- IN HEPATO CELLULAR
CARCINOMA -- ONLY IN ONE
POPULATION -- THESE KINDS OF --
OTHERWISE HEPATO-- IN B CELLS
AND C CELL DEVELOPMENT -- NOW IN
PROSTATE CANCER -- LESS THAN 4
NANOGRAMS -- WHETHER THEY
DEVELOP THE CANCER OR NOT.
IN THAT -- METHYLATION IS COMING
UP AS A VERY STRONGER MARKER.
SO YOU HAVE THE LIVER FROM -- IN
THE SAME PATIENTS WERE ALSO
FOLLOWED.
AND AFTER SOMETIME LUNG
COMPANIES INTERVIEW -- EPI
GENOMIC AND DIAGNOSTIC ACQUIRED
OF THAT.
THIS IS OUT IN WHICH -- CANCER
IS DETECTED BY ALMOST --
MATURATION ALSO.
IN BLADDER CANCER WE EMPHASIZE
ANY TIME YOU DIAGNOSE -- THE
SAMPLE SHOULD BE NON-INVASTIVELY
COLLECTED FOR ANY -- IN THIS
CASE -- THAT WAS FOLLOWED FOR
MET LATION AND BLADDER CANCER
COULD BE FOLLOWED.
NOW, MANY TIMES MULTIPLE CANCERS
IN PATIENTS OR ONE CANCER IS
DEVELOPED IN ONE SITE AND
THEN -- IN OTHER ORGAN CYCLES
ALSO.
THESE METHYLATION PROFILING IN
CANCER IN THE SAME PERSON CAN
ALSO BE FOLLOWED AND -- IN
CALIFORNIA -- DIET PLAYS A ROLE
IN MANY OF THESE DNA --
PROPERTIES, HISTONE
MODIFICATIONS.
THEY ARE PRESENTING IN DIET.
SOME MODELS HAVE BEEN IDENTIFIED
WITH -- OF CANCER AND ALL THAT
BUT A LOT OF THING HAVE BEEN
DONE.
AND IN CANCER -- IF YOU CHANGE
DIET -- THOSE CANCERS THE
STUDIES ARE -- NOW THESE ARE THE
EXAMPLES OF COMPOUNDS I HAVE
SHOWN -- WHICH ARE EITHER
HISTONE DEACETYLATING OR --
PROPERTIES.
IF YOU SEE MATURATION AND
CLINICAL -- AND SOME HAVE
METHYLATION AND HISTONE -- BOTH
HAVE BEEN IDENTIFIED.
AND IF YOU SEE -- ABOUT
COMPOUNDS, COMPOUNDS WHICH ARE
IDENTIFIED IN ACTIVE COMPONENTS.
THEY HAVE BEEN CHARACTERIZED FOR
THE -- AND THESE ARE DIFFERENT
COMPOUNDS FROM THESE -- AND
SOMETIMES HISTONE -- THAT WILL
BE MODIFIED MORE AND SOMETIMES
LESS -- HAS BEEN DONE TO -- AND
IF YOU HEAR ABOUT THE --
MEDICINE THESE COMPOUNDS ARE --
AND THOSE HAVE ALSO BEEN
IDENTIFIED -- ALONE.
NOW, JUST BY CHANGING THE DIET,
WHAT KIND OF MODEL HAVE BEEN
ACQUIRED WHERE YOU CAN DEVELOP
THE SAME KIND OF FEATURES WHICH
ARE IN ANY -- NO CARCINOGEN OR
OTHER -- NOW REGARDING WHAT YOU
SHOULD DO -- SOMETIMES WE NEED
AT LOW LEVELS AND SOMETIMES WE
NEED AT HIGH LEVELS -- YOU HAVE
TO KNOW WHICH WAY YOU WANT TO
DO.
IN MICRO RNA AS YOU KNOW -- AND
THEN CANCER -- BOTH HAVE BEEN
IDENTIFIED AND THESE HAVE
BEEN -- AND IN CANCER CELLS --
MICRO RNA.
THESE ARE THE MICRO RNA
IDENTIFIED IN DIFFERENT CANCERS.
SO USUALLY THEY ARE PROFILING --
WHENEVER YOU HAVE A SAMPLE.
SO DON'T DO ONE TEST BUT DO MANY
TESTS.
MICRO RNA PROFILING -- IF YOU
HAVE -- FORMATION ALSO, THAT HAS
BEEN VERY USEFUL.
NOW THESE ARE SUCH PROGRAMS IN
WHICH EPI GENOME WAS ONE OF
THEM.
TIMES THE MECHANISM -- AND
EPIGENESIS -- THEY DECIDED TO
FOLLOW A WHOLE EPI GENOME.
ALL OF THOSE -- AND THESE ARE
THE DISEASES THAT ARE
REPRESENTATIVE -- AND WHAT
HAPPENS BUT IN THIS INSTITUTE
WILL CONTRIBUTE MONEY FOR THAT
AND 1.5% OF -- SO THAT YOU
CAN -- AND THEN DIFFERENT
INSTITUTES CAN TAKE THE RESULTS
FROM.
