I KNOW MOST EVERYONE
HERE. I WILL TALK ABOUT SMALL
CELL LUNG CANCER AND THE COMMON
THEME WHICH IS HOW MUCH WE CAN
LEARN FROM PATIENTS AND THE
THEME IS YOU DON'T NEED
THOUSANDS OF PATIENTS YOU
PROBABLY NEED A HANDFUL OF
PATIENTS AND YOU CAN MAKE, YOU
KNOW, IMPORTANT DISCOVERIES AND
OBSERVATIONS FROM A HANDFUL OF
PATIENTS, FROM A SMALL NUMBER OF
PATIENTS. SO I HAVE BEEN
STUDYING SMALL CELL LUNG CANCER
FOR THE LAST TEN YEARS AND
GLOBALLY LUNG CANCER IS THE MOST
COMMON CAUSE OF CANCER RELATED
DEATHS ALMOST AS MANY OF THE
NEXT THREE COMBINED, PROSTATE,
COLORECTAL AND BREAST CANCER AND
WITHIN LUNG CANCER, SMALL CELL
LUNG CANCER TENZ TENDS TO BE
THE MOST LETHAL TYPE.
WE FOUND THAT THOSE DETECTED BY
CT SCANS, MOST OF SMALL CELL
LUNG CANCER TENDS TO BE IN THE
ADVANCED OR METASTATIC STAGES
AND THIS COMPARES TO THE MORE
COMMON TYPE OF LUNG CANCER WHERE
IF YOU DO CT SCREENING AT
PATIENTS WITH HIGHER RISK IT
TENDS TO BE EARLIER STAGE AND
THE SURVIVAL HAS NOT CHANGED IN
MANY, MANY DECADES, THIS IS
DECADE GOING BACK TO 2001 AND
GOES UP TO 2016 BUT EVEN BEFORE
THAT THE TWO YEAR SURVIVAL RATE
HAS REMAINED STEADY BETWEEN
10-15% AND MOST PATIENTS WITH
SCLC DIE WITHIN A YEAR OF
DIAGNOSIS AND THE MEDIAN
SURVIVAL IS SEVEN MONTHS. AND
TO MAKE MATTERS WORSE SCLC WAS
NOT ONE OF THE TUMORS INCLUDED
IN TCLJ AND THIS IS BECAUSE IT'S
HIGHLY METASTATIC. AS A RESULT
MOST OF WHAT WE KNOW COMES FROM
CELL SCOMPLIENS MOUSE MODELS AND
THEN HUMAN BEINGS BUT THEN THE
CONVENTIONAL OR TRADITIONAL
RESEARCH.
SO WE HAVE TAKE AN DIFFERENT
APPROACH. YOU CAN CALL IT
REVERSE TRANSLATION OR BEDSIDE
TO BENCH OR WHATEVER YOU LIKE.
BUT THE IDEA IS TO DERIVE
INSIGHTS FROM PATIENTS AND TRY
TO EXPLAIN OBSERVATIONS IN
PATIENTS USING MECHANISTIC
STUDIES IN MORAL SYSTEMS IN
ANIMAL MODELS AND SO FORTH. AND
USING THIS APPROACH, OVER THE
LAST TEN YEARS NOW WE HAVE
CONDUCTED, YOU KNOW, SEVERAL
CLINICAL TRIALS AND ENROLLED A
LOT OF PATIENTS, PERFORMED A LOT
OF RESEARCH BIOPSIES AND
CONDUCTED RESEARCH AUTOPSIES AND
OUR GOAL IS FAIRLY SIMPLE. WE
HOPE TO PROVIDE A PERSONALIZED
PATIENT CARE WHICH ACTUALLY, YOU
KNOW, THE CLINICAL CENTER IN CCR
IS AN IDEAL ENVIRONMENT TO DO
THAT. IN THE SETTING OF
CLINICAL TRIALS, AND WE PERFORM
IN DEPTH TUMOR MOLECULAR
PROFILING TO COME UP WITH
PATIENT VARIABILITIES AND THE
HOPE IS TO ADVANCE SCLC
THERAPIES AND UNCOVER BIOLOGY.
BEFORE I GO INTO WHAT WE'VE
LEARNED, WHAT DOES A TYPICAL
SCLC LOOK LIKE? SO THIS IS A
PATIENT OF OURS WHO PRESENTED
WITH HIGHLY METASTATIC DISEASE,
THIS IS A CT SCAN OF THE CHEST.
AND YOU CAN SEE THAT THERE IS
INVOLVEMENT OF THE LUNG. AS
WELL AS MULTIPLE ORGANS WHICH
YOU CANNOT SEE IN THIS SECTION.
THESE TUMORS TEND TO BE HIGHLY
RESPONSIVE TO A COMBINATION OF
CHEMOTHERAPY WHICH WAS THE ONLY
OPTION FOR THE LAST 30-40 YEARS
OR SO AND THEN IMMUNOTHERAPIES
WERE APPROVED ABOUT 3-4 YEARS
AGO SO THE CURRENT STANDARD IS A
COMBINATION OF THEME THERAPY AND
PD-L 1 INHIBITORS. THE TUMORS
ALMOST MELT AWAY AND YOU THINK
THEY'RE ALMOST CURED.
A LOT OF COMPLETE AND PARTIAL
RESPONSES. BUT UNFORTUNATELY,
THESE TUMORS THEY COME BACK VERY
QUICKLY. AND RELAPSE TENDS TO
HAPPEN USUALLY IN A MATTER OF
WEEK TO MONTHS IN MOST PATIENTS.
AND AT THE TIME OF RELAPSE IN
THIS CASE YOU CAN SEE RELAPSE IN
THE LIVER AS WELL AS IN THE
ADRENAL. IT TENDS TO BE HIGHLY
RESISTANT TO ADDITIONAL
THERAPIES AND THESE ARE THE
TREATMENTS FOR RELAPSE. THIS
PATIENT DIED WITHIN SIX MONTHS
OF HIS DIAGNOSIS. AND LIKE I
SAID, THE MEDIAN SURVIVAL IS
SEVEN MONTHS SO LIVING UP TO A
YEAR TENDS TO BE EXCEPTION
RATHER THAN THE RULE. PLEASE,
PLEASE, YEAH. YES, WHEN YOU
TREAT WITH CHEMOTHERAPY THE -- I
WILL COME TO THE RESISTANCE IN A
BIT BUT IT CAN BE MODELLED IN
ANIMAL SYSTEMS. YEAH, PLEASE
FEEL FREE TO ASK QUESTIONS IN
BETWEEN. SO WHAT DOES IT LOOK
LIKE UNDER THE MICROSCOPE? SO
THIS IS A TYPICAL APPEARANCE OF
SCLC. THE CELLS TEND TO BE
SMALL TO MEDIUM SIZED THERE'S
VERY MINIMAL CYTOPLASM. AND THE
NUCLEAR FEATURES ARE VERY
INTERESTING, THEY'RE FINELY
DISPERSED CHROMATIN, NO DISTINCT
NUCLEI AND WE OBSERVE WHAT'S
CALLED NUCLEAR MOLDING THIS IS A
SITUATION WHERE ADJACENT CELL
NUKE LA CONFORM TO EACH OTHER.
OF COURSE THESE TUMORS DIVIDE
VERY RAPIDLY SO YOU SEE A LOT OF
MITOTIC FIGURES AND THERE'S --
THIS TRAUMA TENDS TO BE STRAND
AND FIE BRO VASCULAR. I WOULD
LIKE YOU TO KEEP IN MIND THESE
THREE FEATURES.
THE NUCLEAR MOLDING AND WE'LL
COME BACK TO IT IN A LITTLE BIT.
AND THEN FINALLY WHAT MAKES A
SCLC SO LETHAL? ONE IS THE
EARLY AND RAPID METASTASIS.
MOST PATIENTS ARE DIAGNOSED WITH
ALREADY STAGE THREE STAGE FOUR
DISEASE. IT'S THE HIGH LEVEL OF
CHEMOTHERAPY RESISTANCE. AND
PROBABLY AN UNDERLYING THEME
WHICH SORT OF ENABLES THESE
OTHER FEATURES IS THE HIGH LEVEL
OF TUMOR HETEROGENEITY. THE
HETEROGENEITY IS NOT DRIVEN BY
MUTATIONAL DIFFERENCES. THIS IS
A WHOLE GENOME SEQUENCE OF ABOUT
100 SCLCS YOU CAN SEE ALMOST
EVERY TUMOR IS MARKED IN RB AND
THESE TWO ARE LOST BY VARIOUS
MECHANISMS. BUT IF YOU LOOK AT
THE OTHER FREQUENT MUTATIONS,
MOST OF THEM INVOLVE MUTATIONS
IN CHROMATIN MODIFIERS OR OTHER
TUMOR SUPPRESSORS AND YOU
TYPICALLY DON'T SEE THE
MUTATIONS IN E.G.FR OR DRUG
MUTATIONS. IF BUT RATHER, THE
HETEROGENEITY IS DRIVEN BY
DIFFERENCES IN TRANSCRIPTIONAL
PROGRAMS RECENT STUDIES HAVE
SHOWN THAT IT CAN BE DIVIDED
INTO TWO GROUPS A LARGER GROUP
SEEN IN ABOUT TWO-THIRDS OF SCLC
SO THIS INCLUDES CELL LINES AND
TUMORS. THE LARGER GROUP
EXPRESSES NEUROENDOCRINE
PROGRAMS AND THESE ARE
REFLECTIVE OF THE CELLS OF
ORIGIN, THESE ARE PART OF THE
CELLS. SO THE LARGE PROPORTION
OF THEM HAVE THE GENE EXPRESSION
PROGRAMS AND A SMALLER
PROPORTION ABOUT A THIRD OF SCLC
THEY HAVE REDUCED OR ABSENT
EXPRESSION OF NEUROENDOCRINE
PROGRAMS. THEY'RE CALLED
NON-NEUROENDOCRINE SCLC AND THEY
LOSE THIS DURING PROGRESSION, SO
WE THINK TRANSCRIPTOMIC IS
LIKELY ALLOWING THIS TO BE CHEMO
RESISTANT AND TO HAVE, YOU KNOW,
VERY DISMAL OUTCOMES. RIGHT.
SO WE KNOW THAT SCLC HAVE
DISTINCT TRANSCRIPTOMIC SUBTYPES
AND LIKE OTHER TUMOR TYPES IF WE
CAN IDENTIFY SUBGROUP SPECIFIC
THERAPIES THIS COULD IMPROVE
OUTCOME. THIS IS THE BASIC
PREMISE THAT WE'RE WORKING WITH
BUT FOR NOW, DESPITE ALL THE
HETEROGENEITY T TREATMENT
STRATEGIES ARE UNIFORM.
AND EVERY SINGLE PATIENT IS
TREATED UNIFORMLY WITH THE SAME
TREATMENTS WHICH WE TALKED ABOUT
BEFORE. CHEMOTHERAPY AND THE
RELAPSE THERE'S A COUPLE
TREATMENTS THAT ARE APPROVED.
ALL RIGHT, SO THAT'S THE
INTRODUCTION SO FOR TODAY, I
WILL PRIMARILY TALK ABOUT TWOS A
PEB
PEBLTS -- ASPECTS OF OUR WORK.
