WELL, WELCOME TO ANOTHER
SESSION IN A COURSE IN BRIDGE
BUILDING WHICH IS OFFICIALLY
TERMED DEMIYSTIFYING MEDICINE
HELD AT THE NATIONAL INSTITUTES
OF HEALTH IN BETHESDA, MARYLAND.
WE'RE NOW IN OUR 22nd YEAR AND
MUST BE DOING SOMETHING RIGHT.
THE PURPOSE OF THIS COURSE IS TO
BRIDGE THE EXCITING DEVELOPMENTS
IN BIOLOGY, ENGINEERING AND
COMPUTER SCIENCES WITH MEDICINE
AND WITH HUMAN HEALTH.
IT IS NOT LAST WEEK'S RESEARCH
SEMINAR.
IT IS MORE AN EXERCISE IN BRIDGE
BUILDING AS EXEMPLIFIED BY THE
PHOTOGRAPH IN THE CONSTRUCTION
OF THE BROOKLYN BRIDGE IN WHICH
WE SEE TWO INDIVIDUALS ON THE
CAT WALK OSTENSIBLY REPRESENTING
ENTIRELY DIFFERENT AREAS OF
KNOWLEDGE AND EXPERIENCE AND
SHARING IDEAS.
THE WHOLE CONCEPT IS WILL
BUILDING BRIDGES IN SCIENCE WILL
FACILITATE NEW IDEAS, NEW
APPROACHES AND SHAKE DOWN
SOMETIMES LONG-ACCEPTED
PARADIGMS.
AND TODAY'S PROGRAM IS AN
ELEGANT EXAMPLE OF THAT AND
WE'LL GET TO IN A MOMENT.
SO, DEMYSTIFYING MEDICINE IS
HELD 3:00 TO 5:00 P.M. EASTERN
STANDARD TIME FROM JANUARY
THROUGH THE MONTH OF MAY.
YOU CAN WATCH IT ON THE
VIDEOCAST LINK SHOWN HERE AND AS
PRESENTED A FEW MOMENTS AGO, THE
CME CODE NUMBER IS 58790.
NOW, WE URGE YOU DURING THE TWO
PRESENTATIONS TODAY TO SUBMIT
QUESTIONS.
AND YOU DO THAT BY CLICKING ON
THE SEND LIVE FEEDBACK WHICH IS
ON YOUR VIDEOCAST DISPLAY.
THESE QUESTIONS WILL THEN FORM
THE BASIS OF WHAT IS INVARIABLY
AN EXCITING EXCHANGE OF IDEAS,
INFORMATION WHICH FOLLOWS BOTH
SPEAKERS.
I BRING TO YOUR ATTENTION THAT
ALL PREVIOUS SESSIONS FOR THE
PAST 22 YEARS ARE AVAILABLE
THROUGH THE VIDEOCAST AT NIH.
THE LINK IS SHOWN ON THE SLIDE
HERE.
THERE'S LINK HOW TO CONTACT US.
THE PROGRAM HAS BEEN GOING ON
SINCE 2003 AND DISTRIBUTED
AROUND THE WORLD IN AS MANY AS
38 DIFFERENT COUNTRIES THAT
PARTICIPATE.
SO TODAY'S SUBJECT IS
HEPATOCELLULAR CANCER.
I'D LIKE TO SAY A FEW WORDS
ABOUT IT WHICH MAY SOMETIMES NOT
BE TOO APPARENT TO THOSE
INTERESTED -- NOT INTERESTED
SPECIFICALLY IN THIS FIELD.
APPROXIMATELY 20 YEARS AGO,
MAYBE A LITTLE MORE, IF A
PATIENT IN AN AMERICAN HOSPITAL
HAT HEPATOCELLULAR CANCER THEY
WOULD BE PRESENTED AT GRAND
ROUNDS.
IT WAS THAT UNUSUAL.
WHEREAS IN CHINA AND JAPAN
HEPATOCELLULAR CANCER WAS THE
MAIN REASON FOR PATIENTS BEING
IN THE HOSPITAL.
WHAT CAUSED THIS ENORMOUS
DIFFERENCE?
AND HOW DO WE NOW GET TO THE
POINT WHERE IN THE WORLD
HEPATOCELLULAR CANCER IS ROUGHLY
THE SEVENTH MOST COMMON IN THE
UNITED STATES?
NOW, IT'S USUALLY ASSOCIATED
WITH CHRONIC LIVER DISEASE,
CIRRHOSIS BUT THERE'S OTHER
SITUATIONS.
FOR EXAMPLE, IN YOUNG AFRICAN
MINE WORKERS DEVELOPED A RAPID
ONSET OF HEPATOCELLULAR CANCER.
TODAY WE'LL LEARN ABOUT ANOTHER
FORM WHICH HAS NOT ATTRACTED
MUCH ATTENTION UNTIL THE WORK
PERFORMED BY ONE OF OUR
SPEAKERS, DR. SIMON.
ONE OF THE BIG PROBLEMS THAT
WHILE TRY TO HEAR HOW DO YOU
REGENERATE A NODULE FROM CORNER
OF CANCER AND IS THERE A WAY FOR
SCREENING FOR THIS?
AND IF YOU DO FIND IT, WHAT DO
YOU DO ABOUT IT?
ONE OF THE THINGS I DON'T OFTEN
EMPHASIZE IS LIVER CANCER IS
FOUND IN THE VERY LATE STAGE AND
THAT'S BECAUSE THE PAIN FIBERS
IN THE LIVER ARE NOT PRESENT
EXCEPT ON THE CAPSULE.
AND THERE'S A HUGE FUNCTIONAL
RESERVE.
USUALLY IF A TUMOR IS IN A
STRATEGIC SITE WHERE IT
OBSTRUCTS A MAJOR BLOOD VESSEL
OR CAUSES A CLINICAL DISEASE YOU
SEE IT AS A PHENOMENON BUT MANY
ARE ASYMPTOMATIC FOR LONG PERIOD
OF TIME.
HOW DO WE DETECT THEM?
AND THE TUMOR IS ALMOST DE NOVO,
PATIENTS NOT SUBJECTED TO MANY
CANCER DRUGS.
HOW DOES THAT HAPPEN?
AND ONE OF THE MAJOR STRESSES --
ONE OF THE MAJOR ASPECTS OF
TODAY'S PRESENTATION IS WHAT CAN
BE LEARNED FROM STUDIES OF RARE
FORMS OF HEPATOCELLULAR CANCER.
AND PARTICULARLY, FIBROLOMELAR
HEPATOCANCER.
OUR TWO SPEAKERS TODAY ARE
DISTINGUISHED IN THIS AREA.
SANFORD SIMON GOT HIS
UNDERGRADUATE DEGREE AT
NEUROSCIENCES AT PRINCETON AND
MASTER'S AND Ph.D. AT NYU AND
WENT TO ROCKEFELLER UNIVERSITY
WORKING WITH GUNTER GLOBEL WHO
IS STILL ONE OF THE LEADING CELL
BIOLOGISTS IN THE FILED.
AMONG HIS CLASSIC STUDIES WAS A
DEMONSTRATION OF A PROTEIN
CONDUCTING CHANNEL IN THE
ENDOPLASM RETICULUM AS PUBLISHED
IN CELL IN 1991.
AND NOW HE'S THE GUNTER BLOBEL
PROFESSOR AT ROCKEFELLER.
AND ABOUT 2013 HIS FOCUS CHANGED
TO CANCER.
AND HE'S PERFORMED A REMARKABLE
SERIES OF STUDIES ON THE RARE
FIBROLOMELAR HEPATAL CANCER.
AND HOW THIS CAME ABOUT WILL BE
PRESENTED IN PART IN HIS
PRESENTATIONS TODAY.
NOW, THROUGHOUT HIS WORK SINCE
2013, THE UNDERLYING THESIS IS
TO FOCUS ON SINGLE EVENTS NOT
GLOBAL.
IN OTHER WORDS, SINGLE PROTEINS,
SINGLE NUCLEAR PORES OR SINGLE
VIRUSES MOLECULES, THAT IS AND
TO PRECISELY IDENTIFY CANCERS TO
IDENTIFY WHAT IS LOST WHEN ONE
AVERAGES ALL THE VARIOUS CHANGES
THAT TAKE PLACE IN A TRANSFORMED
CELL WHICH IS THE USUAL WAY IN
WHICH CANCER STUDIES ARE
PERFORMED.
NOW, AS HE HAS POINTED OUT, THIS
APPROACH ACCELERATES AN
UNDERSTANDING OF MALIGNANT
TRANSFORMATION AND HAS LED TO
CLINICAL TRIALS.
SO SO, HIS CURRENT WORK ON
CHILDHOOD ADOLESCENT AND YOUNG
ADULT CANCERS HAS RUN THE RANGE
THE GAMUT FROM IDENTIFYING
DRIVERS OF MALIGNANT
TRANSFORMATION TO THE DESIGN OF
EFFECTIVE TREATMENT.
THESE ARE MAJOR CHANGES IN THE
PARADIGM OF APPROACH TO CANCER
RESEARCH.
AND WE'RE VERY DELIGHTED THAT
SANDY SIMON HAS BEEN ABLE TO
JOIN US TODAY AND HE WILL BE THE
FIRST SPEAKER.
THE SECOND SPEAKER RECEIVED HIS
MEDICAL DEGREE AT THE ROYAL
COLLEGE OF SURGEONS IN IRELAND
AND MASTER OF HEALTH SCIENCES AT
DUKE UNIVERSITY.
HE TOOK A FELLOWSHIP AT TULANE
WHERE HE WAS ON THE FACULTY AND
CAME TO THE NIH IN 1996.
WHERE HE IS A SENIOR
INVESTIGATOR AND CHIEF OF THE
CLINICAL HEPATOLOGY RESEARCH
SECTION IN THE LIVER DISEASE
BRANCH.
NOW, MARC'S MAJOR FOCUS HAS BEEN
ON CLINICAL STUDIES OF VIRAL
HEPATITIS INCLUDING THEIR
RELATIONSHIP TO HEPATOCELLULAR
CANCER AND RECOGNIZED FOR HIS
EXPERIENCE, KNOWLEDGE, RESEARCH
AND TEACHING ABILITIES.
SO WE'RE VERY GRATEFUL TO YOU
TOO, MARC, FOR TAKING PART IN
TODAY'S PROGRAM.
SO ENOUGH INTRODUCTIONS.
SANDY, PLEASE CONTINUE.
>> THIRST THANK YOU FOR THE
INVITATION TO SPEAK AND
PARTICULARLY THANK YOU FOR YOUR
OPENING INTRODUCTORY SLIDE AS A
BOY WHO GREW UP IN BROOKLYN I
GREATLY APPRECIATE THE PICTURE
OF THE BROOKLYN BRIDGE AND THE
SENTIMENT BEHIND BUILDING
BRIDGES AND REACHING OUT.
TODAY I'LL TELL YOU, AS YOU
HEARD, ABOUT OUR WORK ON FIB
FIBROLAMELLA CARCINOMA AND IF
YOU IDENTIFY THEM YOU CAN MAKE
ADVANCES FOR THAT PARTICULAR
RARE DISEASE AND TAKE HOME
LESSONS TO BE APPLIED TO OTHER
DISEASES AT THE SAME TIME.
THERE'S AN ADVANTAGE IN
PARTNERING WITH THE COMMUNITY
AND IT WAS DESCRIBED AS WHAT YOU
WANT TO BRING IT TO THE KITCHEN
AND HAVE THEM PREPARE THE MENU
AND THE ENTIRE MEAL ALONG WITH
IT.
BY WORKING TOGETHER AS FULL
EQUAL PARTNERS YOU CAN MAKE
TREMENDOUS ADVANCES.
THE THIRD TAKE HOME MESSAGE IS
WITH MODERN SCIENCE AND THE
CHANGES THAT HAVE BEEN OCCURRING
IN TECHNOLOGY WITH OUR
UNDERSTANDING OF THE PAST FIVE
OR 10 IS YEARS WE'RE ON THE CUSP
OF A MAJOR REVOLUTION NOT ONLY
UNDERSTANDING BASIC PHYSIOLOGY
BUT UNDERSTANDING THERAPEUTICS
FOR THE PATHOLOGIES.
AND FROM THE WORK IN
FIBROLAMELLAR WHICH IS
RELATIVELY A RARE CANCER.
IF YOU'RE NOT FAMILIAR IT'S
FIRST DESCRIBED BACK IN THE LATE
'50s ON THE RIGHT IS A
HISTOPATHOLOGY AND SURROUNDED BY
FIBROTIC BANDS, LAMELLAR AND
THERE'S MISDIAGNOSIS.
PEAK DETECTION IS 26 YEARS WITH
MOST PATIENTS BETWEEN YEAR FIVE
AND 40 YEARS OLD.
IN THE U.S. IS 1 IN 5 MILLION
BUT IT'S BEEN MISSED AND UNDER
DIAGNOSED.
IT PRESENTS AS PRIMELY LIVER
TUMOR AS A SINGLE MASS.
THERE'S NO UNDERLYING DISEASE.
FEW SYMPTOMS NOT ASSOCIATED WITH
OTHER RISK FACTORS.
IT'S CODIFIED AS A SUB VARIANT
OF A CARCINOMA.
AS A RESULT MOST PATIENTS ARE
STILL TREATED AS A THEY ARE HAVE
AHEMATO CARCINOMA.
THERE'S NO SYSTEMIC CHEMO OR
THERAPIES AND THE CURRENT
MANAGEMENT IS RESECTION.
WHEN WE STARTED WORKING ON THIS
A DECADE AGO IT WAS NOT OWN AS
ONE DISEASE OR MA MANY DISEASES
WITH A COMMON HISTOPATHOLOGY.
IS IT GENETICALLY INHERITED OR
SOMATICALLY ACQUIRED.
AND APRIL 8, 2008, MY DAUGHTER
IS 12 AT THE TIME WAS DIAGNOSED
WITH FIBROLAMELLAR CARCINOMA.
