>> OKAY, GOOD AFTERNOON.
I'M VERY PLEASED TO BE HERE.
I AM VALL, EXECUTIVE EDITOR OF
THE SCIENCE JOURNALS AND I AM
DELIGHTED TO WELCOME YOU TO THE
12th ANNUAL,A AAS MARTIN AND
ROSE WACHTEL CANCER RESEARCH
AWARDS CEREMONY.
AND I'M SORRY I HAVE TO READ MY
NOTES TO REMEMBER THAT.
SO THIS CEREMONY RECOGNIZES
EARLY CAREER CANCER RESEARCHERS
FOR OUTSTANDING KRIEWKS TO THE
FIELD.
AND THIS YEAR WE'RE DELIGHTED TO
HONOR ALVARRO VILLENUA, AND I
WILL SAY NO MORE ABOUT HIM
BECAUSE HE WILL GET INTRODUCED
LATER BUT I TELL YOU A LITTLE
BIT ABOUT TODAY'S AWARD, IT WAS
MADE POSSIBLE BY AT THE QUESTION
OF MORE THAN $1 MILLION IN
MARTIN WACHTEL, MR. WACHTEL
WANTED TO ESTABLISH AN ENDOWMENT
TO RECOGNIZE A AAS MEMBER WHO
HAS PERFORMED OUTSTANDING WORK
IN THE FIELD OF CANCER RESEARCH.
MR. WACHTEL WAS A BUSINESS MAN
WHO RAISED ALBINO MICE AND RATS
FOR MEDICAL RESEARCH, SO HE HAD
THAT INVOLVEMENT IN MEDICAL
RESEARCH AND HE WAS A FIRM
BELIEVER IN THE POWER OF
SCIENTIFIC RESEARCH TO BENEFIT
MANKIND AND WANTED TO USE HIS
WEALTH TO SUPPORT AND RECOGNIZE
THOSE IN THE MEDICAL COMMUNITY
WHOSE WORK HAS THE GREATEST
IMPACT AND THAT'S WHAT BRINGS US
HERE TODAY.
AND WHY DID HE WANT THIS PERSON
TO BE A MEMBER OF AAAS, AND HE
SELECTED THE PLACE TO ESTABLISH
THE PRIZE BECAUSE HE THOUGHT IT
HAD A LONG AND DISTINGUISHED
HISTORY OF REPRESENTING ALL THE
SCIENCES.
HOPEFULLY MOST OF YOU KNOW AAAS,
BUT IT'S 175 YEAR-OLD NONPROFIT
ORGANIZATION AND OUR MISSION IS
BASED ON THE SAME PRINCIPLE THAT
DROVE MR. WACHTEL'S BUSINESS AND
PHILANTHROPY.
WE BELIEVE THAT SCIENCE AND
TECHNOLOGY ARE THE KEY TO
SOLVING THE GREATEST CHALLENGES
THAT FACE OUR WORLD AND TO
PROVIDING A BETTER LIFE FOR ALL.
THE ASSOCIATION IS COMMITTED TO
SERVING SOCIETY BY ADVANCING
SCIENCE THROUGH INITIATIVES THAT
ENHANCE EDUCATION, ENHANCE
INTERNATIONAL COLLABORATION, AND
ALSO CHAMPION SCIENCE ON CAPITOL
HILL, SO, AAAS IS DOING MANY
THINGS TO PROMOTE SORT OF THE
SCIENCE IN SOCIETY ABOUT MAYBE,
MANY IN THIS ROOM KNOW AAAS
BETTER BECAUSE IN ADDITION TO
BEING THE LARGEST
MULTIDISCIPLINARY SCIENCE AND
ENGINEERING SOCIETY, WITH
120,000 MEMBERS, TRIPLE AAAS
PUBLISHES SCIENCE MAGAZINE ALONG
WITH THE SIBLING JOURNALS,
SCIENCE TRANSLATIONAL MEDICINE,
WHICH ORGANIZED THE PRIZE THAT
WE'RE HERE FOR TODAY, SCIENCE
SIGNALING, SCIENCE ADVANCES,
SCIENCE ROBOTICS AND SCIENCE
IMMUNOLOGY.
AND NOW I WOULD LIKE TO
RECOGNIZE THOSE WHO DID ALL THE
WORK ON THIS PRIZE,
[INDISCERNIBLE] WHO'S TRANSITION
SCIENCE MEDICINE AND ASSOCIATE
EDITORS COURT ME MELLOW WHO IS
ALSO HERE AND DOROTHY HOLBERG,
WHO FOR A VERY GOOD REASON CAN'T
BE HERE TODAY BECAUSE SHE JUST
GAVE BIRTH LITERALLY, JUST.
SO GIVEN HIS HISTORY OF WORKING
WITH NIH RESEARCHERS, I'M SURE
THAT MR. WACHTEL WOULD BE
PARTICULARLY PLEASED TO KNOW
THAT WE ARE NOW COLLABORATING
WITH THE NIH IN THE PRESENTATION
OF THIS AWARD.