HOW WE'RE TRYING TO OVERCOME
CHEMORESISTANCE AND REPLICATION
STRESS AND SECONDLY HOW WE ARE
TRYING TO TARGET HETEROGENEITY
IN PATIENTS AND TO UNDERSTAND
THE DRIVERS AND CONSEQUENCES OF
SCLC HETEROGENEITY SO THE FIRST
PART IS REPLICATION STRESS.
REPLICATION STRESS REFERS TO,
YOU KNOW, ANY PROBLEMS OR
IMPEDIMENTS WITH DNA REPLICATION
AND YOU CAN SEE HERE SOME OF THE
FEATURES THAT DRIVE REPLICATION
STRESS SO THESE INCLUDE ANYTHING
THAT INTERFERES WITH THE DNA
REPLICATION CAN CAUSE
REPLICATION STRESS AND IN SCLC
WE KNOW SOME OF THE KEY FEATURES
WE TALKED ABOUT, THERE'S
AMPLIFICATION THAT'S HIGHLY
FREQUENT. YOU KNOW, ALL OF
THESE ARE KNOWN FACTORS. AND
SCLC ALSO EXHIBITS MANY
CONSEQUENCES OF REPLICATION
STRESS AND THESE INCLUDE ZEENOMA
AND INSTABILITY WHICH IS
MANIFESTED LOAD. AND THESE
HUMANS RESPOND AND LITERALLY
MELT AWAY WITH CHEMOTHERAPY IT'S
ALSO A FUTURE OF TUMORS THAT ARE
UNDER HIGH REPLICATION STRESS.
RIGHT? SO WE HYPOTHESIZED BASED
ON THE REPLICATION STRESS MUST
BE A SCLC AND THE TARGETING
STRESS YOU CAN PRODUCE SUSTAINED
TUMOR RESPONSES IN PATIENTS.
AND THE MAIN TRANSDUCER OF
REPLICATION STRESS IS ATR. AND
AT THE TIME WE WERE THINKING
ABOUT THIS ATR INHIBITORS WAS
STARTING TO COME INTO CLINIC AND
WE FOUND THROUGH A CAT SCREEN
THAT INHIBITORS OF ATR ARE
HIGHLY TOXIC. SO WE TOOK THIS
OBSERVATIONS INTO CLINICAL TRIAL
WHERE WE PERFORMED A PHASE ONE
CLINICAL TRIAL COMBINING ATR
INHIBITOR. SO THIS WAS THE
FIRST THAT HAD COME AROUND
2013-14 THEN WE COMBINED THAT
WITH TOPOTECAN. IT CAN CAUSE
REPLICATION STRESS BY ITSELF.
AND IT'S ALSO AN APPROVED SECOND
LINE TREATMENT FOR SCLC PATIENTS
SO HERE WE ARE TAKING AN SCLC
DRUG THAT'S APPROVED, KNOWN TO
CAUSE STRESS AND YOU'RE
COMBINING THE INHIBITOR WHICH
CAN MESS UP THE RESPONSE BY THE
CELLS AND THE HOPE IS WE CAN
DAMAGE OR SELECTIVELY KILL THE
CELLS. SO IN TUMOR PHASE ONE
TRIAL IS TO KNOW IF THIS IS SAFE
IN PATIENT. THIS IS A
COMBINATION THAT'S NEVER BEEN
TESTED. ATR INHIBITORS HAVE
ALSO NOT BEEN TESTED IN
COMBINATIONS BEFORE SO WE
OBSERVED PHARMACODYNAMIC
ACTIVITY USING GEMMATES SIGNALS
COMING FROM THE HAIR FOLLICLES
AND WE FOUND THERE ARE INCREASED
SIGNALS WITH TREATMENT OF
TOPOTECAN BUT WHEN WE TREAT IT
WITH THE INHIBITOR, WE FOUND
THAT IMMEDIATELY AFTER
ADMINISTRATION OF ATR INHIBITOR
THERE WAS REDUCED
PHOSPHORYLATION IN THE HAIR
FOLLICLES AND WHEN WE COMPARED
TO WHAT WE WERE OBSERVING IN THE
MONONUCLEAR CELLS WHICH DON'T
REPLICATE AS MUCH WE FOUND THE
SIGNALS ARE MUCH REDUCED
SUGGESTING THERE IS SOME SORT OF
THERAPEUTIC INDEX WHERE THE
RAPID CELLS ARE MORE DAMAGED
THAN LESS RAPIDLY REPLICATED
CELLS AND EVEN IN THIS EARLY
PHASE ONE CLINICAL TRIAL WE
FOUND THAT A SMALL NUMBER OF
PATIENTS ABOUT THREE OR FOUR
PATIENT, MANY OF WHOM HAD
RESISTANCE TUMORS HAD TOO MANY
CASES.
SO TO TAKE AWAY FROM THE
STUDIES, IS THAT THE INHIBITORS
WITH TOPOTECAN IS SAFE AND
ASSOCIATED WITH PHARMACODYNAMIC
ACTIVITY. SO THE NEXT QUESTION
IS IS THIS COMBINATION
EFFECTIVE? SO FOR THAT WE
PERFORMED A PHASE TWO CLINICAL
TRIAL OF THE SAME COMBINATION,
ENROLLED ABOUT 25 PATIENT WHO IS
HAD PREVIOUSLY RECEIVED
TREATMENT FOR SCLC.
AND WE FOUND THAT THE
COMBINATION IS INDEED EFFECTIVE.
IN ABOUT 36% OF THESE PATIENTS.
AND INTERESTINGLY EACH BAR HERE
REPRESENTED BEST TUMOR RESPONSE
IN A PATIENT. WE FIND THAT
TUMOR RESPONSES WERE FOUND
REGARDLESS OF WHETHER THE
PATIENT HAD PLATINUM SENSITIVE
OR NOT WHICH MEANS THAT THEY HAD
RESPONDED TO PRIOR PLATINUM OR
NOT. AND THEY ALSO HAD
RESPONSES REGARDLESS OF WHETHER
THEY HAD PRIOR TOPOISOMERASE
INHIBITOR OR NOT. SUGGESTING
THIS MIGHT BE SENSITIZING TUMORS
THAT HAD PREVIOUSLY BEEN
RESISTANT TO TOPOTECAN AND COULD
BE APPLIED TO PATIENTS WHO HAD
RECEIVED THIS. AND YOU CAN SEE
THE RESPONSE IN THESE PATIENTS
AND YOU CAN SEE THAT OF COURSE
NOT ALL PATIENTS RESPONDED
WITHIN THE PATIENTS WHO
RESPONDED SOME OF THEM, MOST OF
THEM LASTED FOR MORE THAN SIX
MONTHS AND IN SOME CASE THE
RESPONSES WERE MORE DURABLE
LASTING MORE THAN 10 MONTHS AND
12 MONTHS IN SOME INSTANCES THIS
IS AN EXAMPLE OF A PATIENT WHO
HAD A VERY NICE TUMOR RESPONSE.
SHE HAD PREVIOUSLY RECEIVED A
COMBINATION OF IMMUNOTHERAPY AND
TOPOTECAN AND THIS WAS HER
BASELINE SCAN. YOU CAN SEE THE
TUMORS IN THE LIVER AS INDICATED
HERE AND THESE SHRANK WITHIN SIX
WEEKS OF TREATMENT AND YOU CAN
SEE THIS TWELVE WEEKS AFTER
TREATMENT. AND THE RESPONSE WAS
SUSTAINED FOR ABOUT 8-10 MONTHS
BEFORE SHE CAME OFF DUE TO
DISEASE PROGRESSION. SO WE FIND
THAT THE COMBINATION CAN CAUSE
DURABLE TUMOR RESPONSES SO WE
FOUND A COMBINATION THAT'S SAFE,
EFFECTIVE, THE NEXT STEP IS TO
SEE HOW DOES THIS COMBINATION
COMPARE TO STANDARD TREATMENTS?
RIGHT? SO THIS -- SO WE
PERFORMED A RANDOMIZED CLINICAL
TRIAL. 60 PARTICIPANTS WERE
RANDOMIZED TO RECEIVE EITHER
TOPOTECAN ALONE OR PLUS THE ATR
INHIBITOR. AGAIN AS WITH THE
PREVIOUS CLINICAL TRIALS THESE
PATIENTS HAD RELAPSED SCLC. HAD
RECEIVED ONE OR MORE TRIAL
THERAPIES AND THIS WAS A -- THIS
WAS ENROLLED ACROSS THE U.S.
THE SIXTEEN CANCER CENTERS
ENROLLED IN THIS CLINICAL TRIAL.
SO HERE LOOKING AT THE RESPONSES
IN THE PATIENTS IN THE LEFT IS
PATIENTS WHO RECEIVED TOPOTECAN
ALONE AND IN THE RIGHT IS
PATIENTS WHO RECEIVED BOTH
DRUGS, COMBINATION. AND YOU CAN
SEE THE RESPONSE RATES WITH
TOPOTECAN ALONE WAS 6%. THIS IS
CONSISTENT WITH WHAT WE EXPECT
WITH THE SINGLE DRUG AND WITH
THE COMBINATION YOU SEE THE
HIGHER RATES OF RESPONSES. AND
THE DURATION OF THE RESPONSE WAS
LONGER, 3.3 MONTHS, 9.3 WITH THE
COMBINATION. THE OTHER WAS THE
PROGRESSION-FREE SURVIVAL. WE
DID NOT SEE A DIFFERENCE IN PFS.
IT WAS ABOUT THREE MONTHS WITH A
SINGLE DRUG AND 3.9 WITH A
COMBINATION. SO THIS IS FROM
THE TIME OF THE ENROLLMENT TO
COMING OFF TREATMENT DUE TO
TUMOR PROGRESSION.
INTERESTINGLY HOWEVER WE SAW
THAT PATIENTS HAD SIGNIFICANTLY
LONGER OVERALL SURVIVAL WHEN
THEY RECEIVED THE COMBINATION.
ABOUT NINE COMPARED TO FIVE
MONTHS AND ABOUT 3-4 MONTHS
DIFFERENCE IN OVERALL SURVIVAL
WHICH IS A MAJOR DIFFERENCE IN
THE SCLC SETTING SO WE FIND THAT
THE COMBINATION RESULTED
IMPROVED RESPONSE, IMPROVED
DURATION OF RESPONSES AS WELL AS
IMPROVED OVERALL SURVIVAL. BUT
CLEARLY AS I THINK SEE NOT EVERY
PATIENT RESPONDS. SOME PATIENTS
RESPOND, SOME PATIENTS DON'T
RESPOND SO HOW DO YOU DETERMINE
WHO IS RESPONDING? SO FOR THIS
WE PERFORMED THE TREATMENT OF
TUMORS OF PATIENTS WHO ENROLLED
AND TWO OBSERVATIONS STOOD OUT.
ONE WAS THAT THE RESPONDING
TUMORS THAT WERE ENLISTED IN
PATHWAYS RELATED TO THE TARGETS
AND CHECKPOINT AS WELL AS
MULTIPLE DNA REPAIR SUGGESTING
THESE ARE TUMORS, THE RESPONDING
TUMORS ARE PROBABLY UNDER HIGH
LEVELS OF REPLICATION STRESS THE
SECOND TAKEAWAY FROM THE
SEQUENCING ANALYSIS WAS THE
TUMORS THAT RESPONDED HAD HIGH
LEVELS OF NEUROENDOCRINE
DIFFERENTIATION. IF YOU
REMEMBER, THIS GENERAL NAYTY
CONSISTS OF TWO BROAD GROUPS A
GROUP OF TUMORS THAT HAVE
DIFFERENTIATION.