AT THE TIME IF YOU LOOKED AT THE
CURVE FOR SURVIVAL SHE HAD ZERO
PERCENT SURVIVAL AT FIVE YEARS.
I SHOULD TO STUDY SINGLE EVENTS,
SINGLE VESICLES FUSING.
I SAID WHY TO THE TAKE ONE
SINGLE CANCER AND STUDY THAT IN
DETAIL INSTEAD OF JOIN ALL
HEEMENT -- HEPATOCARCINOMAS
TOGETHER AND SEE WHAT WE CAN
LEARN.
BUT THERE'S PROBLEMS WITH
STUDYING A RARE DISEASE.
THERE'S A LACK OF INFORMATION
AND LACK OF TOOLS.
THERE'S TOO FEW SAMPLES IF IT'S
VERY RARE AND TOO LITTLE
FUNDING.
MY EARLY GRANT SPACE CAME BACK
WITH A REVIEW OF THIS IS
WONDERFUL SCIENCE BUT TOO RARE
TO BE SIGNIFICANT.
SO WHY STUDY IT?
YOU HEARD IT WAS PRECISELY
DEFINED TO LEARNING THINGS VERY
QUICKLY AND YOU CAN MAKE RAPID
PROGRESS.
FOR EXAMPLE, FROM STUDYING OTHER
RARE DISEASES LIKE GLIAL
BLASTOMA WE LEARNED ABOUT
HYDROGENASES IN CANCER AND WE
LEARNED ABOUT THE TUMOR
SUPPRESSERS.
SO OUR APPROACH WAS TO PART
ANYONE WITH PATIENTS THROUGH
SOCIAL MEDIA.
FIRST STEP WAS MY DAUGHTER MADE
A VIDEO ON YOUTUBE WITH ANOTHER
PATIENT.
>> WHEN I WAS 12 I WAS DIAGNOSED
WITH FIBROLA MELLER.
PEOPLE ARE WORKING ON IT AND
PEOPLE ARE TRYING TO FIND A CURE
AND TRYING TO HELP UNDERSTAND
WHAT THE CANCER IS.
AND WE NEED TISSUE SAMPLES.
SO YOU DO HAVE THE RIGHT TO TAKE
YOUR OWN TISSUE.
YOU CAN ASK A DOCTOR TO SEND IT
TO RESEARCHERS SO PEOPLE CAN TRY
TO DEVELOP A CURE FOR THIS
CANCER.
SO FROM REACHING OUT THROUGH
SOCIAL MEDIA WE GOT INFORMATION
FROM MANY PATIENTS.
AND WE NOW HAVE DATA FROM
HUNDREDS OF PATIENTS OVER 20
COUNTRIES.
THIS IS A REGISTRY PAGE WE SET
UP.
IT'S A NON-PROFIT 5013C RAN BY
PATIENTS AND FAMILIES AND
THERE'S A LIMITED NUMBER IN ANY
ONE COUNTRY.
BY HAVING THE PATIENTS AND
FAMILY MEMBERS RUNNING THIS
MEANS WE CAN FOLLOW PATIENTS
BETWEEN INSTITUTIONS EVEN FROM
COUNTRY TO COUNTRY WHICH ALLOWS
FOR LONGER OUTCOMES AND MORE
NUMBERS BEING INVOLVED.
UNLIKE MOST DATABASES SINCE IT'S
PATIENTS FOLLOWING PATIENTS WE
CAN FOLLOW-UP AND AVOID
DUPLICATION.
IT ALSO MEANS OVER TIME THE
MOLECULAR CHARACTERIZATION OF
CHANGES YOU CAN EDIT THE DATA.
IT'S RUN BY THE PATIENT FAMILY
COMMUNITY WITH THE PROMISE
PATIENT DATA WON'T BE SOLD AND
WE GET HIGH BUY IN FROM
PATIENTS.
WE GOT TOGETHER WITH PATIENTS,
ONCOLOGISTS AND PATHOLOGISTS AND
RADIOLOGISTS AND CAME UP WITH
QUESTIONS OF CONCERN TO OUR
MEMBERS IN THE REGISTRY NOW PART
OF THE MEDICAL RECORD.
NOW, IN ADDITION TO THEM GIVING
THEIR OWN INFORMATION IN
RESPONSE TO QUESTIONS, WE'RE
LINKED BETWEEN THEM AND RESEARCH
CLINICAL COMMUNITY.
FOR EXAMPLE, WE HAVE FREQUENTLY
ASKED QUESTIONS ABOUT
FIBROLAMELLAR CARCINOMA,
DICTIONARIES OF KEY TERMS AND
INFORMATION ON THE SCIENCE AND
VIDEOS HOW IT OCCURS.
WE HAVE AN INTRODUCTION TO THE
LITERATURE.
IF YOU CLICK YOU CAN DOWNLOAD A
VIDEO HOW TO GET INTO PUB MED.
WHAT IS PUB MED?
HOW TO FIND ARTICLES.
WHAT IS A PDF?
HOW DO YOU GET A PDF READER?
HOW DO YOU CONTACT AUTHORS TO
GET COPIES.
WE HAVE VIDEOS OF THE ARTICLES
SUMMARIZING THE RESULTS AND THIS
IS MADE BY MY LAB.
>> IN ORDER TO CONFIRM THE
CHIMERA THEY EDIT THE GENES OF
ADULT MICE USING A NEW CRISPR
TECHNOLOGY AND TOOK THE DNA OF A
MICE AND CREATED THE SAME
DELETION FOUND IN FIBROLAMELLAR
PATIENTS AND WITHIN MONTHS THE
CANCER WITH THE DELETION HAVE
THE CANCER.
THIS EXPERIMENT ONLY TELLS YOU
THE DNA DELETION IS IMPORTANT.
IT DOESN'T TELL YOU WHETHER THE
CHIMERA OR GENES ARE THE CAUSE
AND THEY ADDED EXTRA DNA WITH
CHIMERA AND THE MICE GOT
FIBROLAMELLAR TOO.
>> THE IDEA IS TO MAKE THIS
SCIENCE ACCESSIBLE TO THE
PATIENTS.
ONE OF OUR STRONG BELIEFS IS IN
THE LAB IS WE MAKE STRONG
SACRIFICES.
THE BIGGEST ARE MADE BY THE
PATIENTS.
IT'S THE PATIENTS GIVING THEIR
TISSUE, THEIR BLOOD, SHARING
RECORDS AND IN MANY CASES THEY
WORK AT THE BENCH DOING THE
RESEARCH.
WE HAVE AN OBLIGATION TO MAKE
THIS SCIENCE AS ACCESSIBLE AS
POSSIBLE.
OUR REGISTRY IS IRB APPROVED AT
THE OF THE OF A VARIETY OF
CLINICIANS WE MOVED THE ENTIRE
PLATFORM TO RED CAP AND HAVE
EPIDEMIOLOGISTS AND
STATISTICIANS REVIEWING THE
DATA.
WE FOUND CLUSTERS OF PATIENTS
NEAR EACH OTHER AND THE
CLUSTERING DOES NOT FOLLOW
POPULATION DENSITY AND LEADING
TO ALL SORTS OF STUDIES.
WHAT'S IN COMMON TO THE PATIENTS
THAT LIVE NEAR EACH OTHER AND
MUTATIONAL SIGNATURES IN THE
DNA.
AS THE EXTENSIVE INFORMATION OF
PATIENT SURVIVAL.
WE FOUND SURVIVAL DOESN'T
CORRELATE WITH AGE OF DIAGNOSIS.
WOMEN ARE MORE LIKELY TO GET IT
MORE THAN MEN, ROUGHLY 60% AND
WOMEN HAVE A BETTER SURVIVAL
THAN MEN.
THESE ARE THE OUTCOMES.
WOMEN ARE MORE AWARE OF THEIR
BODIES AND DIAGNOSED EARLIER AND
DIAGNOSED AT THE SAME AGE LED TO
STUDIES LOOKING AT THE ROLE OF
HORMONES AND INACTIVATION OF
GENES ON THE X CHROMOSOME.
AND I WOULD HAVE THOUGHT THE
BIGGER THE TUMOR THE WORSE
CHANCE OF SURVIVAL BUT AT THE
DON'T CORRELATE AND METASTASIS
DON'T CORRELATE TO TUMOR SIZE.
WHAT CORRELATED THOUGH IS THE
EXTENT OF SPREAD OF DISEASE.
WAS THERE INVOLVEMENT OUTSIDE
THE LIVER?
AND THE TUMORS ARE OFTEN IN THE
LIVER AT THE TIME.
PATIENTS WHO GOT SURGERY WHO GOT
THE BEST AND THOSE WHO JUST HAD
SYSTEMIC SURGERIES DID BETTER
THAN THOSE WHO DIDN'T AT ALL AND
MOST THE PATIENTS WITH TUMORS
OUTSIDE THE LIVER HAVE BEEN TOLD
THE TUMOR IS NOT OPERABLE.
CANNOT BE REMOVED AND WE
ENCOURAGED THEM TO GET A SECOND
OPINION AND THEN THEIR SURVIVAL
IS MUCH BETTER THAN OTHERS.
IT'S A STRONG ARGUMENT FOR GOING
OUT FOR SECOND OPINION AT ALL
TIMES.
WE PULLED OUT A FEW DOZEN
PATIENTS WHO RECEIVED CHECKPOINT
INHIBITERS AND THE MEMBERS
RUNNING THE REGISTRY AT JOHNS
HOPKINS TOOK ALL THE SCANS OF
THE MEDICAL RECORDS AND ONE TEAM
READING AND EVALUATING THE
OUTCOMES.
WHAT KIND OF ANALYSIS HAVE WE
GOTTEN IN WHOLE GENOME ANALYSIS
AND ANALYZED THE GENE EXPRESSION
AND TRANSCRIPTOME AND PROTEOMICS
AND FOR BACKGROUND FOR THOSE NOT
FAMILIAR AGAIN ALL THE GENETIC
MATERIAL IS STORED IN TWO VERY
LONG STRANDS OF DNA AND THINGS
WE CALL THE CHROMOSOMES.
IT'S ON EACH CHROME IT WILL
YOU'LL HAVE FOR EXAMPLE A GREEN
GENE AND HERE IS AN ORANGE GREEN
AND INCLUDED IN SHORT SNIPPETS
AND WHAT IS COLORED IS THE
REASON FOR THE GENE.
ARE YOU STILL HEARING ME?
I HEARD BACKGROUND NOISE.
AND IN BETWEEN THERE'S REGIONS
LINKING THEM TOGETHER NOT
CODING.
YOU MAKE A COPY OF THE DNA AND
YOU GO THROUGH COPYING IT AND
MAKE WHAT'S CALLED A MESSENGER
DNA AND THEN THE CELL SPLICES
ALL THE PIECES IN BETWEEN TO GET
THE MESSENGER RNA TO GO IN THE
PROTEINS AND THERE'S A DELETION
THAT FUSES THEM TOGETHER.
YOU HAVE THE START OF THE GREEN
GENE FUSED WITH THE BODY OF THIS
ORANGE GENE.
WE CALL THIS CHIMERIC FROM
MYTHOLOGY AND IT SPLICES OUT IN
BETWEEN AND THE MESSENGER RNA
LEAVES THE NUCLEUS AND GOES OUT
TO THE PERIPHERY WITH THE
MACHINE IN RED CALLED THE
RIBOSOMES.
THEY MAKE THEM INTO PROTEINS.
WHEN THE CHIMERIC AND FUSION
RIBOSOMES COME OUT THEY MAKE A
FUSION PROTEIN SO IT'S A
CHIMERA.
A MIX OF TWO PROTEINS TOGETHER.
WE JUST NEED TO EXPRESS THE
FUSION PROTEIN TO GET THE
COMPLETE PHENOTYPE OF
FIBROLAMELLAR.
WE FOUND THIS IN EVERY PATIENT.
IF WE RECREATE THE SAME DELETION
IN THE LIVERS OF MICE WE GET
TUMORS THAT LOOK LIKE
FIBROLAMELLAR CARCINOMA AND ALL
THE GENE EXPRESSION AND NICE DIE
OF THE TUMORS.
IF WE RECREATE THE SAME DELETION
IN PRIMARY HEPATOCYTES THEY HAVE
THE CHANGES AND GENE EXPRESSION.
SO WHAT ELSE DID WE LEARN?
WE COMPARED IT TO THE TISSUE AND
HAVE LOW LEVEL OF SINGLE NU
NUCLEOTIDE MUTATIONS.
THERE'S LOW LEVELS OF WHAT ARE
CALLED STRUCTURE VARIANTS AND
AMPLIFICATIONS OR GENES BEING
INVERTED.
WE LOOK TO THE TRANSCRIPTOME AND
ANALYSIS AND ALL THE GENES BEING
EXPRESSED AND WE HAD THOUSANDS
OF TRANSCRIPTS THAT CHANGED
SIGNIFICANTLY AND THE CHANGES
WERE SIMILAR FROM PATIENT TO.
PATIENT.
HERE A SUMMARY OF DATA FROM
PATIENTS FROM SEVEN LABS.
MOSTLY OUR LAB.
IT'S A CLUSTERING OF ALL THE
TRANSCRIPTS COMPARED TO THE
NORMAL ADJACENT TUMOR.
ALL THE TUMORS HAVE ALL THE SAME
CHANGES IN THE TRANSCRIPTOME
COMPARED TO THE NORMAL.
THERE'S ALMOST NO DIFFERENCE.
IT'S A VERY HOMOGENEOUS DISEASE
AND HERE'S WHERE ALL THE HEP
HEPATOSILLIC TUMOR AND IT'S V
VERY -- HEEL HEME GENEOUS
PATIENTS.
BECAUSE OF THE HOMOGENEITY AND
IF IT CAN WORK IN ONE PATIENT IT
HAS POTENTIAL TO WORK ON ALL
PATIENTS.
WE GOT WE HAVE TO SHARE WITH THE
PATIENT COMMUNITY.
WE CREATED AN APP PATIENTS CAN
GO INTO AND WE DESCRIBE TO THEM
WHAT ARE THE CHANGES IN THE
TRANSCRIPTOME.