I WANT TO ACKNOWLEDGE JULIA
LAMB, CRYSTAL RIVERA, AND ANKLE
STUBS-DIGS OF THE NCI FOR ALL
THEIR HEALTH AND NOW HERE TO
REPRESENT IS NCI IS THE
CO-DIRECTOR OF THE CENTER FOR
CANCER RESEARCH DR. JAMES GULLY
AND THANK YOU JAMES FOR YOUR
ROLE IN MAKING TODAY'S EVENT A
SUCCESS.
[ APPLAUSE ]
>> WELL, THANK YOU SO MUCH AND
YOU KNOW I JUST WANT TO SAY, I
THINK WE ALL ENJOY A SUCCESS
STORY BECAUSE TODAY D
R. ALVARO QUINTANAL-VIWELL,
LALONGA WILL GIVE US SUCH A
STORY.
GOOD AFTERNOON I'M THE ACTING
DIRECTOR FOR THE CENTER FOR
CANCER EXPRCH ON BEHALF OF
DR. CAROL FIELD, MY FELLOW
CO-DIRECTOR AND ON BEHALF ALSO
OF DR. DEBORAH CITRON, WHO IS
THE SCIENTIFIC DIRECTOR FOR
CLINICAL RESEARCH AND MYSELF, WE
WANT TO WELCOME YOU TO THE
CENTER FOR CANCER RESEARCH GRAND
ROUNDS.
WE'RE DELIGHTED TO 7 AS THE HOST
FOR THIS TENTH ANNUAL AAAS
MARTIN AND ROSE WACHTEL AWARD
LECTURE, SO I WILL KEEP MY
WELCOME REMARKS VERY SHORT.
I JUST WANT TO TALK A LITTLE BIT
ABOUT 1 OF THE GOALS IN THE
NATIONAL CANCER PLAN THAT
DR. RATHANALL LAID OUT.
SO IN THE CANCER PLAN, SHE LAYS
OUT 8 GOAL ANDS 1 OF THOSE
EMPOWERING GOALS AND THE GOAL OF
OPTIMIZING THE WORKFORCE.
SO IN THE CENTER FOR CANCER
RESEARCH WE REALLY BELIEVE THAT
OUR MOST VALUABLE RESOURCE IS
OUR PERSONNEL AND AMONG OUR
DIVERSE AND ILLUSTRIOUS FACULTY
AND STAFF 1 GROUP I'M KEENLY
INTERESTED IN NURTURING IS OUR
JOWNG INVESTIGATORS.
SEE, THIS GROUP OF BRIGHT
VISIONARIES, THEIR IDEAS WELL
PROPEL US TO A BILLIANT FUTURE.
THEIR THOUGHTS ARE FULL OF
TOMORROW'S HOPE AND POSSIBILITY
SAYS GIVING RISE TO FUNDAMENTAL
DISCOVERIES THAT WILL ENABLE NEW
DIRECTIONS AND ALSO NEILD CANCER
THERAPIES OF TOMORROW, TODAY.
SO IN A FEW SHORT MINUTES, I
WILL HEAR A SCIENTIFIC STORY
THAT EMBODIES THESE ASPIRATIONS.
SO AFTER THE PRESENTATION OF THE
AWARD TO
DR. QUINANAL-VILLALONGA, I JUST
LOVE SAYING THAT NAME, I INVITE
TO YOU SIT BACK, RELAX AND ENJOY
THIS INTERESTING STORY HE WILL
SHARE THROUGH HIS KEY NOTE
ADDRESS.
[ APPLAUSE ]
>> THANK YOU DR. GULLY.
GOOD AFTERNOON AND THANK YOU ALL
FOR JOINING US HERE TODAY, I'M
MESSRS. SMITH AND I'M THE EDITOR
OF TRANSLATIONAL MEDICINE WHO
HOST THIS IS PRIZE WITH NYI AND
WE'RE DELIGHTED TO DO SO THIS
YEAR AGAIN.
THE MISSION OF SCIENCE
TRANSLATIONAL MEDICINE IS TO
PROMOTE HUMAN HEALTH BY
PROVIDING AN INTERDISCIPLINARY
FORUM FOR BIOMEDICAL RESEARCHERS
AROUND THE GLOBE, IN SCIENCE,
MEDICINE AND ENGINEERING.
SCIENCE TRANSLATIONAL MEDICINE
IS DELIGHTED TO BE COORDINATING
THE 12th ANNUAL WACHTEL AWARD
ON BEHALF OF,A AAS, AND
RECOGNIZING A LEADER EARLY
CAREER SCIENTIST IN THE FIELD OF
CANCER RESEARCH.