AND THERE ARE SOME TUMORS THAT
LOSE NEURONS. AND WHEN WE LOOK
AT THIS KEY MARKERS INCLUDING
DURATION OF RESPONSE AND
PROGRESSION-FREE SURVIVAL WE
FIND THAT PATIENTS WITH TUMORS
THAT HAD THIS DIFFERENTIATION
HAD SIGNIFICANTLY LONGER
DURATION OF RESPONSE AS WELL AS
PROGRESSION-FREE SURVIVAL
COMPARED TO PATIENTS WHO HAD A
NON DEG REGAGS. TO TAKE -- AWAY
FROM THIS. THERE'S A HIGH
REPLICATION STRESS. AND THESE
ARE TUMORS THAT MIGHT BENEFIT.
FROM THESE COMBINATIONS. ATR
INHIBITOR AND SO FORTH SO HERE
WE HAVE A DISEASE THAT'S
CONSIDERED AS A SINGLE ENTITY.
WE CAN USE LIMITED NUMBER OF
PATIENTS. PRETREATMENT RNA
SEQUENCING AND IDENTIFY WHO IS
MORE LIKELY TO RESPOND VERSUS
NOT. NOW, REPLICATION STRESS IS
NOT A FEATURE THAT IS UNIQUE TO
SCLC. THERE'S A LOT OF OTHER
TUMORS THAT HAVE REPLICATION
STRESS. ALL THE OTHER TUMORS
THAT ARE WORKING RAPIDLY. THE
OTHER QUESTION IS CAN WE DEFINE
THIS TO IDENTIFY REPLICATION
STRESS? THAT'S WHAT WE TRIED TO
DO HERE SO WE USE THESE KEY
OBSERVATIONS FROM THE EARLY IER
DATA THAT I SHOWED. WE USED KEY
FEATURES KNOWN TO BE FEATURED.
SO THESE ARE ACTIVATION OF CHECK
ONE, AND RESPONSES TO CHECK ONE
INHIBITORS AND THESE ARE CELL
LINE DATA AND WE IDENTIFIED AN
18 GENE REPLICATION SIGNATURE
WHICH IS APPLICABLE TO SCLC AND
BEYOND AND WE VALIDATED IT. THE
FIRST OBSERVATION WAS AN
INCREASED REPLICATION STRESS
CODE OR REP STRESS CODE AS WE
CALL IT IS ASSOCIATED WITH HIGH
LEVELS OF INTRINSIC INSTABL
STABILITY THESE ARE ORDERED
BASED ON THE REPLICATION STRESS.
WE FIND THAT HIGHER REP STRESS
CORE CELLS HAVE HIGHER
EXPRESSION OF GAMMA AND WE
CONFIRMED THIS USING THE DNA
ASSAYS WHERE WE LABEL THEM WITH
THE ANALOGS AND WE FIND THAT
CELLS THAT LINE WITH THE STRESS
HAVE SHORTER ORIGIN DISTANCES
AND ALSO ASYMMETRIC FORKS AND
FINALLY WE HAVE APPLIED THIS TO
CELL LINES FROM ACROSS LINEAGES
SO THESE ARE NOW GOING OND
BEY --
BEYOND OTHER SCLCS TO OTHER CELL
LINES. NOW WE HAVE PREDICTORS
OF RESPONSE.
WE HAVE POTENTIAL -- OF COURSE
THESE NEED TO BE CONFIRMED IN
LARGER STUDIES AND SO FORTH.
THE NEXT QUESTION WE ASKED IS
CAN WE IMPROVE THE THERAPEUTIC
INDEX OF THESE THERAPIES? FOR
THIS COMBINATION THAT WE TESTED
TOPOTECAN PLUS ANOTHER. THE
COMBINATION IS RELATIVELY SAFE
BUT ALMOST EVERY SINGLE PATIENT
HAS ANEMIA AND ABOUT 50% OF THE
PATIENTS IT'S SERIOUS AND THIS
IS TO BE EXPECTED BECAUSE
THEY'RE A LOT MORE RAPIDLY
PROLIFERATING CELLS. YOUR HAIR
CELLS, EVERYTHING IS RAPIDLY
PROLIFERATING. SO, YOU KNOW, WE
WOULD EXPECT SOME LEVEL OF
THERAPEUTIC INDEX BECAUSE TUMOR
CELLS ARE MORE RAPIDLY
PROLIFERATING. THEY'RE MORE
RELIANT ON STRESS RESPONSES AND
SO FORTH BUT WE DO SEE
TOXICITIES. ONE APPROACH WE
TRIED TO MITIGATE THE TOXICITY
IS TO DELIVER CHEMOTHERAPY
RATHER THAN USE CONVENTIONAL
CHEMOTHERAPY THIS IS ONE OF THE
EARLIER CONJUGATES WHICH TARGETS
TROP 2 AND IT HAS A PAYLOAD.
RATHER THAN USING TROE POE TEE
CAN PLUS THE INHIBITOR HERE WE
ARE USING THE ISOMERASE
INHIBITOR USING AN ADC WITH AN
ADR INHIBITORS AND WE FIND THERE
IS MUCH LESS TOXICITIES SO WE
SEE A REDUCED FREQUENCY OF
ANEMIA. IT'S MUCH LESS
TOLERABLE. NOT TO SAY THAT THIS
IS COMPLETELY WITHOUT TOXICITY.
YOU KNOW, THE TECHNOLOGY IS NOT
EVOLVED TO A POINT WHERE WE'RE
ABLE TO DELIVER CHEMOTHERAPY
ALMOST EXCLUSIVELY TO THE TUMOR.
I DON'T THINK WE'RE THERE YET
BUT WE CAN SEE IT'S MUCH LESS
AND IN FACT WE'RE FINDING THAT
THE SECOND GENERATION
COMBINATION COMBINING ADC BASE
INHIBITORS PLUS THE OTHER
PRODUCES TUMOR RESPONSES AND
THIS IS A PATIENT WHO HAD
PROSTATE CANCER AND YOU SEE
MULTIPLE TUMORS PROGRESS AFTER
ONE OR TWO CYCLES OF
COMBINATION. OKAY, FINALLY WE
ARE ASKING WHAT IS THE MOLECULAR
BASIS OF REPLICATION STRESS?
AND THIS IS RELATIVELY RECENT
DATA WHICH IS UNPUBLISHED AND WE
FIND THAT AN UNEXPECTED TARGET
MIGHT BE DRIVING REPLICATION
STRESS IN SCLC SO THE USUAL
SUSPECTS ARE ON GENE
AMPLIFICATION. LIKE THE HIGH
AMPLIFICATION STRESS. MAYBE
THERE IS -- IT'S AN UNEXPECTED
TARGET. CALLED LAM ANYONE A
WHICH IS A NUCLEAR PROTEIN.
IT HAS MULTIPLE FUNCTIONS AND
THE INITIAL OBSERVATION WAS THAT
THE CELLS TEND TO HAVE REDUCED
LEVELS OF LAM MINA EXPANSION.
AND THIS IS COMPARED TO OTHER
CANCERS BUT YOU CAN SEE EVEN
WITH THE SCLC THERE IS SOMEWHAT
OF A VARIABILITY WITH SOME CELLS
HAVING HIGH EXPRESSION AND SOME
HAVING LOW LMNA EXPRESSION.
SO WE USED THE ONE WITH THE HIGH
LMNA EXPRESSION AND WE KNOCKED
OUT LMNA AND WE SAW THERE WAS AN
INCREASE COMPARED TO THE
CONTROL.
AND THIS IS EVALUATED BY BLOOD
AND WHEN YOU OVEREXPRESSED THE H
1 WHICH IS A NUCLEAR THAT
SPECIFICALLY DEGRADES RNA IN
HYBRIDS WE FIND THERE'S A
SOLUTION AND YOU CAN SEE THESE
GENOME WIDE BY DNA. THAT LMNA
KNOCK OUT HAVE SPECIFICALLY
MORE. SO WHAT ARE THESE? THESE
ARE RNA/DNA HYBRIDS AND THESE
RESULT IN DISPLACEMENT OF A
SINGLE STRAND DNA HERE AND WE
KNOW THAT R LOOP DEGRADATION HAS
MULTIPLE ROLES BUT DOES CAUSE
GENOMIC INSTABILITY AND WE FIND
THERE IS INCREASED LEVELS OF
GAMMA H 2X WHEN YOU SILENCE LMNA
BUT WHEN YOU SILENCE LMNA IN
ADDITION TO AGGREGATING OTHER
MECHANISMS. INCLUDING
INHIBITION AND USING TOPOTECAN
OR RNA INHIBITION YOU SEE
THERE'S EVEN MORE DAMAGE, RIGHT?
AND THE COMBINATION OF BOTH
DRUGS, TOPOTECAN IN THE SETTING
OF SI LAMINATE TENDS TO CAUSE
MOST DAMAGE SO SUGGESTING THAT
THE LMNA MIGHT BE REPLICATING
STRESS AND ONE OF THE MECHANISMS
OF THESE TWO DRUGS TO BE
EFFECTIVE COULD BE THAT IT COULD
BE INDUCING REPLICATION STRESS
WHICH IS LEADING TO INCREASED
DNA DAMAGE AND FINALLY WE FIND
THAT PATIENTS WHO HAVE REDUCED
LMNA LEVELS AND THEIR TUMORS
TEND TO HAVE WORSE SURVIVAL NOW
THE NEXT QUESTION IS, YOU KNOW,
HOW IS LMNA REGULATED? WE SHOW
THAT REGULATION INCLUDES THE
CATALYTIC COMPLEX. WE KNOW IT
ADDS GROUPS TO HISTONE THREE AT
LYSINE 27 AND THIS CREATES GENE
SILENCING AND WE SEE THIS BINDS
TO LMNA AND EPIGENETIC SEQUENCES
AND THIS SUPPRESSES THE
METHYLATION OF THE GENE AND WHEN
YOU TAKE SCLC CELL LINES, MOST
HAVE REDUCED LEVELS OF LMNA.
AND WHEN YOU USE AN H 2
INHIBITOR IT REEXPRESSES LMNA
AND THERE IS REDUCED H 3
TRIMETHYLATION WITH INHIBITION.
BUT COINCIDENTALLY WITH THIS
INDUCTION WE SEE THAT THESE ARE
THE EASIEST TREATMENT RESULTS IN
RESOLUTION OF R LOOPINGS, AGAIN,
WE FIND THESE ARE R LOOP SIGNALS
SPECIFICALLY FOR R LOOPS USING
RNA WHICH ACTS AS A CONTROL
HERE.