WHY SHOULD THAT BE OF CHANGES
AND WE HAVE A FIBROLAMELLAR
CHANGES AND THE CLASSIC CHANGES
AND THE TUTORIAL HOW TO GO
THROUGH AND EXPLORE THE CHANGES
IN THE TRANSCRIPTOMES.
THIS IS NOW SHOWING THE RESULTS
FROM SEVEN DIFFERENT LABS.
AGAIN, VERY CONSISTENT RESULTS
ACROSS ALL THE LABORATORIES OR
THE CHANGES BETWEEN THE PRIMARY
AND METASTASIS FOR THE TUMORS
AND YOU CAN PROBE THIS WITH ANY
ONE OF THE TRANSCRIPTS.
ONE OF THE DIFFERENCES IN
FIBROLAMELLAR YOU SEE HOW IT
INCREASES COMPARED TO HEP
HEPATOBLASTOMA AND WE'RE TRYING
TO MAKE THIS ACCESSIBLE TO THE
COMMUNITY AND WHAT WE'RE DOING
AND WHY IT'S IMPORTANT AND TO
GET THEIR INPUT.
I WANT TO FOCUS ON THERAPEUTICS
AND THE DEVELOP THERAPEUTICS.
YOU NEED GOOD MODEL SYSTEMS FOR
TESTING THEM.
WE'VE BEEN USING THREE KEY
SYSTEMS IN OUR LAB.
ONE ARE ORGANOIDS.
SMALL MINI LIVERS, IF YOU WISH
GO IN A DISH.
I WON'T GO INTO DETAIL IN THAT
TODAY BECAUSE I WON'T USE THIS
IN THE PRESENTATION, THEY'RE
TESTING CELLS DIRECTLY FROM
PATIENTS.
WE HAVE A LAB AND WE'RE
SCREENING THEM AGAINST VARIOUS
AGENTS OR PLANT TUMORS IN MICE.
THEY'RE CALLED PATIENT DERIVED
XENO GRAPHS.
YOU WANT TO KNOW HOW FAITHFUL IS
REPORTING THE BEHAVIOR OF THE
TUMORS IN THE PATIENTS.
SO THERE'S A SERIOUS CRITERIA WE
USE.
IF YOU LOOK AT THE HISTOLOGY TO
ABOUT WHAT EXTEND ARE THE SAME
FROM THE ORIGINAL TUMORS IN THE
PATIENTS?
WE ONLY USE ONES WHICH CLOSELY
RECAPITULATE WHAT YOU SEE IN THE
PATIENTS.
IF YOU LOOK FOR THE CHIMERIC
FUSION TRANSCRIPT, IS IT THERE?
IT'S ALWAYS THERE IN THE MICE
AND PASSAGES OF THE TUMORS IN
MICE.
DO WE SEE THE FUSION PROTEINS?
HERE'S THE NATIVE PROTEIN.
TWO GENES ARE FUSED TOGETHER AND
THE FRONT END IS FROM A HEAT
SHOCK PROTEIN AND THE BULK IS
CALLED THE CATALYTIC SUBUNIT OF
A PROTEIN KINASE A.
IT'S AN ENZYME A MACHINE THAT
WORKS IN THE CELL BY MODIFYING
OTHER MOLECULES AROUND IT.
YOU CAN MODIFY SUGARS, PROTEINS,
LIPIDS, BY PUTTING A PHOSPHATE
ON THEM BY ACTIVATE OR
INACTIVATE THEM.
THE BULK IS THE SUBUNIT OF
PROTEIN KINASE A.
ALL THE MODEL SYSTEMS TESTED DO
THEY HAVE THE FUSION TRANSCRIPT,
DO THEY HAVE THE FUSION PROTEIN.
WE ALSO LOOK AT ALL THE CHANGES
AND TRANSCRIPTS THAT OCCUR.
ALL THE ONES THAT GO UP.
THERE'S FULL CHANGE GREATER THAN
ZERO AND ALL THE ONES THAT GO
DOWN, HOW DO THEY COMPARE TO THE
CHANGES YOU SEE IN PATIENT
TISSUE.
AND WE'LL HAVE CLOSE
RECAPITULATION AND CORRELATION
HERE.
SO, WHAT ARE THE KINDS OF
STRATEGIES?
FIRST ARE COMPOUNDS RELATIVE TO
FIBROLAMELLAR.
WE TOOK ALL THE COMPOUNDS WE'VE
SEEN IN THE CLINIC AND SHOW NO
DIFFERENCE IN THE RESPONSE OF
THE PATIENT-DERIVED XENOGRAPHS
FROM HEPATOCYTES AND NO
DIFFERENCE FROM THE NORMAL
PATIENTS.
WE ALSO TRIED TUMORS GROWING IN
MICE.
THERE'S NO DRUGS FOR
FIBROLAMELLAR TUMORS LIVING IN
MICE AND WE ASKED WHAT WAS THE
SURVIVAL OF THE CELLS AFTER
TREATMENT?
WE COULDN'T FIND ANY COMPOUNDED
USE SHOWING ANY EFFICACY IN
FIBROLAMELLAR.
WE SAID WHAT IF WE TAKE A
PRECISION MEDICINE APPROACH AND
THOSE TARGETED TO FIBROLAMELLAR.
I TOLD YOU THERE'S A BIG ORANGE
DOMAIN HERE IS FROM PROTEIN
KINASE A.
WHAT IF WE USE DRUGS THAT
INHIBIT PROTEIN KINASE A.
WE USAGE ENTS KNOWN TO INHIBIT
THIS AND THEY SHOWED LITTLE
THROUGHPUT WINDOW BETWEEN
DAMAGING THE FIBROLAMELLAR CELLS
AND THE HEPATOCYTES.
SO IT'S ESSENTIAL FOR SO MANY
CELLS EVEN NORMAL CELLS ARE
DAMAGED WHEN YOU KILL IT.
WE HAVE ALL THE CHANGES IN THE
TRANSCRIPTOME AND PROTEOME.
MAYBE THEY CAN SUGGEST TO US
SOME TARGETS.
FOR EXAMPLE, THE KINASE A
INCREASED.
WHEN YOU USE INHIBITERS, THEY
HAD NO EFFECT IN FIBROLAMELLAR
COMPARED TO THE HEPATOCYTES.
THE TRANSCRIPTOME SHOWED THE AGF
PATHWAY US UP AND USED DRUGS
AGAINST THIS AND THERE WAS NO
CLEAR THERAPEUTIC WINDOW.
AND THE GLUTAMATE PATHWAY IS IT
THERE WAS NO PRIMARY EFFECT TO
THE BLACK COMPARED TO
PATIENT-DERIVED XENOGRAPHS.
A LOT OF THE PATHWAYS AND WE
USED INHIBITERS AND NONE OF THEM
PREFERENTIALLY EFFECTED THE
CELLS COMPARED TO THE PRIMARY
HEPATOCYTES IN BLUE WHETHER YOU
DISASSOCIATED THEM FROM THE
TUMOR IN A DISH OR FOLLOWED THEM
IN MICE AND TRIED TREATING THE
MICE.
NONE AFFECTED THE TUMOR GROWTH.
SO, WE SAW IT RELEVANT TO THE
BIOLOGY OF FIBROLAMELLAR DIDN'T
WORK.
YOUR DNA IS ENCODED BY A, T, C
AND G.
EVERY A COMPLIMENTS BY LETTER T
AND G BY A C.
AND IN THE RNA IT'S SIMILAR A,
U, G AND C AND IF YOU COME UP
WITH A COMPLIMENTARY PAIR TO THE
DNA AND INSTEAD OF BINDS IT'S
RAN BY THE RIBOSOME AND YOU CAN
BLOCK THE SYNTHESIS.
ACROSS THE JUNCTION ARE THE TWO
GENES, WHERE THEY FUSE TOGETHER.
SO THEY GOT EVERY POSSIBLE
SPREAD BECAUSE ALL THE EARLIER
WORK I SHOWED YOU, I SHOWED IF
YOU PUT THIS FUSION GENE IN THE
CHIMERA AND GET THE TUMOR, IT'S
POSSIBLE JUST TRIGGERING IT IT'S
NOT NEEDED ANYMORE.
IS IT CONTINUING TO DRIVE THE
TUMOR?
OTHERWISE IT'S NOT A USEFUL
THERAPEUTIC TARGET.
IF YOU GET RID OF IT, DO THEY
CONTINUE TO GROW?
IF YOU LIMIT TO DRIVER, DO THE
CELLS NORMALIZE OR DIE
>> IF THEY FORMALIZE FOR THE
REST OF THE LIFE OF THE PATIENT
YOU HAVE TO GIVE THE DRUG TO
CREATE THE CHIMERA AND WITH
LONG-TERM TREATMENT THEY CAN
FIND WAYS TO ESCAPE FROM IT.
HS RNA WOULD GET RID OF THE
FUSION PROTEIN BUT NOT AFFECT
THE WILD TYPE PROTEIN.
THEN IF YOU HAD TUMORS GROWING
IN MICE YOU THEN INTRODUCED THIS
SH RNA THE TUMORS WOULD STOP
GROWING.
HERE'S THE TUMOR GROWING AND
THEY ACTUALLY STOP GROWING.
IN FACT WHEN THEY STOP THEY FADE
AWAY.
THIS TELLS US IT'S NOT ONLY
INVOLVED IN TRIGGERING THE TUMOR
BUT CONTINUING TO DRIVE THE
TUMOR.
NOT ONLY DRIVE IT BUT WHEN YOU
TAKE IT AWAY THEY DIE AND FADE
AWAY.
WE'VE BEEN DELIVERING WITH A
SILENCING RNA AND OPTIMIZING
DELIVERY TO THE CELL AND ONE
THERAPEUTIC APPROACH SHOWING
PROMISE.
WHAT'S THE SECOND APPROACH?
COME UP WITH DEGRADER OF THE OPT
GENIC PROTEIN.
IF YOU HAVE SOMETHING THAT BINDS
TO GET RID OF YOU CAN TAKE WHAT
BINDS TO THE PROTEIN YOU WANT TO
GET RID OF AND LINK IT TO AN EN
TIME OR PUT TAGS ON IT AND SEND
IT TO THE GARBAGE DISPOSAL THE
PROTEASOME.
THE TAG IS UBIQUITIN AND IT THE
BIND TO OUR FUSION PROTEIN.
WE SCREEN THROUGH 500,000
COMPOUNDS AND YOU HAVE 14
INHIBITED BELOW 100 NANO MOLE
AND THE FUSION PROTEIN THAT
INHIBITED AT THE SAME INHIBITED
THE WILD TYPE PROTEIN.
THAT'S A PROBLEM.
I SAID EARLIER THE WILD TYPE
PROP
PROTEIN IS IMPORTANT FOR THE
HEALTH OF THE CELL SO CAN WE
FIND A WAY AROUND IT
?
WE NOTICED THE KINASE IS TITLELY
FOLDED.
BECAUSE IT'S TITLELY -- TIGHTLY
FOLDS IT'S BOUND TO THE CELL AND
THIS FUSION DOMAIN IS FLEXIBLE
MAKING IT A GOOD SUBSTRATE AND
HAS THE POTENTIAL TO BE DEGRADED
AND BEYOND THAT HAS MANY AMINO
ACID LYSINES AND THAT'S AMINO
ACID THAT GETS UBIQUITIN ADDED
ON TO TARGET THE PROTEASOME.
IF IT BINDS TO THE WILD TYPE AND
FUSION TOGETHER, IF WE CAN
COMBINED IT WITH AN ENZYME
CALLED E3 LISASE WE CAN DEGRADE
IT.
WE FOUND WE SLIGHTLY DEGRADED IT
OVER THE WILD TYPE MAHSA DID
THIS AND IF YOU'RE TUMOR IS
GROWING IN MICE YOU INTRODUCE
AND THE TUMOR WILL STOP GROWING
AND FADE AWAY.
THESE ARE TWO POTENTIAL
THERAPEUTIC APPROACHES AND
ANTISENSE AND DEGRADER.
THESE ARE ALL UNDERGOING
DEVELOPMENT BUT THE THING IS
PEOPLE ARE DYING NOW AND
PATIENTS ARE WORKING IN THE LAB
AND SICK AND AROUND THE WORLD
ARE SICK.
THE QUESTION IS WHAT IS
IMPORTANT TO THE CLINIC NOW?
--
>> HELLO?
>> YES.
CAN YOU HEAR ME?
>> I THINK YOU'RE OKAY.
WIN MAY BE DOING SOMETHING ELSE.
>> WE TOOK THE DRUGS THAT PAST
PHASE 1 CLINICAL TESTS AND SAW
WHICH HAS EFFECT AT ALL OR
SHOWED A SLIGHT ENCOURAGING SIGN
WE TESTS FROM 10 NANOMOLE TO
MICROMOLE AGAINST THE PATIENT
DERIVED XENOGRAPHS OR ADJACENT
TISSUE.
SOME WORKED WELL AGAINST THE
DECH DEF
THE XENO GRAPH AND IT'S AN
INHIBITER.
WHEN CELLS DIVIDE THEY TAKE A
DOUBLE HELIX AND UNWIND.
AND FIBROLAMELLAR IS A SLOW
GROWING CELL AND FOUND PA
PANOBINOSTAT WORKS AND THERE
WERE INHIBITORS OF THE MOLECULE
THAT PROTECTS THE CELL FROM
UNDERGOING CELL DEATH.
I GOT WORRIED.
NONE OF THESE WERE EXPECTED.
WE WERE TAKING THE TUMORS FROM
PATIENTS AND PLANTING THEM IN
MICE AND SOMETIMES IT TOOK NINE
MONTHS FOR THE TUMOR TO GROW.
WHAT IF OUT OF A BILLION CELLS
599, 9 99 ONE GREW UP.
AND IT REPRESENTED THE NORMAL
TUMORS IN THE PATIENT.
WHEN WE GET RESULTS LIKE THIS,
DOES IT REPORT ON THE BEHAVIOR
OF TUMORS IN THE PATIENTS?