I WOULD LIKE TO THANK OUR
DISTINGUISHED JUDGING PANEL
ELENOIRA [INDISCERNIBLE] FROM
JOHN HOPKINS UNIVERSITY,
[INDISCERNIBLE] FROM
MASSACHUSETTS GENERAL HOSPITAL
AND YOU'LL UNIVERSITY, AND
[INDISCERNIBLE] FROM DUKE
UNIVERSITY AND NOW WITHOUT
FURTHER ADO, I WILL HAND OVER TO
COURTNEY, ASSOCIATE EDITOR OF
TRANSLATIONAL SCIENCE MEDICINE,
WHO WILL INTRODUCE THIS YEAR'S
WACHTEL PRIZE WINNER.
>> HELLO, IT IS WITH IMRAIT
PLEASURE THAT I AM ABLE TO BROUS
OUR 12th ANNUAL A,A AS MARTIN
AND ROSE RESEARCH AWARD WINNER.
THIS YEAR'S WIN SERIES POINTS
DR. ALVARO QINTANAL-VILLA LONGA,
PREVIOUSLY CO DIRECTOR AND LAB
DIRECTOR AT SLOAN KETTERRING WHO
IS NOW THE DIRECTOR AT AFT
RAZENECA, DURING HIS TIME AT
SLOAN KETTERRING, HE WORKED ON
TUMOR PLASTICITY AND HOW LUNG
TUMORS IN PARTICULAR CAN UNDERGO
TRANSDIFFERENTIATION AND DEVELOP
DRUG RESISTANCE, AND HOW THIS
PLASTICITY CAN BE TARGETED.
HE'S HERE TODAY TO TELL US MORE
ABOUT HIS GROUND BREAKING WORK.
ALVARO, CAN YOU PLEASE JOIN ME?
AS THE RECIPIENT OF THE AAAS
WACHTEL PRIZE, PLEASE ACCEPT
THIS PLAQUE, IT HAS AAAS MARTIN
AND ROSE WACHTEL RESEARCH AWARD
PRESENTED TO
ALVARO YUINAANAN-VILLALONGA, FOR
OUTSTANDING RESEARCH IN THE
FIELD OF CANCER WORK BY AN
INVESTIGATOR.
KD--SALLY ARK PLAWZ
[ APPLAUSE ]
IN,A DITION ALVARO'S ESSAY WAS
PUBLISHED ON WEDNESDAY FOR HIS
GROUND BREAKING WORK IN THIS
WEEK'S ISSUE OF TRANSLATIONAL
SCIENCE MEDICINE AND IS
AVAILABLE IN HARD COPY AT THE
TOP OF THE YOU AUDITOR YOWM FOR
ANYONE THAT WOULD LIKE TO GIVE
IT A READ.
TODAY'S WEBINAR IS BEING
RECORDED FOR THE A,A AS
ARCHIVES, AFTER COMPLETION OF
THE TALK, THERE WILL BE 15
MINUTES AVAILABLE FOR QUESTIONS
AND ANSWERS FROM THE AUDIENCE SO
PLOAZ COME UP TO THE 2
MICROPHONES AND WITHOUT FURTHER
ADO, I WOULD INVITE THE DOCTOR
TO DELIVER HIS AWARD LECTURE AND
TELL US MORE ABOUT HIS EXCITING
RESEARCH ON UNDERSTANDING
PLASTICITY AS A RESISTANCE TO
CANCER THR --THERAPY.
[ APPLAUSE ]
>> THANK YOU SO MUCH FOR THE
INTRODUCTION AND THANK YOU SO
MUCH TO THE SCIENCE
TRANSLATIONAL MEDICINE COMMITTEE
AND THE SCIENTIFIC COMMITTEE FOR
MAKING ME HONOR TO RECEIVE THIS
AWARD, AND I MUST CONFESS, I
WHEN I RECEIVED THE INFORMATION
ON THE AWARD, I THOUGHT IT WAS A
SPAM E-MAIL, AND I STILL TODAY I
CAN'T BELIEVE I WAS HONORED WITH
THIS AWARD SO I WOULD LIKE TO
THANK YOU SO MUCH FOR THAT
E-MAIL NOT BEING SPAM.
AND I WOULD LIKE TO TALK TO YOU
ABOUT WHAT I HAVE LEARNED DURING
MY 6 YEARS AT MEMORIAL SLOAN
KETTERRING IN NEW YORK ON
PLASTICITY.
THESE ARE MY DISCLOSURES.
ANOTHER THING RELATED TO THE
WORK TODAY.
AND I WOULD LIKE TO START BY
MAKING A BRIEF INTRODUCTION
ABOUT LUNG CANCER, LUNG CANCER
CAN BE DIVIDED INTO DIFFERENT
SUBTYPES, THEY ACCOUNT FOR
AROUND 15% OF CASES AND THEN
NONSMALL CELL LUNG CANCER THAT
CAN BE SUBDIVIDED INTEREST MORE
TYPES LIKE LUNG SQUAMOUS CELL
CARCINOMA OR LARGE CELL
CARCINOMA WHICH ARE MUCH MORE
PROMINENT.