SO WE FIND THAT THE H 2
INHIBITION RESTORES EXPRESSION
AND SUPPRESSES R LOOPS AND THIS
ACCESS MIGHT BE CONTROLLING
REPLICATION STRESS IN SCLC CELL
LINES AS I MENTION LMNA HAS TO
DO WITH A LOT OF DIFFERENT
THINGS IN ADDITION TO GENE
SILENCING BY METHYLATION FROM
THE AXIS SO LMNA ALSO TRAIFS
HISTOLOGICAL FEATURES SO IF YOU
REMEMBER FROM THE EARLIER SLIDES
THESE ARE THE KEY HISTOLOGICAL
FEATURES AND TWO OF THEM I
HIGHLIGHTED WERE NUCLEAR MOLDING
AND ABSENCE OF NUCLEI. WHEN WE
LOOK AT THESE KNOCKOUT CELLS WE
FIND THAT THESE KNOCKOUT CELLS
ALSO HAVE INDISTINCT NUCLEI AND
ALSO SHOW THEM HUGGING EACH
OTHER AND THIS -- AND, AGAIN,
THEY OBSERVE THE SIMILAR
FINDINGS WHEN YOU KNOCK OUT LMNA
THEY TEND TO BE INDISTINCT AND
THESE FINDINGS SUGGEST THAT THE
LOW LMNA EXPRESSION MIGHT ALSO
EXPLAIN THIS HISTOLOGICAL
FEATURES OF SCLC INCLUDING THE
NUCLEAR MOLDING, LACK OF
DISTINCT NUCLEI AS WELL AS
CYTOPLASM BECAUSE IT ALSO
REGULATES CYTOPLASMIC, THE
AMOUNT THROUGH ITS CONNECTION
WITH THIS LINK COMPLEX WHICH
CONNECTS IT TO THE SAY TO
SKELETAL THROUGH THIS LINK
COMPLEX AND THE KEY PLAYERS YOU
SEE ARE SUM ONE AND NECESSARY
PRINT THROUGH THEM, IT ALSO
CONNECTS -- IT ALSO MAINTAINS
SAY TO SKELETAL INTEGRITY. YES
>> AUDIENCE: (SPEAKER FAR FROM
MIC).
>> VERY GOOD POINT. WE HAVE
USED IN COLLABORATION WITH THE
LAB HERE WE HAVE LOOKED AT ONE
MODEL OF AGING. SO THIS IS
YOUNG AND OLD FIBROBLASTSES FROM
THE SAME INDIVIDUAL DERIVED FROM
WHEN THEY'RE IN THEIR 20S AND
WHEN THEY'RE IN THEIR 60S AND
70S AND WE FIND THAT CONSISTENT
WITH WHAT WE'RE SEEING OLDER
FIBROBLASTS HAVE A REDUCED LMNA
EXPRESSION AND OLDER HAVE AN
INCREASED NUMBER OF R LOOPS SO
THERE SEEMS TO BE A COMMON
MECHANISM BETWEEN SCLC AND
MODELS OF AGING.
WHERE REDUCED LMNA IN THE CLC IT
IS MEDIATED REGULATION. BUT IN
THE OTHER IT CAN BE MUTATIONS IN
LMNA BUT IT CAUSES GENOMIC
INSTABILITY. WE THINK THAT'S AN
INTERESTING ANGLE BECAUSE, YOU
KNOW, THERE'S A LOT OF GENOME
INSTABILITY BUT I'M NOT AN
EXPERT BUT TALKING TO EXPERT I
DON'T THINK WE KNOW FULLY
CLEARLY WHAT EXACTLY CAUSES
GENOME INSTABILITY IN THIS.
>> AUDIENCE: (SPEAKER FAR FROM
MIC).
>> ANDREISH: WE'VE HAD DISCUSSI
WITH TOM ABOUT THIS. THANK YOU.
LMNA HAS A LOT OF DIFFERENT
FUNCTIONS. ANOTHER IMPORTANT
FUNCTION OF LMNA IS NUCLEAR
DEFORMABILITY. WE KNOW THAT
NUCLEAR DEFORMABILITY IS A RATE
LIMITED STEP IN THE MIGRATION OF
CANCER CELLS THROUGH CONFINED
SPACES THROUGH METASTASIS SO
HERE WE HAVE DONE SOME
EXPERIMENTS IN COLLABORATION
WITH WATER MAIN LAB WHERE WE
HAVE DONE THIS, YOU KNOW, THIS
SQUISHING ASSAY OR CONFINEMENT
ASSAY WITH CONSTRAINTS SCLC TO A
HEIGHT OF THREE MICRONS AND THIS
SIMULATES THE DEFINED MATRIX
THAT THE CELLS FACE DURING
METAST
METASTASES. AND NOW TO TEST
WHETHER THERE'S ENHANCED
DEFORMABILITY IN LMNA KNOCK OUT
CELLS HAS THIS THROUGH CONFINED
SPACES. WE HAVE DONE THIS IN
ANOTHER EXPERIMENT. THIS IS THE
ASPIRATION ASSAY. WE FIND THAT
LMNA KNOCK OUT CELLS TEND TO BE
DRAWN FURTHER INTO THESE NARROW
SPACE WHICH ARE ABOUT THREE
MICRON SIZE COMPARED TO THE
CONTROL CELLS. SO THEY ARE
TAKEN IN MUCH MORE RAPIDLY. AND
FURTHER, IF YOU NOTICE LIKE, FOR
EXAMPLE, THIS TIME POINT 60
SECONDS COMPARED TO THE CONTROL
CELLS THEY GO IN MUCH MORE
RAPIDLY COMPARED TO THE CONTROL
CELLS AND THIS IS QUANTIFICATION
HERE SUGGESTING THAT NOT ONLY
ARE THEY MORE DEFORMABLE THEY
TEND OF THE -- TO HAVE INCREASED
TRANSIT. BUT TO FURTHER ADDRESS
THIS, WE HAVE THESE LMNA
KNOCKOUT CELLS AND WE FIND THAT
IT'S INTERESTINGLY THE LATENCY
IS UNCHANGED SO THAT IS THE TIME
TO DEVELOP METASTASIS IS CHANGED
WITH KNOCKOUT COMPARED TO
CONTROL.
AS WELL AS THE OTHER IS CHANGED.
THE NUMBER OF MICE THAT DEVELOP
ME IT'S A TA SI IS SIMILAR IN
BOTH GROUPS.
BUT WE FIND THERE'S MUCH MORE
NUMBER IN LMNA KNOCKOUT CELLS
COMPARED TO INTACT CELLS
SUGGESTING THAT YOU KNOW LMNA
MAY NOT BE AFFECTING THE EARLY
STAGES OF METASTASIS BUT MAYBE
LATER IN THE LOCAL ENVIRONMENT
AND SO FORTH. SO THIS IS AN
AREA THAT WE ARE PURSUING.
COULD YOU MODULATE THESE LEVELS
TO VARY THE LEVELS OF LMNA AND
THAT COULD RESULT IN PHENOTYPES
AND SO FORTH. SO TO GIVE YOU A
QUICK OVERVIEW SO FAR, SO WE'VE
GONE FROM, YOU KNOW, HYPOTHESIS
AND SOME CELL LINE SCREENS THAT
THE COMBINATION OF ATR COULD BE
EFFECTIVE IN A CLC PATIENTS. WE
WENT FROM PHASE ONE TRIAL TO
PHASE TWO TRIAL SHOWING
EFFICACY, CONDUCTED A TRIAL, AND
DEVELOPED SIGNALS THAT CAN BE
EXPLORED TO OTHER TUMORS THAT
ARE UNDER HIGH REPLICATION
STRESS AND THEN MORE RECENTLY
WE'VE DONE MECHANISTIC WORK TO
SOMEHOW THAT LMNA MIGHT BE
DRIVING THIS STRESS NOT ONLY
REPLICATION STRESS BUT ALSO SOME
KEY HISTOLOGICAL FEATURES
INCLUDING NUCLEAR PATTERNS AND
MOLDING AND SO ON AS WELL AS THE
HIGH FREQUENCY OF ME AT THE TA
SIS. SOME OF IT IS STILL
ONGOING.
SO TO, YOU KNOW, SUMMARIZE THIS
SORT OF INITIAL PART WE FIND
THAT SCLC CELLS HAVE HIGH
VARIABILITY BETWEEN PATIENTS AND
THEY RESPOND TO REPLICATION
STRESS TARGETED AGENTS, LMNA
MIGHT BE A KEY DETERMINANT OF A
RESPONSE AND SO ON. SO WHAT
ABOUT THESE TUMORS THAT ARE
UNDER LOW APPLICATION STRESS?
WHAT IS GOING ON WITH THEM? SO
WE'VE DONE ANOTHER CLINICAL
TRIAL HERE ASSIST -- IT'S AN
IMMUNOTHERAPY TRIAL. VERY FEW
PATIENTS RESPONDED IN THIS
TRIAL.
THIS WAS A NEGATIVE CLINICAL
TRIAL AND USING SAMPLES FROM
PATIENTS, PRETREATMENT TUMOR RNA
SEQUENCING WE FOUND THAT IN THIS
CASE TUMORS THAT RESPOND TO
TREATMENT TO IMMUNOTHERAPY IN
THIS CASE AS ONE WOULD EXPECT
THESE TUMORS ARE ENRICHED IN
IMMUNE RELATED PATHWAYS BUT ALSO
IN THE NEURONAL SYSTEM IN
CONTRAST TO THE PREVIOUS DNA
REPAIR TARGETED THERAPIES
SUGGESTIONING IT IS THESE TUMORS
THAT THEY ARE RESPONDING TO.
AND A FELLOW AT THAT TIME TOOK
THESE CELLS, INDUCED NOT IN
THESE NEUROENDOCRINE CELLS. BUT
WE ALSO FOUND THAT WITH THIS
INDUCTION OF NEURAL ENDOCRINE
FEATURES SO YOU CAN SEE THIS IN
THE CELLS, THERE'S ALSO
INCREASED UPREGULATION OF
ANTIGEN PROCESSING AND
PRESENTATION MACHINERY SO
THERE'S A SUGGESTION THAT THE
LOW ENDOCRINE FEATURE IS A
RESULT OF INCREASED IMMUNE
ACTIVATION. THESE ARE THE
PATIENTS WHO THEY ARE MOST
LIKELY TO RESPOND TO
IMMUNOTHERAPY. SO AS I
MENTIONED EARLIER IT'S DIFFICULT
TO BIOPSY THESE PATIENTS AND
WE'RE FORGE NOT -- FORTUNATE
HERE THAT WE HAVE A GREAT IR
DEPARTMENT THAT CAN BIOPSY IN
SHORT NOTICE.
BUT IT WOULD BE NICE TO HAVE A
NONINVASIVE APPROACH TO PROTECT
THESE TUMORS. HERE WE WORKED IN
COLLABORATION TO APPLY THE
TECHNIQUE. THIS IS A FAIRLY
SIMPLE APPROACH. YOU DO THIS
USING ONE OR TWO PATIENTS'
PLASMA YOU CAN LOOK AT ANY MARK
BUT IN THIS CASE THEY LOOK AT
THE TRIMETHYLATION WHICH MARKS
THE ABILITY TO TRANSCRIBE AND
YOU GET A GENE COUNT AND
COMPARED TO THE CONTROLS, SCLC
SAMPLES HAVE SIGNIFICANTLY
INCREASED NUMBERS OF MULTIPLE
MARKERS LIKE DLL 3 AND THIS
PLASMA SCORE IT CORRELATES
POSITIVELY WITH CT SCAN BASED
TUMOR VOLUME. PATIENTS WITH
HIGH SCORES HAVE POORER OUTCOMES
BUT MOST IMPORTANTLY THIS IS
VERY POWERFUL APPROACH BECAUSE
YOU CAN REALLY TELL FROM
CIRCUL
CIRCULA
CIRCULATING P-SEQ IT'S TO THE
GENE LEVEL. NOT ALL HAVE THIS
LEVEL OF ACCORDANCE BUT ABOUT
20% OF THE GENES, ESPECIALLY
GENES WHICH ARE VERY
TUMOR-SPECIFIC SUCH AS SLK 1 AND
NEUROD 1. SO YOU CAN SEE THE
AKOR -- ACCORDANCE.