WE SWITCHED NOW TO GET TUMORS
DIRECTLY TO PATIENTS AND
DISASSOCIATE THEM AND SCREEN
THEM AGAINST THE DRUGS.
THE SAMPLES FROM THE PATIENTS
SHOWED THE SAME RESPONSE
PROFILE.
SO WE USED SAMPLE FROM A VARIETY
OF PATIENTS HERE.
ALL THE PATIENTS RESPONDED IN
CONCENTRATIONS MUCH LOWER THAN
THE CONCENTRATIONS HERE IN BLACK
THE PRIMARY HUMAN HEPATOCYTES
AND HERE SOME PATIENTS WERE
SENSITIVE, SOME WERE
HYPERSENSITIVE.
WE WERE WONDERING, WHY ARE THERE
DIFFERENCES?
WHY ARE SOME SENSITIVE AND ALL
THE CHANGES IN THE GENE
EXPRESSION AND PROTEINS SEEM TO
BE THE SAME PATIENT TO PATIENT.
AND WHAT SURGEONS HAVE TO DO IS
BURN AROUND THE ENTIRE TUMORS TO
INCREASE THE BLOOD FLOW WHEN
WHEN THEY RESET THE TUMOR
THERE'S NOT A LOT OF BLEEDING
AND THE TUMORS HAVE REDUCED
BLOOD FLOW AND OXYGEN ALONG WITH
BEING TREATMENTS AND WHEN WE
DISASSOCIATE A TUMOR MAYBE
BECAUSE OF LOSS OF OXYGEN OR HOW
WE DIGESTED IT, EVERY SINGLE
SAMPLE WAS DIFFERENT.
MAYBE SOMETHING IN OUR
TECHNIQUE?
THERE'S QUITE A FEW PATIENTS HAD
SURGERIES THAT WERE A FEW YEARS
A PART.
AND SOME WERE DONE THREE YEARS A
PART AND WITHIN THE SAME PATIENT
THE RESPONSE EARLIER IS THE
PRIMARY TUMOR HERE'S THE
RESPONSE OF THREE OF THE
PATIENTS METASTASES AND SAME FOR
ALL DRUGS TESTED.
WITHIN A SINGLE PATIENT THE DRUG
RESPONSE PROFILE WAS ALWAYS THE
SAME IT'S TELLING US THE
DIFFERENCE WE'RE SEEING IS NOT A
DIFFERENCE IN OUR PROTOCOL BUT A
DIFFERENCE IN THE RESPONSE FROM
PATIENT TO PATIENT.
AND I MENTIONED ONE OF THE DRUGS
THAT WORKED REALLY WELL WAS A
DRUG THAT INHIBITED THE
ANTI-CELL DEATH PATHWAY AND WE
FOUND BETWEEN THE DIFFERENT
PATIENTS THE ONES SENSITIVE AND
VERY SENSITIVE, THERE WERE
DIFFERENCES IN EXPRESSION OF THE
ANTI-CELL DEATH PATHWAY.
WE ASKED WHAT HAPPENS IF WE
COMBINE TOGETHER WITH A CELL
THAT BLOCKS THE PATHWAY AND
DRUGS WE'RE TREATING?
IN BLUE WAS THE PATIENT LEAST
SENSITIVE.
AND WHEN GOT SAMPLES DIRECTLY
FROM THE PATIENTS THIS IS DONE
THROUGH A LARGE ROBOTIC SYSTEM
WE BLOCKED B CELL EXCEL.
WE FOUND THE MORE WE INHIBITED
THE MORE SENSITIVE AND THE
SENSITIVE WENT DOWN TO SINGLE
DIGIT NANOMOLE.
THE DIFFERENCES WERE DUE TO THE
APOPTOTIC PROTEIN.
OTHERWISE THE PATIENT RESPONSE
WAS PRETTY MUCH THE SAME PATIENT
TO PATIENT.
NOW, A PROBLEM USING NAVIHOCLAX
IT BLOCKS AND ADVERSELY AFFECTS
THE PLATELETS AND CREATES
THROMBOCYTOPENIA AND THEY PUT IN
LIGASES AND DESTROYED IT AND IT
ONLY AFFECTED B CELL EXCEL AND
USED THE LIGASE THAT AFFECT THE
PLATELETS.
WE FOUND WITHIN 24 HOURS OF
TREATMENT IN A MOUSE WE CAN
ELIMINATE THE ABOUT BCL-XL AND
THE PLATELETS INCREASED.
THERE WERE NO CHANGES IN
BILIRUBIN OR AFFECT ON LIVER
ENZ
ENZYMES.
IT THEY INHIBITED IT WELL.
IF WE JUST HAVE THIS TREATMENT
STRATEGY, FIVE DAYS ON, TWO DAYS
OFF, FIVE DAYS ON.
THERE'S THREE ROUNDS OF TWO
TREATMENTS.
YOU SEE WHAT IS EFFECTIVELY
STABLE DISEASE.
NOW, IF YOU STOP TREATMENT THE
TUMOR DOES NOT CONTINUE TO GROW.
NOW IF WE ADD TO THE TREATMENT
OF THE DEGRADER, NOT ONLY DOES
THE TUMOR GROW AWAY BUT YOU STOP
TREATMENT AND THE TUMOR DOES NOT
COME BACK.
IT'S BEING TESTED AS A MODEL
THERAPY TO GO IN OUR PATIENT
REGISTRY WE FOUND NINE PATIENTS
WHO RECEIVED IT AND THEY FOUND
THEIR TUMOR STABILIZED OR
SLIGHTLY DECREASED JUST AS SEEN
IN THE MICE.
A STUDY COMBINING THE TWO IS
INVESTIGATING AND OPENING A
CLINICAL TRIAL AND THE FIRST IS
STARTING SOON.
SHOULD THE DRUGS BE WORKING?
WOULD I GIVE THIS TO MY OWN KID?
THIS IS NOT PREDICTED TO WORK.
WE EXAMINED WHAT IT IS AND IT'S
AN ACTIVE METABOLITE AND ONCE
IT'S IN THE LIVER CELLS THEY PUT
ON A SUGAR GROUP WHICH ALLOWS IT
TO BE EXPORTED INTO THE BILE AND
THE BODY GETS RID OF IT.
THE FUSION GENE, THE CHIMERIC
WHEN IT'S INCREASED IN
EXPRESSION, IT ACTUALLY
REGULATES THE EXPRESSION AND
DOWN REGULATED ABOUT 50 FOLD.
BECAUSE IT'S DOWN REGULATED SO
MUCH THE CELLS NO LONGER HAVE
THE ABILITY TO PUT A SUGAR GROUP
ON AND IT BUILDS INSIDE THE
CELLS.
WE LEAVE YOU WITH FIBROLAMELLAR
CARCINOMA INFUSES TO PRKC KINASE
A AND IT'S SUFFICIENT TO CREATE
IT IN THE LIVER OF MICE AND A
FUNCTIONAL PRECISION MEDICINE
SCREEN IDENTIFIES AGENTS THAT
SHOW EFFICACY ON CELLS
DISASSOCIATED FROM TUMORS IN
MICE AND IN PATIENTS AND TUMORS
GROWING IN MICE AND PATIENTS.
THE EFFICACY OF THE DRUGS CAN BE
UNDERSTOOD FROM AN ANALYSIS OF
THE BIOLOGY OF THE TUMOR.
OFTEN IT'S NOT THE TARGET BUT
THE PATHWAY AND I'LL LEAVE YOU
WITH CHARACTERIZATION OF THE
CANCER, EVEN RARE CANCER CAN
HAVE RAPID ADVANCES THAT CAN
FORM ANY DISEASE.
PATIENTS ARE EAGER TO PARTNER
AND MAKING PATIENTS FULL
PARTNERS NOT JUST AS A SOURCE OF
TISSUE AND DEVELOP CURES, I WANT
TO THANK THE FIBROLAMELLAR
PATIENTS.
THIS IS MY DAUGHTER DESCRIBING
THE DISCOVERY OF THE DELETION
THAT LED TO THE FUSION GENE.
AT THIS POINT SHE'S DESCRIBING
PROMISING YOUNGER CANCER
BIOLOGISTS HOPEFULLY WILL
CONTINUE PURSUING THE STUDIES.
THIS IS JACKSON WHO WORKED ON
THE GENE.
A WONDERFUL CHEMIST WHO
UNFORTUNATELY PASSED AFTER HIS
26th BIRTHDAY AND HELPED DEVELOP
OUR ORGANOIDS AND TAWNEY PASSED
ON THEIR 21st BIRTHDAY AND WITH
DID INFORMATICS AND SHE PASSED
AROUND 25.
SKY IS WORK WITH STEVE.
CHARLOTTE PASSED THIS PAST
AUGUST.
I WANT TO THANK ALL THE MEMBERS
OF MY LAB.
THESE ARE THE CURRENT MEMBERS OF
MY LAB AND DEDICATED TO THE WORK
AND PATIENTS.
I'LL LEAVE THE FINAL WORD TO ONE
OF ME PATIENTS.
>> LADIES AND GENTLEMEN, THE
PRESIDENT OF THE UNITED STATES
ACCOMPANIED BY MS. ALANA SIMON.
>> I'M 19 YEARS OLD AND
CURRENTLY STUDYING COMPUTER
SCIENCE AT HARVARD.
WHEN YOU I WAS 12 YEARS OLD I
WAS DIAGNOSED WITH
HEPATOCELLULAR FIBE RA -- FIB
FIBROLAMELLAR CARCINOMA AND I
EXAMINED A PATIENT GROUP WHICH
ALLOWED THE DISCOVERY.
WE'RE WORKING ON DEVELOPING THE
FIRST DIAGNOSTIC TESTS AND
TREATMENTS FOR FIBROLAMELLAR.
LAST YEAR I MET THE PRESIDENT
AND GOT TO DISCUSS MY RESEARCH
WITH HIM.
IT WAS SUCH AN HONOR TO MEET HIM
THEN SO IT'S WITH GREAT HONOR I
INTRODUCE THE PRESIDENT TO YOU
TODAY.
>> ANYWAY, I WANT TO THANK THE
PATIENTS AND THEIR FAMILIES AND
ALL OF YOU FOR YOUR ATTENTION.
THANK YOU.
>> THANK YOU VERY MUCH, SANDY
FOR THIS EXTRAORDINARILY
EXCITING, PROMISING AND
BEAUTIFUL EXAMPLE AND THE NEED
FOR BRIDGES NOT ONLY WITHIN THE
SCIENCES BUT OF COURSE WITHIN
THE PATIENTS AND ALMOST ALL
DISEAS
DISEASES WITH THE GREATEST
INVESTMENT AND INTEREST.
WE'RE GOING TO PROCEED NOW TO
MARC GHANY.
A REMINDER TO SUBMIT YOUR
QUESTIONS AND WE'LL HAVE A
DISCUSSION AT THE END OF
DR. GHANY'S TALK.
MARC.
>> THAT WAS A WONDERFUL TALK,
SANDY.
THANKS FOR SETTING THE STAGE.
SO THAT WAS A WONDERFUL TALK AND
I WANTED TO EXTEND MY THANKS AND
GRATITUDE TO WIN FOR THE INV
INVITA
INVITATION.
IT'S AN AMAZING COURSE AND WIN
IS AN AMAZING INDIVIDUAL.
THIS COURSE HAS BEEN GOING ON 22
YEARS AND I'VE LEARNED
PERSONALLY A LOT FROM IT AND
HOPE EVERYBODY ELSE PROFITS FROM
WIN'S HARD WORK.
TODAY I'M GOING TO TALK A LITTLE
BIT ABOUT THE MORE COMMON CANCER
WHICH IS HEPATOCELLULAR
CARCINOMA AND CONFINE MY
COMMENTS TO THE EPIDEMIOLOGY
SURVEILLANCE, DIAGNOSIS AND
TREATMENT OF HEPATOCELLULAR
CARCINOMA.
AS YOU HEARD IT'S THE SIXTH MOST
COMMON AND THIRD CAUSE OF DEATH.
IT HAS THE HIGHEST CASE FATALITY
RATES AND ESSENTIALLY IT'S A
DEATH SENTENCE BECAUSE 50% OF
PATIENTS WILL BE DEAD TWO YEARS
AFTER DIAGNOSIS.
IT ACCOUNTS FOR 70% TO 85% OF
CASES.
THE INS INCIDENTS AFFECT WOMEN
MORE THAN MEN.
AND NOW THE DIFFERENT TYPES OF
LIVER CANCER IN ADULTS AND
CARCINOMA WHICH ARISES FROM THE
HEPATOCYTES 75% OF CASES AND
CHOL ANGIOCARCINOMA AND THE TWO
RARE CANCERS ANGIOSARCOMA AND
FIBROLAMELLAR CARCINOMA AND THEN
WE HAVE HEPATOBLASTOMA AND HCC.
YOU HAVE THE RATES FOR 20,000
PERSON BY 2020 BY COUNTRY.
YOU SEE THE VARIATION.
THE LOWEST RATES ARE IN CENTRAL
AND SOUTH ASIA.
THIS SHOWS THE MORTALITY RATE
PER 100,000 PERSONS BY COUNTRY.
THE INCIDENTS RATES IN THE
FORMER SLIDE AND THE LOWEST
MORTALITY RATES BEING IN SOUTH
AND CENTRAL ASIA AND THE HIGHEST
RATES BEING IN EAST AND
SOUTHEAST ASIA.
WITH RATES APPROACHING 16 PER
100,000 PERSONS.
THE HIGHEST RATES ARE IN
MONGOLIA A MORTALITY RATE AND
LOWEST IN SRI LANKA WHERE RATES
ARE 1.2 AND 1.3 PER 100,000
PERSONS RESPECTIVELY.
THE RATES ARE HIGHER IN MALES
COMPARED TO MALES.
THERE'S A SLIDE OF THE
MALE/FEMALE PER 100,000 PERSONS.