THEY PRESENT DIFFERENT MOLECULAR
IMPLICATIONS.
FOR EXAMPLE, LUNG CARCINOMAS
HAVE IDENTIFIED DIFFERENT DRIVER
SET OF PATIENTS THAT ARE
AMENABLE FOR TARGETED THERAPY
AND THESE [INDISCERNIBLE] IN THE
MEDICINE ERA HAS RESHAPED THE
WAY WE TREAT LUNG CARCINOMA IN
PATIENTS.
FOR SQUAMOUS CELL WE HAVE
TARGETING SYSTEMIED POTENTIALLY
TARGETABLE THERAPY, BUT UP TO
TILL NOW THEY HAVE BEEN TREATED
WITH CHEMO THERAPY.
AND UP TILL NOW IT WAS PRETTY
MUCH A BLACK HOLE, WE KNOW THESE
TUMORS ARE CHARACTERIZED BY THE
[INDISCERNIBLE] TUMOR
SUPPRESSORS AND THEY ARE VERY
HARD TO TARGET FARM CO
LONGICALLY SO BASICALLY THERE'S
NOTHING OR NO MATCH AVAILABLE
FOR THE SQUAMOUS CELL TUMORS.
AND YOU CAN SEE THE SURVIVAL FOR
HOW PRECISION MEDICINE HAS
CONVERTED THE WAY WE TREATED
PATIENTS.
YOU CAN SEE HERE THAT COMPARED
TO THE PREVIOUS STANDARD OF CARE
BEFORE TARGETED THERAPY, CHEMO
THERAPY, YOU CAN SEE THE EDFRI
IN THIS CASE FOR PATIENTS WITH A
MUTATION, EDFR, REALLY THAT'S
WAY BETTER THAN CHEMO THERAPY.
THE PROBLEM IS THAT EVEN IF MOST
OF THE TUMORS RESPOND VERY
NICELY TO THIS THERAPY AND THE
TUMOR REALLY SHRINKS, THE
RESPONSE IS ONLY SUSTAINED FOR
SO LONG AND THEN THE PATIENT
RELAPSES AND WE TART THERAPY.
THERE ARE VARIOUS NUMBERS OF
WAYS IN WHICH A TUMOR CAN BECOME
RESISTANT TO TARGETED THERAPY
LIKE FOR EXAMPLE, ADDITIONAL
MUTATIONS IN THE
[INDISCERNIBLE], OR ACTIVATION
FOR THE ONCOGENES KNOWN
ONCOGENES IN THE CARCINOMA, THEN
WE HAVE A PART OF THE
[INDISCERNIBLE] THAT WE DON'T
KNOW HOW THEY BOTTOM RESISTANT
AND THEN A SMALL PROPORTION
AROUND 15% OF TUMORS THAT
UNDERGO HISTORICAL TRANSFORM
EGG, PLEENING WHEN WE HAD A LOOK
AT THESE TUMORS AFTER
PROGRESSION, THEY LOOK LIKE A
DIFFERENT TUMOR TYPE.
AND JUST TO INTRODUCE PLASTICITY
[INDISCERNIBLE] TRANSFORMATION
DURING DEVELOPMENT, WILL ACQUIRE
DIFFERENT MOLECULAR ALTERATIONS,
LIKE FOR EXAMPLE, ADEN O
CARCINOMA, AND THEN ALSO
ADDITIONAL [INDISCERNIBLE]
HETEROGENEITY IN THE TUMOR AND
THESE CAN BE DIFFERENT CLONES
THAT HAVE DIFFERENT MUTATIONS.
IF WE SUBMIT THE TUMOR TO A
SELECTIVE PRESSURE, LIKE FOR
EXAMPLE, TARGETED THERAPY, THERE
MIGHT BE CLONES THAT MIGHT BE
PARTICULARLY RESISTANT TO THE
TREATMENT, LIKE MAYBE THEY HAVE
A MUTATION THAT FIRST RESIST THE
TREATMENT, AND IF WE CONTINUE
THE PRESSURE OF THE TREATMENT,
IN THE END THAT CLONE WILL
OVERTAKE THE TUMOR AND WILL RIDE
THE RESISTANCE THERAPY HOWEVER
IN SOME CASES, THAT TARGET MAY
BE EPIGENETIC AND THEN MIGHT BE
CLONE THAD ARE PARTICULARLY
DIFFERENTIATED OR PLASTIC AND
THEY MIGHT BE PERMISSIVE FOR
DIFFERENTIATION AND THEY MAY
TRANSITION AND CHANGE TO
SOMETHING ELSE.