YOU CAN CONFER A LOT OF PROGRAMS
AND THIS IS SPECIFICALLY
IMPORTANT BUT IT'S NOT DRIVEN BY
MUTATIONS BUT BY GENE EXPRESSION
PROGRAMS. THIS CAN BE
POTENTIALLY USE AND FEEL WE'RE
DOING STUDY UPS WITH THIS. IN
AN IDEAL WORLD IF YOU TAKE THESE
PATIENTS, TREAT THEM WITH STRESS
TARGETED THERAPIES, AND TREAT
THEM WITH IMMUNE ACTIVATORS,
EVERYTHING WOULD BE GREAT, ALL
PATIENTS WOULD BE CURED BUT
UNFORTUNATELY, THIS IS NOT TRUE
BECAUSE THERE'S A LOT OF
HETEROGENEITY AND IT'S A MAIN
CAUSE OF TREATMENT FAILURE SO
HOW DO WE TARGET THIS IN SCLC?
SO IN THE NEXT TEN MINUTES OR SO
I WILL TRY TO HIGHLIGHT SOME OF
OUR EFFORTS. AND I THINK YOU
CAN SORT OF THINK ABOUT IT IN
THIS FRAMEWORK, ONE YOU EVER TO
-- YOU HAVE TO TAKE APPROACHES.
AND WE TALKED ABOUT HOW IT
ENFORCES A NEUROENDOCRINE
DIFFERENTIATION AND YOU HAVE TO
COME UP WITH DRUG COMBINATIONS
TO TARGET POPULATIONS AND
SIMILAR TO THIS IS HOW LEUKEMIA
AND LYMPHOMAS ARE BEING CURED.
YOU COMBINE DRUGS AS MUCH AS THE
PATIENT CAN TOLERATE, TO
HOPEFULLY TARGET MULTIPLE
DIFFERENT CLONES AND, YOU KNOW,
TAKE CARE OF THE CANCER VOLUME.
SO THE FIRST APPROACH IS
CONSTRAINING PLASTICITY WE
TALKED ABOUT ECH 2 INHIBITOR
WHICH IS ALREADY APPROVED FOR A
FEW DIFFERENT INDICATIONS AND
ESSENTIALLY WHAT IT DOES IS IT
REDUCES OR IT INHIBITS
METHYLATION AT 27. NOW WE'RE
DOING A PHASE ONE, TWO CLINICAL
TRIAL. IN THIS CASE WE GIVE IT
EVERYDAY FOR FIFTEEN DAYS. AND
THE HOPE IS THAT IT IS
PROGRAMMING IN THE TUMOR SO THAT
IT REPROGRAMS AND IS MORE
IMMUNOGENIC AND AT THE END WE
TREAT WITH CHEMOTHERAPY. SO
THIS IS AN ONGOING TRIAL BUT I
JUST WANT TO SHARE A PRE/POST
TREATMENT BIOPSY OF THE SAME
PATIENT FROM THE SAME SITE.
BEFORE AS THE MET TO STAT AND
AFTER. SO YOU CAN SEE THERE ARE
TWO. ONE IS MOSTLY FIBROTIC
TISSUE.
AND THIS IS THE CHALLENGE WE
FACE AND HERE WE HAVE DONE
SPATIAL TRANSCRIPTOMICS AND WE
CAN IDENTIFY THE TUMOR CELLS IN
PRETREATMENT AS WELL AS
POSTTREATMENT TUMORS AND YOU CAN
SEE AT LEAST IN THIS ONE SINGLE
CASE YOU LOOK AT THE EXPRESSION
OF ALC 1 WHICH IS A MARKER.
PRETREATMENT COMPARED TO
POSTTREATMENT WE HYPOTHESIZE
THERE IS REDUCTION IN THIS
NEUROENDOCRINE WITH AS THE ME TO
STAT SUGGESTING THIS COULD BE
MODULATING THE TUMOR,
EPIGENETICALLY PROGRAMMING AND
THAT IT MIGHT THEN RESPOND TO
IMMUNOTHERAPY. SO THIS IS AN
ONGOING TRIAL. ANOTHER APPROACH
WHICH WE COULD TRY IS RATIONAL
COMBINATIONS THAT TARGET
HETEROGENEITY. THESE ARE SOME
OF THE CELL SURFACE TARGETS THAT
HAVE BEEN EXPLORED. D 7H 3 AND
SO FORTH AND AS YOU KNOW THERE
ARE MULTIPLE WAYS TO TARGET
THESE CELL SURFACE PROGRAMS NOW.
THERE'S T-CELL ENGAGES AND THEN
CHIMERIC ANTIGEN RECEPTORS IN
THIS WAY WE ARE TARGETING TWO
CELL SURFACE PRO TEENS, DL 3 AND
TROP2 WHICH IS EXPRESSED
UNIQUELY IN THE ENDO CLINIC
CELLS.
HOW DO YOU TARGET THESE OR ANY
OR NON ANY. SO WE'RE DOING A --
PHASE ONE PHASE TWO CLINICAL
TRIAL WHERE WE ARE COMBINING A
BISPECIFIC ENGAGER THAT TARGETS
DLL 3. WHICH IS RECENTLY
APPROVED AND WE'RE COMBINING
THIS WITH AN ADC 3. SO THIS IS
A TRIAL WHICH WE HOPE WILL OPEN
NEXT -- EARLY NEXT YEAR. BY YOU
COULD ALSO THINK ABOUT TARGETS.
WE ARE ASKING PATIENTS HOW MANY
TARGETED TREATMENTS ARE NEEDED
TO ELIMINATE MOST TUMOR CELLS
WHILE WE SPARE NORMAL CELLS
BECAUSE AS I MENTIONED BEFORE
AA
DSH
ADCS ARE ANY OF THESE
APPROACHES. ANOTHER APPROACH IS
WE CAN TARGET ANTIGENS THAT ARE
OBSERVED ACROSS SITES. DOING
CLINICAL TRIALS OF COMBINATIONS
ARE EVEN MORE CHALLENGING,
TRYING TO GET DRUGS FROM TWO
DIFFERENT COMPANIES AND COMBINE
THEM. SO CAN WE IDENTIFY
TARGETS THAT ARE OBSERVED ACROSS
DIFFERENT SUBTYPES AND YOU CAN
SEE THIS IS PDX DATA THAT HAVE
BEEN STAINED FOR SOME OF THEIR
MARKERS. YOU CAN SEE THEY SEEM
TO BE A CONSERVED TARGET ACROSS
MULTIPLE DIFFERENT TUMORS
COMPARED TO DLL 3. SOME TUMORS
HAVE IT AND SOME DON'T.
SO FOLLOWING THIS OBSERVATION,
WE ARE STARTING A CELL TRIAL
FOCUSING ON B 7H 3. THIS IS A
COLLABORATION WITH ST. JUDE
WHICH HAVE DEVELOPED THE VECTOR
AND SHARED IT WITH AND THE
MANUFACTURING THAT WILL HAPPEN
AT NIHCCE THE GOAL IS WE CAN
COLLECT AND LOOK AFTER THESE
PATIENTS EVEN WHILE THEY'RE
GETTING THEIR INITIAL TREATMENTS
OR EVEN AT THE TIME OF DIAGNOSIS
THEY CAN HAVE T-CELLS HARVESTED
AND MODIFIED USING THE
CONSTRUCTS TO BE ADMINISTERED
LATER. SO THIS IS VERY
CHALLENGING PROTOCOL DEVELOPED
BY ONE OF OUR CLINICAL FELLOWS
ESPECIALLY BECAUSE THIS IS A
TUMOR THAT RAPIDLY GROWS, RIGHT?
YOU DON'T HAVE A LOT OF TIME
BETWEEN PROGRESS AND TREATMENT
AND USUALLY IN A MATTER OF WEEKS
YOU HAVE TO GET THE PATIENT
STARTED. SO THIS IS AN ON --
THIS IS ONGOING EFFORT AND WE
HOPE TO START THE PROTOCOL EARLY
NEXT YEAR AGAIN. AND FROM A
PATIENT'S PERSPECTIVE, YOU KNOW,
ONE OF THE MAIN CHALLENGES IS,
YOU KNOW, WHICH OF THE -- OR
FROM A PHYSICIAN'S PERSPECTIVE
OR CHALLENGES, YOU KNOW, YOU
HAVE SO MANY OF THESE TARGETS,
WHICH IS THE TARGET THAT IS MOST
APPROPRIATE FOR ME? OR MOST
APPROPRIATE FOR MY TUMOR? WITH
EACH GROUP WE'RE TRYING TO
LAUNCH THIS PATIENT MINOR
APPROACH WHERE WE HAVE AN OPTION
TO MATCH PATIENTS AND THE TARGET
ANTIGENS SO, AGAIN, THIS IS AN
APPROACH WHERE, THIS IS A
PLATFORM WHERE WE CAN UPLOAD RNA
SEQUENCING DATA FROM A PATIENT
AND THE QUESTION IS, WHAT IS IS
THE BEST CELL SURFACE TARGET FOR
A GIVEN PATIENT? IS IT TROP 2
OR ANOTHER THAT SPREADS ACROSS
TUMOR CELLS? BUT AT THE END OF
THE DAY THESE APPROACHES ARE
GREAT BUT TO TARGET THIS WE HAVE
TO GET A BETTER DETERMINANT.
WE'VE DONE TWO STUDIES IN THIS
AREA, ONE FOCUSING ON INTRINSIC
FEATURES AS I MENTIONED SCLC
STARTS FROM AN ENDOCRINE CELL OF
ORIGIN BUT OVER TIME IT
PROGRESSES TO A
NON-NEUROENDOCRINE STATEMENT.