THE HCC IS SHOWN IN BLUE AND THE
ANGIOC
ANGIO CAR
ANGIOCARCINOMA AND THERE'S 1.6
TO 1 IN THE CARIBBEAN AND
CENTRAL AMERICA TO HIGH IN
WESTERN EUROPE FOR
HEPATOCELLULAR CARCINOMA AND
THERE'S NOT AS DRAMATIC AS THE
SCENE IN THE HEPATOCELLULAR
CARCINOMA WHERE THE HIGHEST
PROPORTION OF MALES TO FEMALES
AND IS FLIPPED IN SOUTH AMERICA
WHERE FEMALES OUT NUMBER MALES
AND THE REASON FOR THE HIGHER
RATE REMAINS UNEXPLAINED.
SO THE ETIOLOGY ALSO VARIES
GLOBALLY.
AND IN EAST AND SOUTHEAST ASIA
MOST ARE RELATED TO CHRONIC
HEPATITIS B SHOWN BY THE ORANGE
PORTION OF THE PIE CHARTS.
WHEREAS IN CENTRAL EUROPE AND
EASTERN EUROPE MOST ARE RELATED
TO ALCOHOL SHOWN BY THE BLUE
PARTS OF THE PIE CHARTS AND IN
AFRICAN AND WESTERN EUROPE AND
NORTH AMERICA MOST ARE RELATED
TO CHRONIC HEPATITIS C SHOWN BY
THE GREEN PORTIONS.
GLOBALLY IT ACCOUNTS FOR IT 42%
OF CASES.
FOLLOWED BY ALCOHOL AND THEN
HEPATITIS C.
ONE POINT I'D LIKE TO MENTION IS
NON-ALCOHOLIC LIVER DISEASE
METABOLIC LIVER DISEASE IS NOW
AN EMERGING CAUSE IN THE ABSENCE
OF CIRRHOSIS IN WESTERN
COUNTRIES.
FOR THE REST OF THE TALK I'M
GOING TO TALK ABOUT THE
HEPATOCELLULAR CARCINOMA AND
TALK ABOUT SCREENING AND HOW WE
IDENTIFY CANCERS IN PATIENTS WHO
ARE AT RISK.
AND WHY DO WE SCREEN FOR HCC?
THAT IS BECAUSE TUMOR STAGE OF
PRESENTATION HAS BEEN SHOWN TO
BE THE STRONGEST PREDICTOR OF
OUTCOME IN PERSONS WHO PRESENT
WITH EARLIER STAGE DISEASE
AMENABLE TO CURATIVE THERAPY THE
MEDIAN SURVIVAL IS GOOD FIVE TO
10 YEARS.
IN CONTRAST INDIVIDUALS
PRESENTING WITH LATE STAGE
DISEASE WHOSE TUMORS ARE ONLY
AMENABLE TO PALLIATIVE THERAPY
THE SURVIVAL IS POOR, 1-3 YEARS.
THERE'S DATA FROM RANDOMIZED
TRIALS AND OVER 18,000 POSITIVE
SUBJECTS WERE RANDOMIZED TO
RECEIVE ULTRASOUND PLUS
SURVEILLANCE AND COMPLIANCE WAS
ONLY 58% BUT DESPITE THAT AMONG
THE SCREENED GROUP A GREATER
PROPORTION WAS IDENTIFIED AT 60%
COMPARED TO 0% OF THE CONTROL
GROUP.
HAD TUMORS THAT WERE ABLE TO
UNDERGO CURATIVE RESECTION, 47%
VERSUS 8% AND HAD SIGNIFICANTLY
BETTER FIVE-YEAR SURVIVAL RATES
APPROACHING 50% IN THE SCREENED
GROUP COMPARED TO ZERO IN THE
NOT SCREENED GROUP.
TWICE YEARLY SCREENING WAS SHOWN
TO REDUCE MORTALITY BY 37%.
WOULD YOU GET SIMILAR RESULTS IN
A POPULATION COMPLETELY SIR
CIRRHOTIC AND MAYBE THERE'S ALSO
SHOWING HCC SURVEILLANCE
IMPROVES SURVIVAL.
THIS SLIDE SHOWS META-ANALYSIS
OF 12 STUDIES WHICH CONTROL TO
LEAD TIME BIAS SHOWING THAT
SURVEILLANCE WAS ASSOCIATED WITH
A 33% IMPROVEMENT IN SURVIVAL
COMPARED TO PATIENTS RECEIVING
SCREENING.
WHO IS AT RISK?
THESE ARE SHOWN ON THE SLIDE
HERE.
PERSONS WITH CIRRHOSIS THAT IS
WELL COMPENSATED AOB OF ANY
ETIOLOGY OR CANDIDATES TO UNDER
GO SURVEILLANCE AND TRANSPLANT
CANDIDATES SHOULD UNDER GO AND
THOSE WITH INCREASED RISK OF
CANCER AS SHOWN HERE.
AND THOSE WITH NON-CIRRHOTIC OR
NON-ALCOHOL LIVER DISEASE
BENEFIT FROM SURVEILLANCE.
WHAT TEST DO WE SCREEN WITH?
ULTRASOUND IS THE MODALITY OF
CHOICE BECAUSE IT'S WIDELY
AVAILABLE, SAFE AND RELATIVELY
INEXPENSIVE.
IT IT'S BEEN SHOWN TO BE COST
EFFECTIVE THEREFORE THE AMERICAN
ASSOCIATION FOR THE STUDY OF
AMERICAN LIVER DISEASES DOES
RECOMMEND ULTRASOUND AS THE
SCREENING MODALITY AND THE
OPTIMAL IS FOUR TO EIGHT MONTHS
BASED ON TUMOR TIME OF
APPROXIMATELY SIX MONTHS.
THERE ARE LIMITATIONS OF THE
SCREENING METHODS AND ULTRASOUND
IS DEPENDENT ON THE OPERATORS
AND SEVERITY OF LIVER DISEASE
AND ADHERENCE.
THE OPTIMAL SCREENING INTERVAL
IS CURRENTLY BASED ON A
SIX-MONTH INTERVAL.
IT'S BASED ON TUMOR DOUBLING
TIME AND WE KNOW HCC TUMORS ARE
QUITE HETEROGENEOUS.
SCREENING RATES ARE LOW.
FEWER THAN 50% OF NEWLY
DIAGNOSED HCCs ARE DETECTED BY
SCREENING.
IT'S UNCLEAR IF IT'S BENEFICIAL
FOR POPULATIONS IN WHOM THERE'S
A LACK OF ACCESS TO CURE
OPTIONS.
GIVEN THE LIMITATIONS THERE'S
CLEARLY A NEED FOR BETTER
SCREENING STRATEGIES.
SOME EMERGING STRATEG STRATEGIE
ULTRASOUND FOR EARLY AND 86% IN
THE VERSUS 26% IN THE CASE OF
MR.
THEY'RE ASSOCIATED WITH DOWN
SIDES.
AND REPEATED CT IMAGING AND
ISSUES WITH CAPACITY AND COST
WITH MRI.
THERE'S BLOOD BASED MARKERS.
UNFORTUNATELY THEY HAVE LOW
SENSITIVITY AND SPECIFICITY FOR
DETECTION OF EARLY TUMORS IN
CASE CONTROL STUDIES.
BUT THERE IS ONE I DID WANT TO
HIGHLIGHT AND THIS IS GALADD
WHICH ENCOMPASSES GENDER, AGE,
PROTEIN L3 AND
DCP SHOWN TO HAVE HIGH
SENSITIVITY IN PATIENTS WITH
CIRRHOSIS.
THOUGH IN THIS ANALYSIS HERE IT
SEEMED TO PERFORM AS THE PROTEIN
L3 BY ITSELF.
NEVERTHELESS IT'S UNDERGOING
CONTINUED ASSESSMENT AND
CURRENTLY IN A RANDOMIZED
CONTROL PHASE 4 STUDY TO COMPARE
TO ULTRASOUND FOR EARLY
DETECTION OF HEPATOCELLULAR
CARCINOMA BEING THE END POINT.
THERE'S GREAT INTEREST IN
LOOKING AT LIQUID BIOPSY AS A
BIOMARKERS FOR EARLY DETECTION
OF HCC AND INCLUDE LOOKING AT
DNA FRAGMENTS, LOOKING AT EXTRA
CELLULAR VESICLES OR EVEN TUMOR
CELLS THEMSELVES.
NOW, BECAUSE METHYLATION IS AN
EARLY STEP IN HEPATO PAPATHOGENS
THERE'S METHYLATION BEING PUR
AND COMPANIES HAVE DEVELOPED
TEST FOR HYPERMETHYLATION
CURRENTLY AVAILABLE AND CAN BE
PURCHASED.
HOWEVER, THERE'S A NUMBER OF
ISSUES THAT NEED TO BE RESOLVED
AND CHALLENGES AND LOW SENSITIVE
AND ISSUES WITH STANDARDIZATION
AND THE DIFFICULTY OF
REPLICATING A FAVORABLE
MICROENVIRONMENT THAT CAN
MAINTAIN CIRCULATING TUMOR CELLS
TO ALLOW THESE TYPES OF STUDIES
TO BE PERFORMED.
THERE'S UNANSWERED QUESTIONS AND
THE IMAGING PLUS THE BIOMARKER
AND WHAT SHOULD THE FREQUENCY
BE?
EVERY SIX MONTHS OR THREE
MONTHS?
A RECENT STUDY SHOWED A SHORTER
INTERVAL OF THREE MONTHS WAS FLO
BETTER COMPARED TO SIX MONTHS.
SECOND, THEY SHOULD BE MOVED TO
PRECISION SCREENING.
FOR EXAMPLE, ULTRASOUND PLUS THE
PROTEIN IS NOT SUFFICIENT IN
NON-OBESE PATIENTS COMPARED TO
MORE SENSITIVE IMAGING AND
BLOOD-BASED STRATEGIES MAY BE
MORE EFFECTIVE IN OBESE AND
SHOULD IT DIFFER FROM HCC RISK
AND THE HIGHEST PATIENTS BENEFIT
FROM MORE INTENSIVE SCREENING MR
OR CT AND OTHERS ULTRA SOUND
WITH OR WITHOUT A BIOMARKER.
ONCE A LESION HAS BEEN
IDENTIFIED IN AN AT RISK
INDIVIDUAL THE NEXT STEP IS TO
DIAGNOSE WHETHER IT'S INDEED HCC
OR NOT.
AND THERE'S MODALITY FOR
DIAGNOSIS.
THE BIOPSY IS NOT ROUTINELY
REQUIRED BECAUSE OF THE
SPECIFICITY AND THE CHOICE OF
USING CT OR MR DEPENDS ON
FACTORS I WON'T GO INTO IN ANY
DETAIL.
GIVEN THE DEPENDENCE OF ACC,
RADIO LOGIC CLASSIFICATION WAS
DEVELOPED TO TRY TO STANDARDIZE
THE REPORTING AND INTERPRETATION
OF IMAGING TESTS.
AND TO COME UP WITH THE
LIKELIHOOD SCORE THE LESION
OBSERVED IS LIKELY TO BE A
HEPATOCELLULAR CARCINOMA AND
THERE'S SEVEN CATEGORIES AND
ASSIGNS THE SCORE USING ARTERIAL
PHASE, HYPERENHANCEMENT AND SIZE
OF THE LESION AND ENHANCING
CAPSULE, NON PERATIVE VAL WASH
OUT OR INTERVAL THRESHOLD
GROWTH.
AGE THE CATEGORIES ONE AND TWO
ARE BENIGN LESIONS AND GENERALLY
DON'T REQUIRE FOLLOW-UP AND THE
INTERMEDIATE PROBABILITY AND 5
IS DEFINITE HCC.
THERE'S TWO ADDITIONAL
CATEGORIES WHICH STAND FOR
METASTATIC MALIGNANT DISEASE
WHICH IS NOT PRIMARY HCC BUT
LIKELY METASTATIC DISEASE AND
TIV FOR TUMOR IN VAIN.
-- TUMOR IN VEIN.
BECAUSE OF THE CLOSE ASSOCIATION
BETWEEN THE CATEGORY AND RISK OF
LESION BEING HCC, WE CAN ALSO
USE IT TO DETERMINE THE
SUBSEQUENT FOLLOW-UP OF LESIONS
DETECTED AND THAT'S SHOWN HERE
ON THIS SLIDE.
SO LIRADS 1 AND 2 PROBABLY
BENIGN CAN RETURN TO
SURVEILLANCE.
LIRADS ARE 20% TO 40% BEING ATC
SHOULD UNDER GO REPEAT IMAGING
WITH A MODALITY MORE SENSITIVE
AND IN THE SURVEILLANCE INTERVAL
REDUCED TO LIKELY THREE MONTHS.
FOR LESIONS, LIRADS 4 AND 5
REPRESENT PROBABLE HCC OR
DEFINITE HCC SUBSEQUENT
FOLLOW-UP SHOULD BE BASED ON
PRESENTATION OF THE CASE TO
MULTIDISCIPLINARY ROUNDS FOR
CONSENSUS FOR FURTHER
EVALUATION.
FINALLY, FOR THE LAST TWO STAGES
M AND TIV AND THERE WERE
DISCUSSIONS FOR TAILORED WORK
UP.
THE NEXT STEP FOLLOWING
DIAGNOSIS IS TO STAGE THE EXTENT
OF THE DISEASE.
NOW, UNLIKE OTHER CANCERS, TUMOR
BURDEN ALONE IS NOT THE ONLY
PREDICTOR MUCH OUTCOME.
-- OF OUTCOME.
AND OTHER FACTORS SUCH AS THE
SEVERITY OF THE UNDERLYING LIVER
DISEASE AND PERFORMANCE OF THE
INDIVIDUAL ARE IMPORTANT THAT
DETERMINE OUTCOME OF HCC.
THEREFORE A NUMBER OF STAGES
SYSTEMS HAVE BEEN DEVELOPED.
THE MOST COMMONLY USED IS THE
BARCELONA CLINIC LIVER CANCER
STAGING SYSTEM.
THIS HAS FIVE STAGES AND A
THROUGH D AND B INTERMEDIATE AND
C ADVANCED AND D TERMINAL STAGE.