AND THIS CAN BE FOR EXAMPLE, A
DIFFERENT STORY OF LUNG CANCER
LIKE SQUAMOUS CARCINOMA OR ALSO
[INDISCERNIBLE] CARCINOMA, AND
THEN AT THIS POINT WE WILL HAVE
A [INDISCERNIBLE] TUMOR AS PART
OF THE CARCINOMA REGULAR
HISTOLOGY AND THEN OUR SECOND
COMPONENT THAT MAY BE SQUAMOUS
OR SMALL CELL AND IF WE CONTINUE
SELECTIVE PRESSURE OF THE
TREATMENT WHICH IS BASICALLY
TARGETING THE ADEN O CARCINOMA,
WILL POTENTIALLY DEPLETE THIS
COMPONENT AND AT THE TIME OF
PROGRESSION WILL DETECT THIS
FULLY OR MOSTLY FULLY
DIFFERENTIATED TUMOR THAT SHOWS
A DIFFERENT HISTORY TO THE REAL
1.
AND THIS OF COURSE IN MANY
DIFFERENT SETTINGS AND MANY CAN
[INDISCERNIBLE] IN SETTINGS
WHERE THERE'S NO TREME, I GUESS
SPONTANEOUSLY, BUT THE CONCRETE
MOLECULAR BACKGROUND, WHAT HAS
BEEN THE MOST EXTENSIVE STORY IS
IN [INDISCERNIBLE] CARCINOMA,
WHERE UP TO 9% OF THE TUMORS AT
THE MOMENT OF PROGRESSION WITH
[INDISCERNIBLE] THE TARGETED
THERAPY THEY RELAPSE AS SQUAMOUS
CARCINOMA AND 14% OF THE TUMORS
RELAPSE FOR SMALL CELL.
AND IT ALSO HAPPENS IN A
DIFFERENT SETTING,
[INDISCERNIBLE] RECEPTOR
INDEPENDENT OF THE CARCINOMA,
WHERE UP TO 30% OF TUMORS
RELAPSE AND THEY ARE
[INDISCERNIBLE] CARCINOMA WITH
THE TARGETED THERAPY IN THIS
CASE [INDISCERNIBLE].
SO, BASIC FEATURES ABOUT
HISTORICAL TRANSFORMATION, FIRST
[INDISCERNIBLE] SMALL CELL
TRANSFORMATION IS CHARACTERIZED
BY THESE TUMORS EXPRESSION OF
THE DRIVER GENE, IN THIS CASE,
EDFR, YOU CAN SEE IN THIS
MATCHED BIOPSY OR EXPRESSLY IN
PREAND POST RESISTANT ESPECIALLY
WITH EDFI'S LOST AND THE
EXPRESSION OF THE MARKERS LIKE
AT THE [INDISCERNIBLE].
THEY ALSO SHOW REGULAR SMALL
CELL TUMORS HOWEVER WHEN YOU
INDUCE ACTIVATION IN LUNG
CARCINOMA THAT DOESN'T INDUCE
TRANSFORMATION OR EVEN RESISTANT
TO TARGETED THERAPY SO WITH THAT
DIFFERENT REGULATIONS ARE
REQUIRED FOR TRANSFORMATION TO
OCCUR AND VERY IMPORTANTLY WE
HAVE CELLS THAT ARE
[INDISCERNIBLE] IN OUR YOU
HADITANT DID WORSE ON THAT
THERAPY AND THEY TEND TO RESPOND
FOR SHORTER TIME AND HAVE
INCREASED RISK FOR
TRANSFORMATION, SO BASICALLY, WE
ARE ABLE TO IDENTIFY THE SUBSET
OF PATIENTS THAT ARE AT RISK OF
TRANSFORMATION THERE.
HOWEVER, EVEN THOUGH WE KNOW
THESE PATIENTS ARE, WE DON'T
REALLY HAVE ANY THERAPY TO
PREVENT THE TRANSFORMATION AND
ON THE SQUAMOUS SIDE, WE KNOW
THEY BEAR LYE --BARELY DO, YOU
SEE THE POSITIVE, NEGATIVE AND
THEY INDUCE EXPRESSION OF
JAMILLE REYNOLDSOUS MARKERS LIKE
B40, AND WE KNOW ABOUT THE
DRIVERS IN THIS PROCESS, WE
CAN'T YET IDENTIFY THE PATIENTS
OF HIGH RISK AND WE DON'T HAVE
ANY THERAPIES AVAILABLE TO
PREVAIL OR TREAT THIS
TRANSFORMATION, SO THIS IS WITH
AN ARK FILLIATE, SO THIS WILL BE
DIVIDED INTO DIFFERENT WORKS
THAT ILLUSTRATE IN THE LAST 6
YEARS, AND THE FIRST 1 WILL BE
FOCUSING ON THAT AND THE
AVAILABILITY THAT WE HAVE FOUND
BETWEEN THE ENDOCRINE AND
SQUAMOUS CELL TRANSFORMATION.