SO THE QUESTION IS WHAT IS THIS
DRIVING THE TRANSITION AND IN
ANIMAL MODELS PEOPLE FIND IT IS
THIS UPREGULATION THAT DRIVES
THE TRANSITION AND IN ONE OF OUR
RECENT STUDIES WE FOUND THAT
EXTROE SEW MALL DNA MIGHT HAVE
THE BURST THAT ALLOWS IT TO ANY
TO NOT ANY STATE. ANOTHER IS
THE FEATURES. WHAT ARE THE
TUMOR EXTRINSIC FEATURES DRIVING
THIS HETEROGENEITY. WE FIND
THAT THE MICROENVIRONMENT CAN
SHAPE SUBTYPES. AND I WANT TO
HIGHLIGHT THAT, YOU KNOW, IN
BOTH THESE STUDIES, ESPECIALLY
STUDIES OF INTRATUMOR
HETEROGENEITY IT IS HARD TO GET
THIS FROM A PATIENT WHO IS
ALIVE. WE HAVE THIS PROTOCOL
WHICH IS REALLY AN AMAZING
OPPORTUNITY TO GET TUMOR
BIOPSIES FROM DIFFERENT SITES
AND THIS IS A COLLABORATION
WORKING WITH MULTIPLE GROUPS
PARTICULARLY IN THE PATHOLOGY
WHERE PATIENTS COME INTO THE
HOSPITAL AND THEY SPEND THEIR
LAST DAYS OR HOURS IN THE
HOSPITAL AND AS SOON AS THEY
PASS, WORKING WITH THE PATHOLOGY
TEAM, WE DO A RAPID AUTOPSY
USUALLY WITHIN AN HOUR OR TWO
AND OBTAIN MULTI-REGION
SEQUENCING AND SO ON. SO,
AGAIN, THIS IS A VERY USEFUL
TOOL TO ASSESS INTRATUMOR
HETEROGENEITY AND USING THIS TO
STUDY THE ENVIRONMENT WE ASK
THIS QUESTION, HOW IS THE TUMOR
DIFFERENT FROM NE AND NON-NE
TUMORS AND THIS IS LOOKING AT
LIGAND INTERCEPTORS AND THIS IS
USING AN OLDER PLATFORM. WE
FIND THAT NON-NE TUMORS TEND TO
HAVE MUCH MORE INTERACTIONS WITH
THIS TRAUMA COMPARED TO ANY
OTHER TUMORS.
YOU WONDER WHAT ARE THESE ACTION
AND WE FIND THAT FDF ARE MUCH
MORE ENRICHED AND NON-NE TUMORS
AND WE HAVE DONE SOME INTRO --
INVITRO STUDIES. WE HAVE A
TRIAL TO HOPEFULLY INTERFERE
WITH THIS NE AND NON-NE
REACTIONS WITH THIS TRAUMA AND
THIS IS AN ONGOING EFFORT AND IN
THE SPACE WE HAVE FOUND THAT
THIS CAN BE DRIVEN BY EXTRA
CHROMOSOMAL DNA SO HERE, WHEN WE
LOOK AT S SKRSHGSLC CELL LINES
WAS WE SEE THERE ARE SOME CELL
LICENSE WITH EXCEPTIONALLY HIGH
LEVELS OF GAINS.
AND THIS IS COMMONLY SEEN FOR
THE GENES. AND THESE TEND TO BE
MORE INTERESTED IN CELL LINES
COMPARED TO TUMORS. WHEN HE DID
THIS WORK, HE PROBED FURTHER, HE
FOUND THESE FOCAL AMPLIFICATIONS
COVER SMALL PORTIONS OF THE
GENOME ABOUT 15,000 TO A MILLION
BASE PAIRS AND FINALLY WE
CONCLUDED THAT THESE ARE ECD
AMPLIFICATIONS WHICH ARE FOCAL
AMPLIFICATIONS THAT INVOLVE
SEGMENTS FROM DISTINCT LOCI THAT
ARE ARRANGED IN A SINGLE
AMPLIFIED REGION IF YOU'RE NOT
FAMILIAR, THERE'S A LOT OF
ATTENTION THESE DAYS. I THINK
THEY ARE VERY COOL TO, FROM A
BIOLOGY STANDPOINT BUT OF COURSE
VERY LETHAL. THEY ARE FORMED
WHEN THERE'S DNA DAMAGE. SO ANY
FORM OF DNA CAN FORM THIS. AND
REARRANGEMENT INTO A SINGLE
REGION. SO THERE'S MULTIPLE
MECHANISMS. IF YOU HAVE A
DOUBLE STRAND REARRANGEMENT YOU
CAN HAVE A SIMPLE DNA. BUT YOU
CAN ALSO HAVE MASSIVE DNA DAMAGE
OR CHROMOSOME SHATTERING WHICH
CAN RESULT IN COMPLEX EC DNA BUT
WHY ARE THEY SO COMPLICATED
BECAUSE THEY DON'T HAVE
CENTRALNESS. THEY HAVE UNEQUAL
SEGREGATION THAT MEANS THEY CAN
CONCENTRATE IN SOME CELLS MORE
THAN OTHERS. AND THERE ARE
OTHER FUTURES OF EC DNA THAT
DRIVE HIGH ONCOGENE EXPRESSION.
THERE'S ENHANCERS AND CON TESTS
AS WELL AS HIGHER CHROMATIN
ACCESSIBILITY AND THIS IS ONE
EXAMPLE. IN THE SCLC CELL LINE
THERE'S TWO DNA'S. HERE YOU CAN
SEE THE SINGLE STRUCTURE. AND
WHEN WE DO SEQUENCE WE FIND
THAT, YOU KNOW, EACH COLUMN HERE
IS A SINGLE CELL. THERE'S A LOT
OF VARIABILITY IN THE
HETEROGENEITY. SO YOU CAN
IMAGINE THE COMPLEXITY OF THESE
CELLS THAT HAVE, YOU KNOW, SOME
DNA AND SOME DON'T HAVE EC DNA
SO THIS IS PROBABLY ONE FEATURE
THAT DRIVES THE HETEROGENEITY
AND THEY ALSO HAVE
COAMPLIFICATION OF REGULATORY
ELEMENTS. PROBABLY MOST
INTERESTING GOING BACK TO THIS
AUTOPSY OF THIS PATIENT WHO HAD
MULTIPLE SAMPLES. AND WE
PERFORMED WHOLE GENOME
SEQUENCING AND WE FOUND THAT MYC
IS FOUND IN DIFFERENT LEVELS.
SO WE HAD THE MYC AMPLIFIED
COMPARED TO LUNG AND ADRENAL
WHERE MYC IS MUCH MORE SMALLER
AMPLIFIED AND WHEN WE HOOK AT --
LOOK AT THE DNA WE SEE THIS AS A
STAINING REGION WHICH IS WITHIN
CHROMOSOME BUT IN THESE OTHER
LINES IT'S AN EC DNA. THERE'S
HIGHER LEVELS OF TRANSCRIPTIONAL
OUTPUT AND WE SEE THAT LIVER,
WHERE IT'S AMPLIFIED, THE TUMOR
HAS AN ASCL 1 END STATE BUT WHEN
IT GOES TO THE LUNG, YOU CAN SEE
THAT YOU START TO SEE THIS. SO
THIS SEEMS TO BE SUBTYPES THAT
SUGGESTS THIS IS ENHANCED BY THE
META STATIC SITES. THE QUESTION
THAT'S IMPORTANT FOR US IS TO
SEE IF IT CAN BE TARGETED.
AND THERE'S A LOT OF INTEREST.
THERE'S A RECENT PAPER SHOWING
THAT YOU CAN ENHANCE, THERE'S
MUCH MORE TRANSCRIPTION
HAPPENING AND ONE WAY TO TARGET
IT IS BY ENHANCING TRANSCRIPTION
REPLICATION CONFLICTS AND HERE
THEY USED CHECK ONE INHIBITORS
AND USING THE SAME APPROACH CHIP
THAT I MENTIONED EARLIER, YOU
CAN REALLY IDENTIFY EC DNA'S IN
MA. -- PLASMA.
YOU CAN SEE THE WHOLE GENOME
SEQUENCES AT THE TOP AND YOU CAN
SEE ALMOST MATCHED PROFILES FOR
BOTH CF AS WELL AS WHOLE
SEQUENCES AND OF COURSE IT'S --
IT LEADS TO FATALITY, AND THIS
TENDS TO HAVE MUCH WORSE
OUTCOMES AND ABOUT 20% OF SCLCS
HAVE EC DNA REPLICATION. TO
CONCLUDE, WE ARE TRYING TO
COMBINE THE DUAL POWERS OF
CLINICAL OBSERVATION. AND I
THINK THE POWER OF CLINICAL
OBSERVATION IS SOMEWHAT
UNDERESTIMATED THESE DAYS. IT'S
STILL VERY POWERFUL EVEN IN THE
AGE OF GENOMICS WE'RE TRYING TO
COMBINE IT WITH THE POWERS OF
GENOMICS AND WE'RE FINDING THAT
SCLC, A SINGLE DISEASE IS REALLY
A GROUP OF DECIDINGS -- DISEASES
THAT HAS UNIQUE VULNERABILITIES.
WE TALKED ABOUT MECHANISMS THAT
DRIVE THESE INCLUDING LMNA
SUPPRESSION BY ECH 2 WHICH MAY
EXPLAIN THE OTHER FEATURES AND
NOTCH MEDIA UPREGULATION IN THIS
CASE. SOME, YOU KNOW, SUBTYPES
WHICH WE DIDN'T TALK ABOUT WE
FOUND THAT NEVER SMOKERS, THEY
HAVE THEIR OWN GENOMIC FEATURES
AND THERE'S A COMPONENT OF
MUTATED SCLC THAT JUST GERMLINE
MUTATIONS IN KEY DNA REPAIRED
GENES AND THIS IS IMPORTANT
BECAUSE SCLC IS -- VERY CLOSELY
ASSOCIATED WITH SMOKING. ALMOST
ALL PATIENTS HAVE SMOKED AT SOME
POINT OR SECONDHAND SMOKE
EXPOSURE. WE TALKED ABOUT
DRIVERS OF SCLC. AND WE'RE NOT
AT A POINT WHERE WE CAN TARGET
THEM YET AND THE DRIVER AND
THERE ARE APPROACHES THAT YOU
CAN USE TO TARGET THEM AND THEN
NONINVASIVE SUBTYPES AND ONE WAY
TO TARGET HETEROGENEITY IN
PATIENTS IS BY USING
COMBINATIONS, BY STRAINING
PLASTICITY. THIS IS A VALUE OF
DEATH. THIS IS WHERE PATIENTS,
DRUGS, IDEAS DIE BUT WE FOUND
ONE APPROACH TO BRIDGE THIS
DIVIDE IS TO REALLY FOCUS ON THE
PATIENT AND OF COURSE, YOU KNOW,
I WANT TO THANK THE PATIENTS,
AND THANK CLINICAL GROUP AND TO
HAVE A GREAT CLINICAL GROUP AND
WE'RE FORTUNATE FOR THAT. WE
HAVE A GREAT RESEARCH GROUP AS
WELL AS THE NUMBER OF
COLLABORATORS BOTH WITHIN THE
BRANCH AND OUTSIDE THE BRANCH.
NUMBER OF FORMER FELLOWS WHOSE
WORK I HIGHLIGHTED AND OF COURSE
TECH TRANSFERS, STATISTICS AND
OF COURSE THANK YOU ALL FOR
COMING AND HAPPY HOLIDAYS.
>> AUDIENCE: (APPLAUSE).
>> AUDIENCE: THAT WAS GREAT,
THANK YOU. MIGHT BE A QUESTION.
I WAS UNDER THE QUESTION P 53
WAS A MAJOR EFFECT OF DEATH
AFTER STRESS. BUT YOU TOLD US
THEY HAD MUTATIONS. WHAT DO YOU
KNOW ABOUT THE MECHANISM OF
DOWNSTREAM OF REPLICATION STRESS
IN THESE CELLS? IS THERE
REMAINING? IS THERE SOME OTHER
MECHANISM WHAT DO YOU KNOW ABOUT
THAT?