THE ADVANTAGE OF THE SYSTEM IS
IT'S BEEN VALIDATED IN MULTIPLE
POPULATIONS AND IT ALLOWS US TO
RISK STRATIFY PATIENTS IN TERMS
OF THEIR PROGNOSIS.
IN 2022 THE BCLC STAGING SYSTEM
WAS UPDATED TO INCLUDE MORE
OBJECTIVE CRITERIA ON THE
UNDERLYING LIVER DISEASE
INCLUDING INCORPORATION OF
MODELS OF UNDERLYING LIVER
DISEASE SUCH AS THE MODEL FOR
END STAGE LIVER DISEASE USED TO
ASSIGN ORGANS TO PATIENTS FOR
LIVER TRANSPLANTATION AND THIS
ALLOWS MORE OBJECTIVE ASSESSMENT
OF UNDERLYING LIVER DISEASE.
FOR YOUR KNOWLEDGE I'VE INCLUDED
THE ONCOLOGY GROUP DESCRIPTORS
FOR FUNCTIONAL STATUS USED AS
PART OF THE BARCELONA CLINIC
CANCER SCORING SYSTEM.
OTHER IMPORTANT CAVEATS OF THE
BCLC STAGING SYSTEM IS IT ALLOWS
FOR THE HETEROGENEITY OF THE
PATIENTS.
FOR THE BALANCE OF THE TALK I'M
TALK ABOUT TREATMENT.
THERE'S BEEN SIGNIFICANT
DEVELOPMENT IN THE TREATMENTS
FOR HEPATITIS B PARTICULARLY
SYSTEMIC THERAPY.
I'LL TOUCH UPON THOSE LATER IN
THE TALK.
BROADLY WE CAN VIEW TREATMENTS
FOR HCC AS THOSE CURATIVE AND
THOSE NON-CURATIVE.
CURATIVE TRIES TO REMOVE
COMPLETELY THROUGH RESURGICAL
RESECTION OR LIVER
TRANSPLANTATION OR ABLATION.
WHEN YOU APPROACH IS PALLIATIVE
AND SOME QUALITY OF LIFE THROUGH
OTHER MEASURES SUCH AS TUMOR
EMBOWLIZATION AND STEREO TACTIC
BODY RADIATION AND BECAUSE OF
THE TYPES OF THERAPIES, AND
THERE'S ONCOLOGIST AND
PATHOLOGIST INVOLVED.
A LOT OF THE EVIDENCE USED TO
ASSESS TREATMENT HAS COME FROM
SMALL COHORT STUDIES BUT THERE'S
SOME CONTROLLED RANDOMIZED
STUDIES PROVIDED DATA AND THE
RECENT META-ANALYSIS HAS SHOWN
SURGICAL RESECTION LIVER
TRANSPLANTATION ABLATION CHEMO
ABLATION AND IMMUNE CHECKPOINT
INHIBITORS HAVE BEEN ASSOCIATED
WITH INCREASED SURVIVAL.
THIS ALGORITHM SHOWS THE
RECOMMENDATIONS OF THE BARCELONA
CLINIC CANCER STAGE BASED ON
LIVER BURDEN AND FUNCTION
SEVERITY AND PHYSICAL STATUS.
FOR PATIENTS WITH EARLY STAGE
DISEASE THEY'RE EXPECTED
SURVIVAL IS GREATER THAN FIVE
YEARS.
FOR THOSE WITH INTERMEDIATE
STAGE DISEASE, THESE PATIENTS
ARE BEST MANAGED WITH CASE OR
TRANS TUMOR ARTERIALIZATION AND
THEIR SUR VIVAL IS 3 TO 5 YEARS
AND TERMINAL STAGE DISEASE OR
STAGE D BEST MARKED WITH BETH
SUPPORTING YEAR AND THEIR OVER
ALL SURVIVAL IS ONLY ABOUT THREE
MONTHS.
NOW, THIS ALGORITHM I SHOWED YOU
HE
HERE IN GENERALIZATION AND THE
APPROACH FROM AN INDIVIDUAL
PATIENT IS MORE NUANCES.
WHAT I WANTED TO INTRODUCE HERE
WAS AN EMERGING CONCEPT AND THAT
IS OF TREATMENT STAGE MIGRATION.
WHERE IF A PATIENT MIGRATES OUT
OF A STAGE AND NO LONGER ABLE TO
RECEIVE THE RECOMMENDED APPROVED
THERAPY FOR THAT PARTICULAR
STAGE, ONE CAN EITHER USE AN
ALTERNATIVE THERAPY AVAILABLE
FOR THE SAME STAGE OR TRANSITION
TO THE NEXT ADVANCED STAGE AND
OFFER THE PATIENT THERAPY FOR
THAT STAGE.
FOR EXAMPLE, A PATIENT WITH
EARLY STAGE DISEASE WHO OTHER
WISE WOULD RECEIVE CURATIVE
TREATMENT MAY BENEFIT FROM CHEMO
LIBATION OR SYSTEMIC THERAPY AND
SO FORTH.
NOW LET'S LOOK AT THE MANAGEMENT
OF THROWS PATIENTS WITHOUT
CIRRHOSIS.
FOR PATIENTS WITH CIRRHOSIS
ADDITIONAL FACTORS NEED TO BE
CONSIDERED.
PARTICULARLY THE SEVERITY OF THE
UNDERLYING LIVER DISEASE AS WELL
AS THE FUNCTIONAL LIVER RESERVE.
HOW MUCH IS LEFT TO SUPPORT THE
PATIENT.
NOW, FOR INDIVIDUALS WITH A
SINGLE LIVER LESION WHO ARE WELL
COMPENSATED CIRRHOSIS IN THE
ABSENCE OF CLINICALLY
HYPERTENSION AND ESTIMATED LIVER
RESERVE OF MORE THAN 40%, SUCH
PATIENTS CAN BE MANAGED WITH
SURGICAL RESECTION AND THOSE
WITHIN THE CRITERIA CAN THEN BE
SALVAGED WITH LIVER
TRANSPLANTATION.
FOR THOSE INDIVIDUALS WHO HAVE
MORE THAN ONE LESION, THEY'RE
ELIGIBLE FOR LIVER
TRANSPLANTATION AND PATIENTS
WITH MORE THAN ONE LESION WITHIN
THE DOWN STAGING CRITERIA, THESE
SELECTED PATIENTS CAN BE DOWN
STAGED AND THEN OFFERED LIVER
TRANSPLANTATION AND HAVE GOOD
OUTCOMES.
SO I WANT TO REVIEW THE
CONTROVERSIES REGARDING
MANAGEMENT OF HEPATOCELLULAR
CARCINOMA PEOPLE I'LL BEGIN WITH
SURGICAL RESECTION OR ABLATION.
THEY GENERALLY HAVE A GOOD
PROGNOSIS BUT UP TO
THREE-QUARTERS MAY HAVE A TUMOR
RECURRENCE AT FIVE YEARS AND
THEIR ROLE FOR ADJUVANT THERAPY
TO REDUCE THIS RATE OF NON
RECURRENCE AND THE ANSWER HAS
BEEN EVOLVING.
WHEN I FIRST GAVE THIS TALK
ABOUT SEVEN OR EIGHT YEARS AGO
THE ANSWER WAS NO.
HOWEVER, IN 2023 THE ANSWER WAS
YES AND THAT'S BECAUSE DATA
BECAME AVAILABLE FROM
INDIVIDUALS UNDERGOING SURGICAL
RESECTION OR LOCAL ABLATION WHO
HAD FEATURES OF HIGH RISK FOR
REOCCURRENCE WHO UNDERWENT
THERAPY WITH A MONOCLONAL
ANTIBODY WERE SHOWN TO HAVE
SIGNIFICANTLY BETTER OUTCOMES AT
17 MONTHS COMPARED TO THOSE NOT
RECEIVING ADJUVANT THERAPY AND
THEREFORE THE RECOMMENDATION WAS
TO OFFER ALL PATIENTS ADJUVANT
THERAPY BUT WITH LONGER TERM
FOLLOW-UP AND IT SHOWS THE
IMPORTANCE OF THAT, THE SURVIVAL
ADVANTAGE DISAPPEARED.
SUCH THERE WAS NO DIFFERENCE IN
OUTCOME BETWEEN THE GROUP THAT
RECEIVED ADJUVANT THERAPY AND
NOT.
IN 2025 THE GUIDANCE REVERTED
BACK TO NOT RECOMMENDING
ADJUVANT THERAPY FOR RESECTIONAL
ABLATION.
I WOULD SAY STAY TUNED.
BECAUSE WITH IMPROVEMENTS IN
SYSTEMIC THERAPY, THIS
RECOMMENDATION IS LIKELY TO BE
REVISED YET AGAIN.
ANOTHER QUESTION IS HOW SHOULD
PATIENTS WITH CIRRHOSIS MANAGE.
THESE PATIENTS MAY BE ELIGIBLE
FOR LIVER TRANSPLANTATION BUT
NOT ELIGIBLE FOR RECEPTION
POINTS.
WHILE WAITING ON THE LIST FOR
LIVER TRANSPLANTATION SHOULD THE
PATIENTS RECEIVE IMMEDIATE
ABLATION OR TAKE A WAIT AND SEE
APPROACH?
IN GENERAL WHILE ON THE WAIT
LIST ONLY 10% OF PATIENTS
EXPERIENCE TUMOR PROGRESSION AND
THEREFORE THE RECOMMENDATION IS
CURRENTLY TO TAKE A WAIT AND NOT
ABLATE APPROACH HOWEVER THEY
NEED TO RECEIVE IMAGING UNTIL
TUMOR PROGRESSES TO MORE THAN 2
CENTIMETERS IN SIZE TO BE
ELIGIBLE TO RECEIVE ACCEPT
POINTS AND LISTED FOR LIVER
TRANSPLANTATION.
THE ONE EXCEPTION IS THOSE WITH
ELEVATED ALPHA PROTEIN LEVELS
AND THEY'RE AT GREATER RISK FOR
TUMOR PROGRESSION AND THESE
PATIENTS THE SUBSET OF PATIENTS
SHOULD RECEIVE IMMEDIATE
ABLATION.
ANOTHER DILEMMA IS THOSE AWADING
LIVER TRANSPLANT RECEIVE
THERAPY?
THE IDEA IS WHILE A PATIENT IS
WAITING DELIVER TRANSPLANTATION
WE CAN USE THE THERAPY TO
PREVENT PROGRESSION OF LIVER
DISEASE WHILE WAITING FOR A
GRAFT TO BECOME AVAILABLE
BECAUSE IF PATIENTS PROGRESS
THEY'RE NO LONGER ELIGIBLE TO
RECEIVE EXCEPTION POINTS AND MAY
HAVE TO BE RELISTED AND THE
CHRIST WAS DEVELOPED TO BENEFIT
PATIENTS AND IT'S DEFINED AS A
SINGLE LESION LESS THAN 5
CENTIMETER IN SIZE OR THREE UP
TO LESS THAN 3 CENTIMETERS
WITHOUT VASCULAR INVASION.
PATIENTS TRANSPLANTED HAVE
EXCELLENT PROGNOSIS 85% SURVIVAL
AND THOSE OUTSIDE THE CRITERIA
HAVE MORE MODERATE SURVIVAL ONLY
50% FOR FOUR YEARS.
AND WE HAVE TRANS ARTERIAL CHEMO
ABLATION AND IT'S BASED ON THE
UNDERLYING SEVERITY OF THE LIVER
DISEASE AND PERFORMANCE
CHARACTERISTICS OF THE
INDIVIDUAL PATIENT.
SOME TO BRIDGE ARE THE RISK OF
HEPATIC COMPENSATION AND NAY
RECOMMENDED BRIDGING THERAPY FOR
ALL WITHIN THE CRITERIA AWAITING
REGARDLESS MUCH WHAT OCCURS
WHILE WAITING FOR THE LIVER TO
BECOME AVAILABLE.
SHOULD PATIENTS OUTSIDE THE
MILAN CRITERIA BE DOWN GRADED
AND THE SHORT ANSWER IS YES BUT
THERE'S MANY CAVEATS.
THEY'RE THE OPTIMAL FORM OF DOWN
STAGING THERAPY IS NOT YET
KNOWN.
THERE'S NO RECOMMENDED OPTIMAL
TIME FOR TRANSPLANTATION AFTER
DOWN STAGING AND NO STANDARDIZED
CRITERIA OTHER THAN WITHIN THE
MILAN CRITERIA.
AND THE MOST WIDELY USED AND
BEST ARE THE UCF CRITERIA
ASSOCIATED WITH 81% SURVIVAL.
SIMILAR TO THAT IN PATIENTS
WITHIN MILAN CRITERIA AT TIME OF
LISTING.
THE ONLY SECTION IS THE INITIAL
BURDEN EXCEEDING THE MILAN
CRITERIA THOSE MEETING THE
CRITERIA SHOULD ALL BE
CONSIDERED FOR TRANSPLANTATION
FOLLOWING SUCCESSFUL DOWN
STAGING TO WITHIN MILAN CRITERIA
WITHIN A THREE TO SIX MONTH
PERIOD OF OBSERVATION.
THE FINAL CONTROVERSIAL ISSUE IS
WHETHER LOCAL THERAPY IS
EFFECTIVE FOR PATIENTS WITH
CIRRHOSIS WITH THAT ARE NOT
CANDIDATES FOR CURATIVE THERAPY.
FOR THESE PATIENTS, THE QUESTION
IS WHETHER THEY'D BENEFIT FROM
LOCAL REGIONAL THERAPY.
THERE'S BEEN SEVERAL ANALYSIS
AND SYSTEMIC REVIEW COMPARING IT
TO PLACEBO.
SHOWING VARIABLE RESULTS LIKELY
BECAUSE OF INHERENT BIASES AND
LOCAL REGIONAL THERAPY IS
BENEFICIAL AND THE PROCEDURE OF
CHOICE IS THERMAL ABLATION RADIO
FREQUENCY OR MICROWAVE ABLATION
TO MARK THE PATIENTS WHICH IS
PREFERRED OR ARTERIAL OR EX TERM
RADIATION PROTON BEAM THERAPY OR
CHEMOTHERAPY.