IN THIS WORK WE HAVE
[INDISCERNIBLE] SPECIMENS
UNDERGOING TRANSFORMATION IN
THIS CASE IT WAS EDFI
DIAGNOSTIC, IT IS REALLY
DIFFICULT TO FIND PREAND POST
TRANSFORMATION SAMPLES SO WE
COULD ONLY FOCUS ON 1 DRIVER
EDFR, SO WE TOOK 1 SAMPLE UNDER
1 TRANSFORMATION THAT WE COULD
LOCATE AND WHAT WE SEE WHEN WE
WHAT WE FIRST PERFORMED
METHYLATION STUDIES IN THESE
SAMPLES IS THAT WHEN WE COMPARE
4 DIFFERENT CATEGORIES OF
SAMPLES IN THIS CASE, ADEN O
CARCINOMA, THAT NEVER TRANSFORMS
THEN WE HAVE IN CLEAR BLUE, THE
CARCINOMA THAT WOULD LATER
TRANSFORM TO SMALL CELL, THEN
HERE, TRANSFORMS MORE CELLS
PREVIOUSLY OF THE CARCINOMA, AND
THEN THE SMALL CELL WHICH IS
LIKE SMALL CELLS THAT WERE NEVER
WITH THE CARCINOMA BEFORE, AS
YOU CAN SEE HERE, IN THESE LIKE
BCA CLUSTER, THAT BASICALLY
CLUSTERS, THE SAMPLES ACCORDING
TO SIMILARITIES IN THE
METHYLATION PROFILE, YOU CANEE
THERE'S A BIG OVERLAP BETWEEN
THE TRANSFORMAD SMALL CELL WITH
THE ADENO CARCINOMA AND THEN THE
SMALL CELL AND THE CLASSES
DIFFER.
AND IF WE HAVE A LOOK AT THE
SQUAMOUS TRANSFORMATION SAMPLE,
WE SAW VERY DIFFERENT BUT
SIMILAR RESULTS, YOU CAN SEE THE
TRANSFORMATION THIS BINK
OVERLAPS WITH THE ADEN O
CARCINOMAs WHILE DE NOVO
[INDISCERNIBLE] CLASS
DIFFERENTLY.
SO THIS RESULT SUGGESTS THAT THE
TRANSFORMAD TUMORS, OR TO SMALL
CELL RETAIN BOTH SCALE AT THE
EPIIMENETTIC FEATURES WITH THE
CARCINOMA, SO YOU SEE THEY MIGHT
HAVE A DIFFERENT BIOLOGY AND
POTENTIALLY DIFFERENT THERAPY
ABILITIES.
THEP WE TRY TO LEVERAGE THE DATA
TO ESTABLISH THE TRANSFORMATION
AND WE TODAYED BODIES THAT WERE
IN THE PROCESS OF
[INDISCERNIBLE] OR MAUL CELL.
WE FOUND REASSURING PALGT WAYS
SO INCREASED PHENOTYPE WHICH WAS
SUSPECTED AND OF COURSE NEURON
DIFFERENTIATION IN SOAZ CELLS
UNDERGOING NEURAL
DIFFERENTIATION, BECAUSE AS WE
KNOW EGFR IS REPRESSED WITH THE
TRANSFORMATION TO SMALL CELL,
BUT THEN WE WILL SURPRISED TO
FIND THIS ACTUALLY DIFFERENT
PATHWAYS THAT ARE CONVERGENTLY
UPREGULATED IN THE
[INDISCERNIBLE] INCLUDING REPAIR
CYCLE, THE [INDISCERNIBLE]
COMPLEX HAS BEEN WITH
PLASTICITY; AND WE ALSO HAD DOWN
REGULATION OF A NUMBER OF
PATHWAYS THAT WERE LINKED TO
IMMUNE RESPONSE SUGGESTING THAT
SOME OF THE TRANSFORMATION MAY
UNDERGO SOME SORT OF ANTITUMOR
IMMUNE SUPPRESSION.
AND LASTLY WE OBSERVED SAMPLES
INCLUDING UPREGULATION OF
[INDISCERNIBLE] AND SIGNALING.
THIS DATA LED US TO THINK TO A
POTENTIAL MODEL WHERE ADEN O
CARCINOMA BEFORE TRANSFORMATION
MAY UNDERGO AN INTERMEDIARY
STATE THAT IS CHARACTERIZED BY
THE SUPPRESSION OF UMPIRESUNE
RESPONSE AND UPREGULATION OF
THESE PATHWAYS THAT WERE
PREVIOUSLY MENTION EXCLUDE THEN
THESE POTENTIAL, INTERMEDIATE
PLASTIC STATE MAY ULTIMATELY
UNDERGO TRANSDIFFERENTIATION TO
A GIVING FATE ACCORDING TO THE
OCCURRENCE OF ADDITIONAL
MUTATIONS THAT MAY PUSH TOWARDS
A PARTICULAR PHASE THEREFORE
EXAMPLE THE [INDISCERNIBLE]
SIGNALING TRANSFORMATION EMPLOY
BUT WE TRY TO FOCUS ON 2
MOLECULAR FACTORS ATK SIGNALS
AND NYC BECAUSE THEY BOTH LEAD
TO CANCELING STEM PLASTICITY SO
WEY DECIDED TO SEE IF THESE
WOULD BE TRANSFORMATION DRIVERS
AS L. SO TO DO THAT WE TOOK THE
MUTANT, IN THE CARCINOMA LINES
AND WE OVEREXPRESS MYC AND
[INDISCERNIBLE] AKT, AND THEN WE
PUT THESE TUMORS INTO MICE AND
WE [INDISCERNIBLE] WITH THERAPY
IN THIS CASE, [INDISCERNIBLE].