>> ANISH: THAT'S A GOOD
QUESTION. SO I DON'T KNOW, IN
THE MECHANISMS, SO INDEED IT IS
P 53 MEDIATED. SO I'M THINKING
THAT, YOU KNOW, YEAH I DON'T
KNOW THE NON P 53 MECHANISMS
THAT MEDIATES THAT, YEAH.
>> AUDIENCE: ANISH, REALLY
BEAUTIFUL LECTURE, THANK YOU. I
HAD A QUESTION ABOUT THE
REPLICATION STRESS ASPECT OF
YOUR WORK. OBVIOUSLY A LOT OF
TUMORS ARE REPRODUCING QUICKLY,
THEY HAVE A LOT OF REPLICATION
STRESS. THOSE THAT RECUR AFTER
CHEMOTHERAPY, DOES IT STAND TO
REASON THAT THEY WOULD HAVE LESS
REPLICATION STRESS OR THERE ARE
OTHER MECHANISMS OF RESISTANCE
THAT COME UP?
>> ANISH: RIGHT SO WE'RE NOT
COMPREHENSIVELY LOOKED AT
MECHANISMS OF RESISTANCE THAT
OCCUR AFTER TREATMENT. SO ONE
OF THEM COULD BE DOWNREGULATION
OF REPLICATION STRESS RELATED
PATHWAYS. ONE COULD BE EMT, YOU
KNOW, SO WE HAVE SEEN THIS IN
SOME, AGAIN, IT'S VERY DIFFICULT
TO GET PRE/POST TREATMENT
BIOPSIES AND THAT'S REALLY A
MAJOR CHALLENGE SO EMT COULD BE
ONE AND HOW WE KNOW THAT IS WHEN
WE DO CIRCULATING TUMOR CELLS,
WE CAN PROFILE THEM USING
EPITHELIUM MARKERS, EP CAM AND
MAC ONE AND SO FORTH. WE FIND
THAT CTCS THAT ARE OBTAINED AT
THE TIME OF RELAPSE OR AT THE
TIME OF DISEASE PROGRESSION,
THEY TEND TO LOSE THESE
EPITHELIAL MARKERS SO MAYBE THAT
IS ONE MECHANISM. RIGHT. AND
THEN DRUG REFLEX TRANSPORTERS.
WE HAVE NOT FOUND IT BUT OTHER
PEOPLE HAVE. ABC 1, THEY CAN BE
AMPLIFIED ON DNA'S, THAT COULD
BE A THIRD MECHANISM.
BUT I THINK THE CELLS ARE SO
PLASTIC, SO TRANSCRIPTIONALLY
PLASTIC I FEEL MORE SO THAN
MUTATIONS IT IS, OR GENOMIC
ALTERATIONS, IT IS
TRANSCRIPTOMIC CHANGES INCLUDING
EMT AND POTENTIALLY OTHERS THAT
MIGHT BE DRIVING THIS RESISTANCE
AND FOR INSTANCE, PEOPLE HAVE
SHOWN THAT TUMORS OBTAINED AT
THE TIME OF RELAPSE THEY TEND TO
BE MORE NEUROENDOCRINE SO THAT
COMES WITH MORE FEATURES,
REDUCED REPLICATION STRESS,
CHEMOTHERAPY RESISTANCE AND
RADIOTHERAPY RESISTANCE I THINK
IT'S GOING TO BE A LITTLE BIT OF
EVERYTHING.
>> AUDIENCE: SO THE OTHER, IF
CAN I ASK ANOTHER QUESTION, I
WANTED TO FOLLOW UP WITH LMNA.
ONE OF THE FEATURES IS THAT ONE
OF THE TREATMENTS FOR PROJEER YA
HAS BEEN INHIBITORS WHICH BY THE
WAY WERE PERFORMED FOR TREATING
TUMORS. WHAT WOULD YOU EXPECTS
FOR ISOLATION INHIBITORS TO DO
IN YOUR SYSTEM AND MIGHT THEY
SENSITIZE MORE CELLS TO THE
REPLICATION STRESS TREATMENTS?
>> ANISH: SO WE'VE NOT TRIED THE
FAR THAT CELL TRANSFERASE
INHIBITORS IN THIS CASE BUT I
THINK THOSE AGENTEDS MIGHT BE
MORE SPECIFIC TO THE SETTING OF
PROJAR YA WHERE THERE'S AN LMNA
MUTATION.
BUT IN THIS CASE WE SEE IT'S
PROBABLY A SUPPRESSION OF LMNA
AND MAYBE THE AGENTS MIGHT BE A
WAY TO REACTIVATE LMNA RATHER
THAN USING FAR THAT CELL
INHIBITORS. I THINK, YOU KNOW,
THE CONSEQUENCE IS PROBABLY
SIMILAR THAT AS A DYSFUNCTIONAL
LMNA BUT MAYBE THE MECHANISMS
ARE SLIGHTLY DIFFERENT AND THE
DRUGS MIGHT NOT NECESSARILY
TRANSLATE.
>> AUDIENCE: HEY, I AM A BIG
FAN. SO I AM BIASED. AMAZING
WORK. BUT ALSO AMAZING
CHALLENGES. I MEAN, SO
CHALLENGING AND DIFFICULT TO
MAKE IT END?
>> ANISH: YEAH, WE HAVE A
PERSONAL THERAPIST FOR THE
GROUP.
>> AUDIENCE: YOU KNOW I HAVE
SOME SKILLS IN THAT DOMAIN.
CHEAP IS CHEAP. I KNOW. I
KNOW. YEAH, SO JUST A FEW
COMMENTS AS FAR AS I STILL
REMEMBER, SO ONE, YOU REMEMBER
SJ. WE HAVE A PREDICTOR OF
EXTRACELLULAR DNA FROM THE
SLIDES. IT'S ACTUALLY, WE HAVE
ALL THAT. SO THAT'S ONE
DIMENSION. I MENTION IT BECAUSE
I WILL NOT REMEMBER. THE SECOND
THING IS, THAT WE CAN LOOK AT
THE PREDICTED SPATIAL
DESTRUCTION. -- SPATIAL
DISTRIBUTION.
WE SHOULD DO THAT.
THIRDLY, YOU KNOW I COULDN'T
HELP THINKING ABOUT THIS MAYBE
SOME ANALOGY, MAYBE IT'S TOO
SIMPLISTIC TO NEURAL BLASTOMA
SO, YOU KNOW, ALSO FROM THE --
FROM -- CAROL IS HERE? OH.
YEAH, SO CAROL JUST SENT HER
FELLOWS SENT US SOME POSTER, MY
NAME WAS IN IT, I'M CLUELESS BUT
I READ IT WITH MY INTEREST AND
APPARENT LY CAROL CAN SAY MORE
BETWEEN THESE. AND MAKE HIGHLY
INVOLVED -- I WONDER ABOUT THIS
ANALOGY AND YOU SHOULD TALK TO
CAROL. THE WORK YOU D DID YOU
HAVE TO DO COUNCIL CELL CAPTURE?
>> ANISH: IT'S A FAIRLY SIMPLE
PROCEDURE. THEY LOOK AT PLASMA
AND THEY HAVE THE ANTIBODIES
AGAINST THE PARTICULAR HIS TOME
MODIFICATION. THEY CAPTURE AND
THEY DO SEQUENCING. SO THERE'S
NO CANCER CELLS INVOLVED.
IT'S JUST PLASMA THAT'S ISOLATED
FROM PATIENTS. SO WE DOUBLE
SPIN PLASMA THAT'S COLLECTED IN
TUBES AND THEY LOOK AT THIS HIS
TOME MODIFICATION DIRECTLY.
>> AUDIENCE: WHEN YOU SAY IT'S
COLLATED WITH 26 TRANSCRIPT, IT
EXCITED ME. YOU MEAN CELLS IN
THE TUMOR BUT YOU MEAN WHAT?
TUMOR CELLS, BULK EXPRESSION?
>> ANISH: THE EXPRESSION IS CUE
MORE CELLS. TWO CIRCULATING
SUB-SEQ BASED EXPRESSION OF THAT
GIVEN GENE.
>> AUDIENCE: BUT IS IT BULK
EXPRESSION OF THE TUMOR TME OR
THE EXPRESSION OF TUMOR CELLS?
>> ANISH: TUMOR CELL.
>> AUDIENCE: WOW SO THAT'S
AMAZING. WE SHOULD TALK BECAUSE
WE CAN -- THAT'S AMAZING.
>> ANISH: I THINK IT'S A REALLY
POWERFUL TOOL WE WORKED WITH A
LOT OF DIFFERENT APPROACHES IN
CIRCULATING FREE DNA STARTING
FROM LOOKING AT MUTATIONS,
METHYLATION, MODIFICATIONS IN
PLASMA, FLAG MEN TOMICS, BASED
IN THE POSITIONING AND SO FORTH
BUT BY FAR, THIS IS PROBABLY THE
BEST APPROACH. TO INFER TUMOR
GENE EXPRESSION PROGRAM AGAIN,
IF IT'S A GENE THAT'S EXPRESSED
IN NORMAL TISSUE, LIKE, FOR
EXAMPLE, IF YOU'RE LOOKING AT
ENVIRONMENT YOU DON'T SEE THE
CONCORDANCE BECAUSE NORMAL
TISSUE IS SHEDDING IT AND YOU
DON'T SEE THAT. BUT IF IT'S A
TUMOR-SPECIFIC GENE WE CAN
DETECT THAT.
>> AUDIENCE: BUT WE CAN INFER
THROUGH THE BIOMARKERS DIRECTLY
THROUGH THE BLOOD FOR MANY DRUGS
AND TARGETS AND FINE
SENSITIVITIES. WITHOUT A NEED
FOR BAY BIOPSY.
>> ANISH: YES, AND WE SHOULD
TALK. THIS EPITHELIAL, YOU
KNOW, IT'S VERY EVIDENT IN
NEUROBLASTOMA, IT HAS A LOT OF
COMMONALITIES, THE CELL OF
ORIGIN IS NOT THE SAME BUT THERE
IS A LOT OF COMMONALITIES, CELL
STATE TRANSITIONS, DRUG
SENSITIVITY, YES.
>> AUDIENCE: BUT IT IS MUCH MORE
STILL RESPONSIBLE TO THERAPY.
OF COURSE IT IS EXTENSIVE SO
WHY, YOU AND CAROL SHOULD -- I
CAN SERVE COFFEE, I'LL BRING YOU
AND CAROL TO THE SAME ROOM. WE
MUSTN'T -- WHY, I STILL DIDN'T
COME OUT FROM THE -- YOUR TALK
WITH AN UNDERSTANDING WHY IS IT
SO DIFFICULT TO TREAT?
>> ANISH: I THINK THE COMMON
THEME IS HETEROGENEITY AND --
>> AUDIENCE: BUT MANY ARE --
>> ANISH: THIS IS PROBABLY AN
EXTREME CASE.
>> AUDIENCE: I THINK IT'S THE
DYNAMICS OF THE RESISTANCE BUT
WHAT DO I KNOW? THANK YOU SO
MUCH.
>> ANISH: THANK YOU.