NOW FOR THE REMAINDER OF THE
TALK CARCINOMA.
IN THE LAST TWO DECADES THERE'S
BEEN SIGNIFICANT ADVANCEMENT IN
SYSTEMIC THERAPY FOR
HEPATOSTATIC CARCINOMA AND LATER
THERE WAS STUD YOZING THE THE
IMMUNE CHECKPOINT INHIBITERS AND
THEY HAVE EXPECTED SURVIVAL
OUTCOMES.
IN GENERAL THE SURVIVAL OUTCOMES
WITH SYSTEMIC THERAPY COMPARED
TO PLACEBO ARE APPROXIMATELY
THREE TO SIX MONTHS.
WE USE THE SYSTEMIC THERAPY AND
WE HAVE THOSE THAT ARE IMMUNE
CHECKPOINT INHIBITERS AND
THERE'S MULTI-KINASE INHIBITERS
AND THOSE OF ANGIOGENESIS AND
MONOCLONAL ANTIBODIES.
THE IMMUNE CHECKPOINT INHIBITERS
THAT PROGRAM DEATH AND THE
LIGAND AND THERE'S FIRST LINE
AGENTS EVALUATED IN RANDOMIZED
CONTROL TRIALS COMPARED TO THE
STANDARD OF CARE AND SEE IN THE
FIRST BOX THERE THE MEDIAN OVER
ALL SURVIVAL RANGES FROM 14
MONTHS TO 19 MONTHS.
EXPECTED INCREMENTAL SURVIVAL IS
THREE TO SIX MONTHS.
MEDIAN PROGRESSION FREE SURVIVAL
IS 3 TO 7 MONTHS.
UNFORTUNATELY THE AGENTS ARE
ASSOCIATED WITH SIGNIFICANT AND
SUBSTANTIAL ADVERSE EFFECTS.
AND WHILE THE AGENT DIFFERS WE
CAN MAKE GENERALIZATIONS IN THE
KINASE INHIBITORS ARE ASSOCIATED
WITH A RASH THAT AFFECT THE
HANDS AND FEET ASSOCIATED WITH
WEIGHT LOSS AND FATIGUE AND HAVE
HIGH RISK OF BLEEDING AND THE
IMMUNE CHECKPOINT INHIBITORS ARE
ASSOCIATE WITH IMMUNE RELATED
ADVERSE EVENTS THAT CAN AFFECT
ANY BODY SYSTEM BUT
PREDOMINANTLY THE G.I. TRACT AND
LIVER AND THYROID COMBLAND.
-- GLAND.
BECAUSE OF THESE IMMUNE RELATED
ADVERSE EVENTS THE INHIBITERS
ARE CONTRAINDICATED IN PATIENT
WITH AUTOIMMUNE AND
CONTRAINDICATED BECAUSE OF THE
POTENTIAL INCREASED RISK FOR
GRAPH REJECTION.
HERE'S A SELECTED SECOND LINE
STUDIES AFTER FAILURE OF
TREATMENT.
AND THE OVER ALL SURVIVAL RANGES
FROM NINE MONTHS TO 22 MONTHS IN
THE CHECK MATE TRIAL WHICH
EVALUATED A COMBINATION OF TWO
IMMUNE CHECKPOINT AND WE HAVE
THERAPY AT 22 MONTHS.
THE RESULT HAS NOT BEEN ABLE TO
BE REPLICATED IN OTHER STUDIES.
AND THE COMMON ADVERSE EVENTS
ASSOCIATED ARE SIMILAR TO THE
ONES I'VE PREVIOUSLY MENTIONED.
THIS PUTS IT TOGETHER AND
SUMMARIZES THE USE OF SYSTEMIC
AGENTS IN PATIENTS WITH
UNRESECTABLE HCC.
THE RECOMMENDED SYSTEMIC THERAPY
OR APPROACH FOR PATIENTS WITH
ADVANCED UNRESECTABLE HCC
IMMUNOTHERAPY IN COMBINATION
WITH AND MANY PATIENTS HAVE
CONTRAINDICATIONS LISTED NOTICES
OF THE SLIDES AND THOSE WITH
CONTRAINDICATIONS FIRST LINE
THERAPY WOULD BE WITH ONE OF THE
MULTI-KINASE INHIBITORS.
PATIENTS WHO FAIL FIRST LINE
THERAPY ARE ELIGIBLE TO RECEIVE
FIRST LINE THERAPY SHOWN IN THE
BLUE BOX AND SOME MAY BE
ELIGIBLE FOR THIRD LINE
TREATMENT OR REFERRED FOR
EXPERIMENTAL THERAPY IN CLINICAL
TRIALS.
SO THAT AN OVERVIEW OF
MANAGEMENT OF HEPATOSTATIC
CARCINOMA AND HEALTHY LIFE
STYLES ARE THE MEASURES TO
REDUCE HCC RATES.
SCREENING FOR HEPATOCELLULAR
CARCINOMA WITH THE PROTEIN IS
ASSOCIATED WITH IMPROVED
SURVIVAL AND HAS BEEN SHOWN TO
BE COST EFFECTIVE AND SHOULD BE
DONE IN ALL PATIENTS AT RISK FOR
HEPATOCELLULAR CARCINOMA AND FOR
THOSE WITH LESIONS THERE'S
APPROACHES SURGICAL RESECTION,
TRANSPLANTATION OR ABLATION.
OUTCOME IS GENERALLY QUITE GOOD.
FO
FOR PATIENTS WITH LATE STAGE
THERAPY ARE ASSOCIATED WITH
THREE TO SIX MONTHS SURVIVAL
TIMES COMPARED TO PLACEBO.
SO THANK YOU SO MUCH FOR YOUR
ATTENTION AND I'M HAPPY TO TAKE
QUESTIONS.
>> THANK YOU.
THANK YOU VERY MUCH.
BOTH OF OUR SPEAKERS.
WE MIGHT BEGIN BY ASKING, SANDY,
OR MARC DO YOU HAVE QUESTIONS OR
EACH OTHER AT THIS POINT RELATED
TO THE TWO PRESENTATIONS ANY
TAKERS.
>> MARC, I'M CURIOUS TO KNOW IF
YOU HAVE A PATIENT PRESENTING
WITH HCC BUT THE TWO VARIANTS
BUT DON'T KNOW AND HOW DO MAKE A
DECISION BEFORE GOING AHEAD ON
THERAPY?
>> THANKS FOR THE QUESTION.
WITH A LA CART RADIO LOGIC
IMAGING WE CAN DETERMINE THEM
AND MOST TRY TO AVOID FORMING
LIVER BIOPSY WHICH IS THE GOLD
STANDARD BECAUSE OF THE RISK OF
POTENTIALLY CAUSING METASTASIS.
MOST CAN BE DIFFERENTIATED WITH
IMAGING ALONE BUT THERE ARE
SELECTED CASES WHERE IMAGING IS
NOT ABLE TO DISTINGUISH BETWEEN
THE DIFFERENT FORMS AND ONE
NEEDS TO RELY ON LIVER BIOPSY.
UNFORTUNATELY THERE'S NO
BIOMARKERS CURRENTLY AVAILABLE
TO HELP YOU DISTINGUISH.
IN THE CASE OF FIBROLAMELLAR
CARCINOMA ONE CAN LOOK FOR THE
CHIMERA BUT THERE AREN'T ANY
BIOMARKERS I'M AWARE.
>> GO AHEAD, SANDY.
>> I WAS JUST THANKING HIM FOR
HIS ANSWER.
>> THERE'S CONSIDERABLE
INTEREST, SANDY IN THE
INVOLVEMENT YOU MENTIONED OF
XENOBIOTIC METABOLISM AND THE
TRANSFERASE.
THIS IS WITHIN THE TUMOR OR IS
THIS WITHIN THE PART OF THE
LIVER?
DO THESE INDIVIDUALS WHO HARBOR
FIBROLAMELLAR CARCINOMA HAVE A
DEFECT IN GLUCURONDATION AND
SOME ARE INNOCUOUS AND THOUGH
THERE'S A FAMILY OF TRANSFERASES
THERE'S LITERATURE ON WHAT WE
CALL MORE CONVENTIONAL
PHARMACOLOGIC AGENTS.
DO YOU WANT TO ELABORATE A
LITTLE BIT MORE, PLEASE ON THIS
RELATIONSHIP
>> IN THE CASE OF TICAN IT
REDRE
DI
DEUCES ITS ABILITY AND IT'S
METABOLIZED TWO OR THREE
PATHWAYS AND YOU HAVE TO
IDENTIFY WHAT WERE THE DRUGS
BEING SOLELY IDENTIFIED BY THOSE
METABOLIC PATHWAYS AND
METABOLISM DOWN REGULATED SUCH
AS THE UDP18 FAMILY OR 634
FAMILY.
>> ARE THEY CANCER CELLS?
>> THERE'S NO CLEAR SIGNS OF
POLARIZATION ON THEM.
SO MOST THE TRANSPORTERS SEEK
THEY'RE NOT EXPRESSED OR NOT
WHERE THEY SHOULD BE?
>> ACTUALLY WE HAVE NOT EXAMINED
THOSE.
>> WE HAVE ANOTHER QUESTION.
WHY ARE THE TUMORS LOADED WITH
FIBROUS TISSUE?
WE TOOK
>> WE TOOK PRIMARY HEPATOCYTES
AND PUT IN THE FUSION GENE AND
FOUND ALL THE CLASSIC
TRANSCRIPTS ARE INCREASED OR DIE
-- DECREASED AS YOU'D EXPECT.
I'LL GIVE AN EXAMPLE.
>> IS THIS COMMUNICATION WITH
THE STELLATE CELLS?
>> WHEN YOU PUT IN WILD TYPE OR
FUSION YOU GET ALL THESE CHANGES
THAT ARE PRETTY MUCH THE SAME.
THEY GIVE YOU PRETTY MUCH ALL
THE CHANGES YOU SEE IN
FIBROLAMELLAR.
THE ONE EXCEPTION IS COLLAGENS
WHICH GO DOWN.
THEY WERE DECREASED.
SO IF YOU LOOK OVER HERE, THESE
ARE A SERIES OF CLASSIC MUC13
TWO UP IN THE PATIENT TUMORS IN
BLACK AND IN THE PRIMARY
HEPATOCYTES BY PUTTING IN THE
TRANSFUSION TRANSCRIPT AND
COLLAGEN GOES DOWN AND WERE
CONFUSED WITH THAT AND DID
SINGLE CELL SPATIAL
TRANSCRIPTOMICS.
HERE THE TUMOR CELLS AND IN BLUE
THE NORMAL AND IN GREEN THE
STROMAL STELLATE CELLS.
IT'S IN THE STELLATE CELLS IN
GREEN, THE WISPY CELLS THEY'RE
EXPRESSED AND THE COLLAGEN IS
DECREASED IN THE FIBROLAMELLAR
CELLS.
WE HAVE THE RESPONSE TO THE
FIBROLAMELLAR CELLS.
>> THERE'S ANOTHER QUESTION THAT
SPILLS TO YOU, MARC.
ARE THE TUMORS FIBROLAMELLAR OR
HEPATOCELLULAR CANCER ARE OFTEN
DISCOVERED MORE THAN ONE
KNOWLEDGE -- NODULE OR SO IN THE
LIVER.
ARE THOSE SEPARATE ENTITIES OR
METAST
METASTASES?
YOU SHOWED THEY ALL SHOWED THE
SAME EXTRAORDINARY TRANSCRIPTOME
BUT HOW DO YOU INTERPRET THAT?
ARE THOSE LIKELY TO BE
METASTASES AND FOCAL SITE.
>> THE BREAK OCCURRING IS VERY
SLIGHT.
WE NEVER SEE IT IN SIBLINGS OR
FAMILY MEMBERS IN THE SAME AREA.
I THINK IT'S A RARE EVENT.
IT'S MORE LIKELY TO BE A
METASTASIS WITHIN THE LIVER BUT
COULD BE INDEPENDENT.
SINCE WE DON'T SEE GENETIC
DIFFERENCES BETWEEN THEM WE
DON'T HAVE THE DATA TO CLEARLY
RESULT BETWEEN THE TWO.
IT'S MORE OF SPECULATION NOT
SOMETHING WE HAVE GOOD
EXPERIMENTAL DATA TO RESOLVE ONE
WAY OR THE OTHER.
>> MARC, WHAT ABOUT IN THE MORE
COMMON HCC?
>> MOST COMMONLY IT PRESENTS AS
A SOLITARY LESION.
BUT YOU CAN GET MULTIFOCAL HCC
AS WELL.
I THINK MOST ARE CLONAL.
THE SAME MUTATIONS DRIVING THE
TUMOR.
MOST HCC OCCUR IN THE BACKGROUND
OF CIRRHOSIS AND CIRRHOSIS IS
CONSIDERED A PREMALIGNANT
CONDITION AND THAT'S WHY REALLY
TO PREVENT HCC THE GOAL SHOULD
BE TO PREVENT CIRRHOSIS FROM
DEVELOPING.
CANCERS DEVELOP IN THE ABSENCE
OF CIRRHOSIS.
THE ONE EXCESSION IS NOW
EMERGING AS AN INCREASING CAUSE
FOR CANCER IN THE ABSENCE OF
CIRRHOSIS.
THE OTHER IS HEPATITIS B.
THAT IS BECAUSE IT CAN DRIVE
CANCER THROUGH TWO MECHANISMS.
ONE IS THROUGH THE REPEATED
INJURY AND REGENERATION THAT
LEADS TO THE DEVELOPMENT OF
MUTATIONS TO DRIVE THE CANCER
AND ALSO REMEMBER IT CAN
INTEGRATE IN THE HOST GENOME AND
FIT GENERATES OR TURNS OFF THE
GENES CAN LEAD TO ONCOGENESIS
THROUGH A DIFFERENT PATHWAY BUT
ONLY 20% OF HPV RELATE THE
CANCERS GROW IN THE ABSENCE OF
CIRRHOSIS.