YOU CAN SEE HERE IN GRAY, YOU
CAN SEE THE EXPRESSING TUMORS IN
THE ABSENCE OF THE TARGETED
THERAPY THEY WOULD GROW THE SAME
BBUT THEN WE WHEN WE TREAT THEM
WITH [INDISCERNIBLE], WE THOSE
THOSE TUMORS ARE REABLE TO
RELAPSE SIGNIFICANTLY EARLIER
THAN THOSE WITHOUT MYC, AND AKT,
SO SUGGIEST THAGOREAN THEY WERE
RESISTANT TO THERAPY.
BUT MOST IMPORTANTLY WHEN WE
COLLECTED THESE TUMORS AND
ANALYZED EXPRESSION OF
DIAGNOSTIC AND SQUAMOUS MARKERS,
WHAT WE OBSERVE IS THAT IN THE
CONTROL, TUMORS WITH THE
SEMANTIS SHRIMP NIB, WE
DEPARTMENT GET ANY EXPRESSION OF
THESE MARKERS, HOWEVER IN THOSE
TUMORS THAT ARE EXPRESSING MYC
AND AKT, AND THESE RESULTS WERE
LIKE FATHERRER POTENTIATED TO
WORK WITH THOSE, SO IN THAT
TARGETING SYSTEMIED THERAPY WERE
LIKE FARTHER PROMOTE OR AT LEAST
ENRICH FOR TRANSFORMATION.
THEN WE DORPHED THAT WITHIN OUR
PREVIOUS PLATFORM, THERE WAS A
DIFFERENT PDX THAT WAS A
DIFFERENT CARCINOMA THAT WHEN
TREATED WITH [INDISCERNIBLE] IT
WOULD SHOW SENSITIVITY BUT
EVENTUALLY BECOME RESISTANT AND
AT THE MOMENT OF RESISTANCE IT
WILL SHOW A SQUAMOUS TYPE
PHENOTYPE, AND THIS WAS
CHARACTERIZED BY THE DOWN
REGULATION OF THE MARKER TTF1
AND UPREGULATION OF B40 AND 5 OR
6, AND WE DECIDE TO LEVERAGE
THIS MODEL AS A TRANSFORMATION
AND WE DECIDE TO TRY DIFFERENT
THERAPEUTIC APPROACHES TO SEE
WHETHER IT WILL BE ABLE TO LIKE
BASICALLY PREVENT THIS
TRANSFORMATION TO OCCUR.
BUT WE ALSO TREATED THESE
[INDISCERNIBLE] WITH A
COMBINATION OF [INDISCERNIBLE]
TARGETED THERAPY AND 1 INHIBITOR
OF AKT, WITH [INDISCERNIBLE], WE
OBSERVE THAT THE TUMORS WOULD
RESPOND TO THERAPY MUCH STRONGLY
AND THEY WILL SHOW LIKE
DRAMATICALLY EXTEND THE RESPONSE
TO THERAPY, SO THIS WOULD ALSO
SUGGIEST THAT THIS
[INDISCERNIBLE] MIGHT BE A
THERAPEUTIC APPROACH FOR TUMORS
THAT EXPERIENCE REGIONAL
TRANSFORMATION, AND THESE IS IN
LINE WITH A SCIENCE PAPER FROM
THE [INDISCERNIBLE] LAB WHERE
THEY ARE STUDYING CROSS
FORMATION FROM THE ADENEE
CARCINOMA TO SMALL CELL AND THEY
HAVE DISCOVERED THAT LUNG ADIN O
CARCINOMA MAY UNDERGO
[INDISCERNIBLE] PLASTIC STATE
THAT [INDISCERNIBLE] THE COMEGZ
OF MYC AND AKT TO TRANSITION TO
A DIFFERENT PHENOTYPE IN THIS
CASE SMALL CELL.
SO CONCLUSIONS FROM THIS PART IS
THAT TRANSFORMED TUMORS SEEM TO
RETAIN BOTH SCALE FEATURES FROM
THE PREVIOUS ADEN O CARCINOMA
STATE AND THEN WE CAN
DISTINGUISH THEM FROM THE NOVEL
TUMORS, WE SEE THERE'S A NUMBER
OF PATHWAYS THAT ARE
CONVERGENTLY DISREGULATED BOTH
IN THE BRAIN AND SQUAMOUS
TRANSFORMATION AND WE SEE THAT
THE INDUCTION OF NYC SIGNALING,
THE SQUAMOUS TYPE IN THE ADEN'S
CARCINOMA IN VIVO MODELS.