AND THIS IS EIGHTY IN 2008 --
AFTER 2015 THE COMMITMENT IS
THERE FOR 219 AND NOW -- BECAUSE
NOW WE ARE AT THE STAGE WHERE WE
HAVE THE POPULATION AND
COMPOUNDS HAVE COME WHICH ARE
PROMISING -- AS WELL AS
DISCIPLINES ALSO BEING DONE IN
THERE.
AFTER THESE CHARGES -- THEN IN
EUROPE -- HUMAN EPI GENOME
CONSORTIUM.
YOU REALIZE WITHOUT WHATEVER IS
LEFT THAT WE WANT TO DO.
SO WHAT THEY DID FROM DISEASE
SAMPLES -- BUT THE NCI WE HAVE
PCG PROGRAM, CANCER GENOMIC
ANATOMIC PROGRAMS IN WHICH --
THEN THEY ARE CHARACTERIZE HOW
MUCH MUTATIONS ARE THERE, HOW
MUCH -- HIGH QUALITY.
SIMILARLY EUROPE -- SO THAT IS
THE -- BUT WE ARE PART OF THAT
ALSO AS REPRESENTATIVE TO CHECK
THERE IS NO OVERLAP AND
INFORMATION IS COMPLETED IN
HERE.
WE HAVE INITIAL MEETING AT
IHEC -- IN WHICH THESE ARE
ENROLLED IN IHEC PROGRAM.
DIFFERENT FUNDING AGENCIES THEY
ARE CONTRIBUTING UNTIL
COMPLETE -- SCIENTIFIC
FOUNDATION -- ARE THERE.
AND -- ABOUT THIS PROGRAM.
AACR, THEY ARE VERY MUCH
INTERESTED.
SO IDEALLY COME THAT WHEN THEY
DO -- REFORM AND MICRO RNA --
AND AS YOU KNOW -- PERSONALIZED
MEDICINE -- NOW WE ARE WHERE WE
CAN FOLLOW UP GENESIS OR
EPIGENESIS WE CAN FOLLOW --
THERE ARE OTHER BENEFITS ALSO.
WE HAVE TO THINK ABOUT THESE --
COMBINED THERAPY.
THEN ON THIS WE CAN -- AND THESE
ARE THE -- WHO ARE THINKING
ABOUT USING THESE EPIGENESIS
APPROACHES TO IDENTIFY ETHNIC
GROUPS SPECIFIC FACTOR FOR
IDENTIFYING ALL WE CAN I DON'T
IN COMBINATION OF THESE MARKERS.
BECAUSE SOME CANCERS ARE VERY
MUCH -- PEOPLE HAVE COME FROM --
COUNTRIES SO -- AND ALSO FROM
TIME TO TIME THIS IS CALLED --
GENOME-WIDE STUDIES WERE DONE --
SIMILARLY -- WE ARE TRYING TO
FIND OUT THAT WHAT ARE THE
METABOLITES AND THESE ASSOCIATED
METABOLITES SO THAT WE HAVE --
EPI GENOME INFORMATION AND
METABOLIC INFORMATION.
THEN WE CAN PUT TOGETHER.
AND IN METABOLIC WHEN THEY COME
OUT -- AND THEY JUST LEFT --
VERY VERY USEFUL.
SO ANY PROGRESS -- THINK ABOUT
PHENOTYPE AND GENOTYPE BUT EPI
GENOTYPE IS ALSO THERE WHICH YOU
SHOULD CONSIDER.
AND THESE ARE THE -- AND I WILL
TAKE ANY QUESTIONS.
[APPLAUSE]
YES.
>> [INDISCERNIBLE].
>> THAT IS THAT PLACE WHERE A
LOT OF PROGRAMS -- OKAY THE WAY
RESEARCH WORKS IN HERE MOST OF
THE TIME FROM THE --
INVESTIGATORS WILL SUPPORT --
BUT THE WAY YOU ARE -- THEN THEY
DO -- WHICH IS GOOD TO GET
INFORMATION.
IN OUR PROGRAM, WE WANT TO MA
ACTUALLY ZIPS ALL THIS
INFORMATION IS KNOWN, WHAT IS
HAPPENING FOR ALL THESE --
SEVERE PAIN OR AMOUNT OF PAIN --
IDENTIFY PEOPLE WHO CAN DO THAT.
AND GIVE THEM SAMPLES AT
DIFFERENT TIMES AND ASK THEM
SPECIFICALLY HOW MUCH IS GOING
ON -- WHICH ONE IS MORE WHICH
ONE IS HIGH SO THAT INFORMATION
IS THERE.
THOSE STUDIES ARE NOT IN MANY
NUMBERS BUT THOSE -- ISSUE PUT
FORTH HISTONE MARKERS AND
DEFINITION MARKERS TOGETHER --
AND --
>> [INDISCERNIBLE].
>> BUT IT IS NOT NECESSARY ALL
GENES ARE AFFECTED ALL THE
TIME -- EMPHASIZING THE
ENVIRONMENT.
ENVIRONMENT AND -- SO ALL -- AND
THEY ARE ALSO ENVIRONMENTAL.
SO IN THAT PATHWAY WHAT GENES
ARE AFFECTED.
AND SIMILARLY -- OR SOMETIMES --
THEN ONLY YOU SEE THAT OTHER
GENES ARE AFFECTED.