THE MOST OCCUR IN THE CIRRHOTIC
BACKGROUND.
>> IN THE ABSENCE OF CIRRHOSIS
AND I'M THINKING OF THE DAYS
WHEN THERE WAS A VIRTUAL
EPIDEMIC OF PRIMARY LIVER CANCER
IN HEALTHY PEOPLE FROM ZIMBABWE
AND THEN THERE WAS EVIDENCE THAT
I WERE EXPOSED TO THINGS LIKE A
AFLOTOXIN IS THAT STILL A IN
THOSE WHO HAVE CIRRHOSIS?
IS IT A FACTOR?
>> IT'S STILL CONSIDERED A TOXIN
IN DEVELOPING HEPATOCARCINOMA
AND THERE WERE WORK SHOWING THAT
IN TUMOR REPRESSOR GENES.
NOWADAYS PEANUT MODEL BECAUSE OF
THE IMPROVEMENT IN STORAGE
AFLOWTOXIN HAS BEEN REDUCED AND
IT'S NOT AS SIGNIFICANT FACTOR
AS MAYBE 30, 40 YEARS AGO.
THERE ARE OTHER TOXIN THAT CAN
CONTRIBUTE TO ACC DEVELOPMENT.
OBESITY IS CLEARLY ONE OF THEM.
>> WE HAVE SEVERAL QUESTIONS
WHICH GET DOWN TO THE SAME
THING.
THE LIVER CELL NORMALLY LIVES A
YEAR BEFORE IT DIVIDES.
IN CIRRHOSIS IS THERE A
RELATIONSHIP BETWEEN CELLULAR
TURN OVER AND THE PROPENSITY OF
MALIGNANCY?
>> THE LIFE SPAN OF A LIVER CELL
IS APPROXIMATELY 180 DAYS OR UP
TO MAYBE A YEAR.
WITH CHRONIC INFLAMMATION
TURNOVER OCCURS MORE RAPIDLY AND
OCCURS IN DAYS OR WEEKS AND
CONTINUOUS REPEATED BOUTS OF
NORTH AND REGENERATION CAN LEAD
TO MUTATIONS THAT CAN THEN DRIVE
HCC.
>> WE HAVE ANOTHER QUESTION,
MARC, AND DO YOU WANT TO SAY
SOMETHING ABOUT ALPHA FETAL
PROTEIN AND WHEN IT WAS
DISCOVERED ALMOST 40 YEARS AGO
IT ENJOYED A BRIEF MOMENT IN
FAME IN CANCER GENESIS AND
DIAGNOSIS AND NOW IT SEEMS AS
IT'S BEEN RESURRECTED AS THE
MOST SENSITIVE SCREENING TEST.
DO YOU WANT TO EXPLAIN MORE
ABOUT THAT?
>> IT'S NOT A SENSITIVE MARKER
OR SPECIFIC.
COMBINED WITH ULTRASOUND IT HAS
BETTER SENSITIVITY BUT NOT SO
MUCH SPECIFICITY UNLESS THE
LEVEL IS HIGH.
THE PROBLEM IS A SIGNIFICANT
PROPORTION OF HCCs DON'T MAKE
THE PROTEIN PARTICULARLY THE
WELL DIFFERENT IS THAT IATED TU.
IT'S A MARKER OF THE IMMATURE
HEPATOCYTE AND THOSE WELL
DIFFERENTIATED DON'T MAKE THE
PROTEIN MAKING IT NOT USEFUL FOR
DIAGNOSIS OR FOR TRACKING
OUTCOME FOLLOWING SURGICAL
RESECTION OR ABLATION.
THE OTHER ISSUE WITH THE PROTEIN
IS YOU CAN GET FALSE POSITIVE
RESULTS BECAUSE DURING BOUTS OF
REGENERATION IT CAN BE FALSELY
REGENERATED AND THERE'S OTHER
TISSUES THAT CAN PRODUCE THE
PROTEIN WHICH CAN LEAD TO FALSE
POSITIVES AND LEAD TO A WHOLE
MASSIVE WORKUP TRYING TO LOOK
FOR THE CARCINOMA WHEN IT'S
PRESENT.
SO IT'S NOT A VERY GOOD
BIOMARKER BUT ONE OF THE BEST WE
HAVE AND I WOULD NOT HANG MY HAT
ON ALPHA BETA PROTEIN.
>> YOUNG PEOPLE WITH
FIBROLAMELLAR CANCER DO NOT HAVE
UNDERLYING CHRONIC LIVER DISEASE
AND ARE DETECTED AS YOU POINTED
OUT IN YOUR DAUGHTER'S CASE BY A
MASS.
AND SYMPTOMOLOGY IS USUALLY A
LATE MANIFESTATION NOT AN EARLY
ONE UNLESS IT'S IN A STRATEGIC
PLACE IN THE LIVER.
IS THE PRESENTING COMPLAINT THE
PATIENT'S PRIMARILY FEEL A MASS
IN THEIR ABDOMEN OR HOW DO THEY
COME TO ATTENTION?
>> IT'S OFTEN DISMISSED IN MY
DAUGHTER'S TAKE THEY SAID IT WAS
DUE TO LACTOSE INTOLERANCE AND
SAID SHE MUST BE CHEATING AND
YOUNG WOMEN IN THEIR EARLY YEARS
IT'S A GIRL, IT'S STRESS.
BUT YOU KNOW YOUR KIDS AT A
CERTAIN POINT AND IN THIS CASE
THERE'S ONE THING ON THE SIDE
AND THERE WAS A SHARP PAIN SO WE
BROUGHT HER INTO THE
PEDIATRICIAN, HE SAID OH, IT'S
APPENDICITIS.
IT'S BEEN TWO YEARS.
IT CAN'T BE.
YOU'RE GOING RIGHT TO THE
HOSPITAL AND FORTUNATELY THEY
DID A SCAN AND WHAT THEY SAW WAS
NOT NOTHING WRONG WITH THE
APPENDIX BUT MASS IN THE LIVER
AND SAID IT'S BACTERIAL ABSCESS.
THEY PUT IN A TUBE TO DRAIN IT
AND OF COURSE NOTHING DRAINED
OUT.
IT'S ESSENTIALLY BEEN
MISDIAGNOSED IN THESE PATIENTS
FOR YEARS.
I'M NOT A CLINICIAN BUT RIGHT
NOW IN MY RECOMMENDATION WOULD
BE IF A KID IS COMPLAINING FOR
AN EXTENDED PERIOD OF TIME ABOUT
ABDOMINAL ACHES IS AN ULTRASOUND
AND SEE IF THERE'S A MASS OR NOT
AND ASSAYS WITH THE TUMOR DNA TO
PICK UP SIGNS OF THE FUSION DNA.
>> WHAT ARE THE IDEAS IN THE
RELATIONSHIP WITH SAY TO CANCER
IN GENERAL BUT CERTAINLY TO THE
MORE COMMON HEPATOCELLULAR
CANCER?
>> THINGS GET UP REGULATED FOR
VARIOUS REASONS.
YOU CARE FUNCTIONALLY WHAT IS
DRIVING THE TUMOR.
AND DO A FUNCTIONAL PROVISION
MEDICINE.
AND
>> AND SCREEN AGAINST EVERY DRUG
TEST AND WHAT IS DRIVING IT.
IT NOW BECOMES A USEFUL
THERAPEUTIC AND ONE WAY TO GO IS
NOT FROM A GENERALIZED
THERAPEUTIC BUT MUCH MORE
TARGETED.
IF IT'S DRIVEN BY FUSION
PROTEIN, YOU CAN COME UP WITH A
DEGRADER THAT TARGETS THE
PROTEIN AND BEYOND CANCER FOR
PROTEINS MISFOLDS OR AGGREGATED
WITHIN THE BODY.
THE TECHNOLOGY AND KNOWLEDGE OF
THESE TECHNOLOGIES WE DEVELOPED
I'M VERY FORTUNATE TO DO SCIENCE
IN A TIME WHEN WE CAN LEARN FROM
EACH OTHER QUICKLY AND THERE'S
ALL THESE NEW APPROACHES COMING
ONLINE NOW AND I THINK THE TERM
YOU'D SAY IS WE BUILD BRIDGES
WITH PEOPLE OF DIFFERENT
DISCIPLINES WHETHER IT'S
GENOMICS OR ELSEWHERE AND
TOGETHER WE AS A COMMUNITY NOW
ARE ABLE TO START APPLYING SOME
OF THESE PRECISION LESSONS AND
DEALING WITH OTHER KAERNLSS.
>> CAN I ASK SANDY A QUESTION,
IF I MAY?
>> SURE.
>> FIRST, THAT WAS A GREAT TALK.
MY QUESTION IS NOT ONLY HAVE YOU
PUT TOGETHER THIS PATIENTS WITH
FIBROLAMELLAR CANCER BUT HAVE
YOU IDENTIFIED ANY RISK FACTORS
THAT MIGHT HELP YOU IDENTIFY
PATIENTS WHO MIGHT BENEFIT FROM
SCREENING.
IT'S A RARE CANCER AND TENDS TO
PRESENT LATE BECAUSE UNTIL THE
GOES TO A CERTAIN SIZE IT WILL
BE LARGELY ASYMPTOMATIC.
MOST THE NERVE ENDINGS ARE IN
THE CAPSULE AND THERE ISN'T
NERVE ENDING WESTBOUND THE
LIVER.
CAN YOU IDENTIFY RISK FACTORS
THAT HELP CLINICIANS IDENTIFY
WHICH PATIENTS MIGHT BE AT RISK
FOR THIS PARTICULAR TYPE OF
TUMOR?
>> MANY PATIENTS ARE CLUSTERED
TOGETHER IN DIFFERENT PLACES.
THREE KIDS A FEW BLOCKS WITHIN
EACH OTHER THERE WAS A DRY
CLEANER CLOSED BY ENVIRONMENTAL
PROTECTION AGENCY.
WE HAVE MANY PEOPLE IN CLUSTERS
OUTSIDE OF MINNEAPOLIS WITH
THESE FOREVER CHEMICALS ARE
BEING DUMPED.
WE HAVE CLUSTERS TO THE WEST OF
PHOENIX NOT IN PHOENIX BUT AN
AREA THAT'S A KNOWN CANCER
ALLEY.
IT COULD BE AN ENVIRONMENTAL
TOXIN BUT DEPENDING ON WHERE IT
HITS ONE PERSON PRODUCES CANCER
X AND ANOTHER CANCER J AND THE
SAME ENVIRONMENTAL TOXIN.
WE KNOW THERE'S MUTATIONAL
SIGNATURES.
WE SEE CLUSTERS OF PATIENTS AND
WORKING TOGETHER WITH A GROUP
FROM CHICAGO FORMING THE
PEDIATRIC CANCER DATA COMMONS TO
SEE WHICH OTHER CANCERS HAVE
SIMILAR GEOGRAPHICAL CLUSTERS.
MY SUSPICION IS IN GENERAL THAT
PARTICULAR ENVIRONMENTAL TOXIN
IF THAT'S WHAT IT ENDS UP BEING
IS A RISK FACTOR FOR DISRUPTING
THE DNA AND MAY PRODUCE A CANCER
DEPENDING WHERE IT HITS IN THE
GENOME.
WE HAVE TO FIND WHAT'S TRIGGERED
IT BUT NOT SURE IT'S AN
APPROPRIATE MARKER FOR
SCREENING.
>> WE'RE RUNNING OUT OF TIME BUT
MARC WE HAVE WHAT IS AN
INEVITABLE QUESTION OF HOW
EXPENSIVE IS THE DRUG TREATMENT
OF HEPATOCELLULAR CANCER AND
WHAT IS THE QUALITY OF LIFE
OCCURRING THE PERIOD OF MONTHS
THAT IN THE OVER ALL LIFE IS
EXTENDED?
>> THESE DRUGS ARE OBVIOUSLY NOT
CHEAP.
THEY RUN IN THE THOUSANDS OF
DOLLARS FOR A MONTH OF COST.
THEY'RE ASSOCIATED WITH SIDE
WITH QUALITY OF LIFE AND THE
RASH WITH SOME AND GI HEMORRHAGE
IF IT OCCURS CAN CONTRIBUTE TO
THE PATIENT'S DEMISE.
AND PARTICULARLY WITH THE IMMUNE
CHECKPOINT INHIBITORS IF YOU
DEVELOP A COMPLICATION FROM
THESE IMMUNE RELATED
COMPLICATIONS THESE CAN BE
DIFFICULT TO MANAGE AND REQUIRE
LONG TERM THERAPIES.
TRYING TO FIND THE BALANCE
BETWEEN EFFICACY AND SAFETY HAS
BEEN CHALLENGING.
I THINK MOVING FORWARD I THINK
THINGS WILL IMPROVE.
NOW, IN TERMS OF COST, UNTIL
THERE'S COMPETITION TO DRIVE
DOWN COST IT'S PROBABLY NOT
GOING TO HAPPEN IN THE NEAR
FUTURE
>> DO INSURANCE COMPANIES
GENERALLY COVER THESE COSTS?
>> IF THEY'RE APPROVED THEY'LL
COVER THEM.
>> WELL, LISTEN.
WE HAVE RUN OUT OF TIME.
I WANT TO THANK YOU BOTH REALLY
FOR VERY EXCITING PRESENTATIONS
ON BOTH SIDES OF THE BRIDGE AND
I REALLY APPRECIATE BOTH OF YOU
TAKING THE TIME TO SHARE THE
EXCITEMENT OF YOUR WORK.
IT'S GREAT TO SEE YOU BOTH.
THANKS AGAIN ON BEHALF OF THOSE
ALL WATCHING AND AROUND THE
WORLD WHO IF NOT WATCHING TODAY
WILL SEE THIS THROUGH NIH VIDEO
ARCHIVE.
THANK YOU AGAIN FOR SHARING YOUR
EXCITING WORK.
>> THANKS FOR THE TALK.
WIN, THANKS FOR THE INVITATION.
>> THANK YOU, WIN, FOR THE
INVITATION.
HOPE TOO SEE YOU SOON, WIN.
>> OKAY.