>> AUDIENCE: TERRIFIC WORK AND
IT'S SO NICE OF YOU TO SHOW THE
BENCH TO BEDSIDE EFFORTS MY
QUESTION IS ABOUT THE
HETEROGENEITY. SPECIFICALLY,
YOU MENTIONED THAT THIS IDEA
THAT I THINK WE'VE -- MY TEAM
HAS BEEN PRETTY INTERESTED IN
LOOKING AT, WHAT IS THE
HETEROGENEITY AT THE EARLIEST
POINT OF METASTASIS, BEFORE YOU
HAVE THIS BULK TUMOR AND THESE
COLONIZING CELLS WHAT IS THE
NECESSARY HETEROGENEITY THERE?
HOW DO THEY INTERACT WITH EACH
OTHER? IS IT MORE COOPERATIVE
THAN SURVIVAL OF THE FITTEST AND
FROM THERE, WHAT ARE OBVIOUSLY
THE CROSS TALK BETWEEN THE
MICROENVIRONMENT AND THAT
ALTHOUGH PERHAPS THEY'RE
PARALLEL EVENTS. YOU KNOW, THE
EVOLUTION OF THE
MICROENVIRONMENT AND THE
EVOLUTION OF THE TUMOR MAYBE
HAPPENING CONCURRENTLY BUT NOT
NECESSARILY SYNERGISTICALLY.
ALTHOUGH MAYBE. SO MY QUESTION
IS YOU DID MENTION ABOUT TARGETS
TO THAT. AND TRYING TO WORK
WITH THEM ABOUT WHAT IS THE GOAL
NUMBER OF TARGETS? I WONDER
ABOUT THAT TOO. IF WE THINK
IT'S COOPERATIVE THAT EACH SUB
CLONE ACTUALLY IS BETTER IN A
GROUP OF OTHER DIFFERENT CLONES,
YOU KNOW, LIKE TEAMWORK MAKES
THE DREAM WORK ALMOST.
RATHER THAN ONE CLONE HAVING TO
BE DOMINANT THAN WHAT IS THE
NUMBER THAT YOU WOULD NEED, WHAT
ARE THE TARGETS BECAUSE I THINK
THE DAYS -- AND YOU KNOW, THE
DAYS OF THAT SINGLE APPROACH
WHICH WE'RE DOING WITH
IMMUNOTHERAPY BY THE WAY, THIS
IS A GREAT TARGET BUT IT'S ONLY
ONE, MAYBE OVER -- AND I WANT TO
KNOW ARE WE GETTING CLOSER TO
KNOWING THE NUMBER AND DOES IT
MATTER THEN THE CONTINUUM?
TARGETING SOMETHING
NEUROENDOCRINE-LIKE OR SOMETHING
TARGETING SOMETHING IN BETWEEN
AND WHAT IS THAT CRITICAL
NUMBER?
>> ANISH: THANK YOU. ALL GREAT
THOUGHTS. WE HAVE NOT REALLY
TRIED TO ADDRESS THE EARLIER
STAGES OF METASTASIS AND THE
CHALLENGES. WE MOST LIE DEAL --
MOSTLY DEAL WITH PATIENTS. WE
WORK WITH MODEL SYSTEMS AND
THERE ARE NOT MODEL SYSTEMS AT
THE EARLY STAGES OF METASTASIS
DEVELOPMENT IN SCLC.
DEFINITELY, YOU DON'T GET
PATIENTS AT THAT EARLY STAGES
OUR TUMOR SAMPLES ARE AT THAT
EARLY STAGES THAT'S A BIG
CHALLENGE TO UNDERSTAND THE
COOPERATIVITY AT THE EARLIEST
STAGES BUT, YOU KNOW, THAT'S WHY
I HAVE THIS, BECAUSE THE EARLIER
STAGES OF SMOKING, IF YOU STOP
SMOKE SOMETHING -- SMOKING?
I READ THERE'S NOT MUCH ON THIS
DISEASE. IT STARTED TO BE
REPORTED AS SMOKING CAME UP.
IT'S IMPORTANT TO GO AS EARLY AS
YOU CAN BUT BEFORE THE
METASTASIS FORMATION IT'S
DIFFICULT TO INTERCEPT THEM
EITHER BY DEVELOPING MODEL OR IN
OUR CASE BY FOLLOWING PATIENTS.
>> AUDIENCE: SO WE'RE NOT CLOSE
WE ARE PATIENTS BY SCREENING
MAYBE BY BLOOD SCREENING, BY
IMAGING? WE'RE NOT CLOSER.
>> ANISH: NOT REALLY. WE LOOKED
AT CT SCANS, SMOKERS SCREENED BY
CT SCANS FOR IT TO BE EFFECTIVE,
TO DEFECT IT WE HAVE TO DETECT
IT BEFORE IT SHOWS UP ON A CT
SCAN. THERE'S A LOT OF HOPE
WITH BLOOD BASED TESTING AND
WE'LL SEE WHAT SHA SOME -- THAT
SHOWS.
TO YOUR SECOND POINT IN TERMS OF
MESSING WITH INTERACTIONS, YOU
KNOW, THERE'S A LOT OF
INTERACTIONS. BUT THE QUESTION
IS, LIKE, WHAT ARE THE KEY
INTERACTIONS? IS THERE LIKE ONE
OR TWO KEY INTERACTIONS THAT ONE
CAN TARGET? AND I THINK YOU
KNOW, PROBABLY THE DATA IS A
GOOD STARTING POINT. WE MAY
NEED TO EXPERIMENT. IS SGF THE
MOST IMPORTANT VULNERABILITY? I
WOULD IMAGINE THAT YOU HAVE
DRIVER INTERACTIONS AND MAYBE
JUST PASSING THEIR INTERACTIONS.
AND YOU KNOW, EITHER
EXPERIMENTALLY YOU PROBABLY HAVE
TO FIGURE OUT WHICH ONES ARE,
YOU KNOW, TARGETABLE, WHICH ONES
WE HAVE A DRUG AGAINST AND STUFF
LIKE THAT.
>> AUDIENCE: ARE YOU SUCCESSFUL
AT GETTING POSTTREATMENT
BIOPSIES.
>> ANISH: VERY DIFFICULT.
>> AUDIENCE: THAT WOULD HELP.
>> ANISH: THANK YOU.
>> THANKS ANISH, THAT WAS REALLY
FASCINATING AND YES, WE HAVE
SPOKEN ABOUT THE SIMILARITIES.
THERE IS A LOT. ALTHOUGH THERE
ARE SOME MAJOR DIFFERENCES. SO
I WAS REALLY INTRIGUED WITH THE
EXPERIMENTS AND THINGS LIKE
THAT. WE'VE RECENTLY FOUND THAT
INHIBITORS CAN ACTUALLY PREVENT
TRANSITION OF THE CELLS INTO
DIFFERENT PHENOTYPIC TYPES AND
THERE IS A COMPOUND THAT'S INN
CLINICAL TRIALS. HAVE YOU
EVALUATE THAT HAD IN YOUR MODELS
TO SEE IF YOU CAN --
>> ANISH: THANK YOU. WE HAVE
NOT EVALUATED THAT COMPOUND BUT
I KNOW OTHER GROUPS HAVE USED
THIS INHIBITORS. SPECIFICALLY
IN THE CNC I THINK IT'S MARKED
BY EXPRESSION. AND THAT IS, YOU
KNOW, IS A SPECIFIC
VULNERABILITY SO I THINK
EPIGENETIC MODULATION THEY'RE
USING IS EH 2 OR THE OTHER COULD
POTENTIALLY REPRESENT AN AVENUE
TO GET AT THESE TUMORS.
>> AUDIENCE: AND DO YOU SEE WITH
PROGRESSIVE THERAPY? I MEAN, I
WONDER IF YOU -- IT SEEMED AS
THOUGH -- YOUR TRIALS WERE
TREATING RELAPSE PATIENTS. AND
SO MY QUESTION, HAVE THERE BEEN
CONSIDERATIONS OF TRYING THIS
UPFRONT SO THAT YOU DON'T GIVE
THE PATIENTS A BUNCH OF HIGH
DOSE CHEMOTHERAPY AND YOU SET
YOURSELF UP FOR OTHER THINGS
DOWN THE LINE.
>> ANISH: AS YOU KNOW IT'S
DIFFICULT TO SUBTRACT. ONCE
SOMETHING IS ESTABLISHED IT'S
DIFFICULT. REALLY RUNNING UP
AGAINST A MOUNTAIN TO TRY TO
SUBTRACT SO FOR EXAMPLE WITH
CHEMOTHERAPY COMBINATION OF
CARBOPLATIN IS THE STANDARD
REGIMEN BUT WE KNOW THAT
CARBOPLATIN IS SUBSTANTIALLY
LESS EFFECTIVE. IT REALLY
DOESN'T CONTRIBUTE THAT THE
SYNERGY OF THE COMBINATION BUT
IT DOES CONTRIBUTE TO A LOT OF
TOXICITY. IF I HAVE TO START A
CLINICAL TRIAL SAYING I'M GOING
TO REDUCE THE CARBOPLATIN THE
BAR IS SO HIGH EVEN THOUGH THESE
INITIAL REGIMENS ARE NOT --
>> AUDIENCE: THIS I CAN TELL YOU
WAS THE -- WHEN I STARTED AT A
BIOLOGIST AT A CLINICAL
DEPARTMENT AND I KEPT SAYING WHY
CAN'T WE CHANGE IT UPFRONT AND
THEY CONTINUALLY SAID BECAUSE
THE TUMORS RESPOND HOWEVER IF
YOU CONTINUE TO HAVE 80% RELAPSE
OR, YOU KNOW, AS YOU SAY, THIS,
THEN IT'S JUST AS UNETHICAL TO
CONTINUE TO DO THE SAME THING.
AND I THINK WE REALLY OWE IT TO
TRY CHANGE THAT MINDSET IN SOME
WAY. I DO KNOW IN THE COMMUNITY
THEY HAVE TAKEN THINGS OUT TO
DECREASE THE LONG-TERM
TOXICITIES ASSOCIATED WITH OUR
SURVIVO
SURVIVORS. ITS INCUMBENT UPON
US BECAUSE IT WAS GOOD. BUT IF
THE RELAPSE RATES CONTINUE TO BE
THE SAME AND THE DEATH RATES THE
SAME, THEN IT'S NOT, YOU KNOW.
>> ANISH: TOTALLY AGREE. IT MAY
HAVE TO COME FROM A PATIENT
STANDPOINT. THERE ARE NOT MUCH
SURVIVORS AND NOT MUCH IN TERMS
OF PATIENT ADVOCACY AND STUFF
LIKE THAT. BUT, YEAH.
>> AUDIENCE: OKAY, THANKS,
ANYWAY, IT'S GREAT AND WE NEED
TO CONTINUE TALKING. THINK
THERE'S A LOT OF PEOPLE
INTERESTED IN NEUROENDOCRINE
TUMORS AND DIFFERENT TYPES OF
TUMORS LIKE PROSTATE. I THINK
THERE'S SOMETHING INTERESTING.
PEOPLE HAVE BEEN FOCUSED ON
EPITHELIAL BUT ENDOCRINE ARE THE
BAD GUYS OF ALL THE TUMORS.
THANKS A LOT.
>> ANISH: THANK YOU, EVERYONE.
>> AUDIENCE: (APPLAUSE).