THE SECOND PART OF STORY AND
THIS IS THE PUBLISHED DATA, AND
THERE'S MANY SDN EDITORS IN THE
ROOM AND IT'S ABOUT THE ROLE OF
RB-PATHWAY INACTIVATION IN
SQUAMOUS TRANSFORMATION, SO
RB PATHWAY HAS BEEN LINKED TO
THE SMALL CELL ACTIVATION,
BECAUSE THEY'RE PRETTY MUCH
HALLMARKS OF SMALL CELL TUMORS
AND HERE WE PROVIDE EVIDENCE
THAT IT MOOT BE LINKED TO
PLASTICITY IN GENERAL AND ALSO
TO SQUAMOUS TRANSFORMATION.
SO FOR THIS PROJECT, WE TRY TO
DO AN APPROACH THAT WAS PRETTY
SIMILAR TO THE PREVIOUS 1 AGAIN,
WE ALSO TRY TO DO
CHARACTERIZATION OF TUMORS
UNDERGOING SQUAMOUS CELL
TRANSFORMATION BUT IN THIS CASE,
WE FOCUS ONLY ON E, HOPING THAT
BY DECREASING THE
HETEROGENERRITY OF THE SAMPLES
WE COULD SEE SIGNALS THAT WE
WERE OVERLOOKING IN THE PREVIOUS
PROJECT.
WHICH PARTICULARLY WE COLLECTED
CONTROLS OF CARCINOMAS THAT WERE
NEVER TRANSFORMED,
[INDISCERNIBLE] THAT WERE NEVER
BEFORE, AND THEN SOME SAMPLES
THAT UNDERWENT TRANSFORMATION.
AND WE BERNEA DEET FORMED A
COLLABORATION AT THE ELF OF
GENOMICS, METHYLATION, RNASEQ
TOGETHER WITH [INDISCERNIBLE].
WHEN WE UNDER GO THE
TRANSFORMATION, THE FIRST THING
WE NOTICE WAS THAT THERE WAS A
HIGH FREQUENCY OF HIGH MUTATIONS
OR BRINGING MEMBERS OF THE
PATHWAY, CONSISTENT WITH THE
DATA I'VE SHOWN BEFORE, LINKING
NEGATIVE PATHWAY TO SQUAMOUS
TRANSFORMATION BUT WE WERE
OBSERVED TO FIND ALSO THAT THERE
WERE VERY FREE RADICALS QUEPT
MUTATIONS IN THE RB PATHWAY AS
WELL.
IN THE END, WHEN WE COMPARE THE
FREQUENCY OF MUTATIONS IN THESE
FROM THE RB AND NEGATIVE PATHWAY
BETWEEN ADEN O CARCINOMA AND
SQUAMOUS CARCINOMA FIRST IN THAT
THIS COHORT IS AVAILABLE, CAN
YOU SEE THAT ACTUALLY DENOVAE
SQUAMOUS CARCINOMA ARE ENRICHED
FROM THE [INDISCERNIBLE] OF BOTH
PATHWAYS AND BASED ON THESE
RESULTS WE CAN OBSERVE
[INDISCERNIBLE] WHERE WE COMPARE
THE ADEN O CARCINOMA AND JAMILLE
REYNOLDSOUS WITH A MIXTURE OF
[INDISCERNIBLE] AND COMOPPOSITE
BEHAVIORIAL PHENOTYPENTS AND
SQUAMOUS CARCINOMA.
YOU CAN SEE AGAIN THAT THERE'S
AN ENRICHMENT IN THESE PATHWAYS
FOR THE RB PATHWAY, SUGGESTING
THAT THESE 2 PATHWAYS MAY BE
SPECIFICALLY LINKED TO THE
SQUAMOUS CELL TRANSFORMATION BUT
MAYBE JUST SQUAMOUS TUMORS.
AND THEN, SEEING THIS ENRICHMENT
MUTATIONS IN POAGHT BOTH
PATHWAYS IN SAMPLES UNDERGOING
TRANSFORMATION, WE DECIDE TO SEE
WHETHER THESE MUTATIONS MAY HAVE
THE POTENTIAL TO PREDICT TUMORS
FOR HIGH TRANSFORMATION TO
SQUAMOUS, SO IT WAS TO COMPARE
THE FREQUENCY OF MUTATIONS IN
THE DIFFERENT GENES IN EACH OF
THE PATHWAYS FOR SAMPLES THAT
WERE LATER GOING TO TRANSFORM AS
SQUAMOUS CARCINOMA,
[INDISCERNIBLE], IN GREAT,
VERSUS A COHORT OF NEVER
TRANSFORMING THE CARCINOMA IN
BLACK AND AS CAN YOU SEE HERE
MANY OF THESE MUTATIONS SHOW
LIKE ENRICHMENT FREQUENCY, IN
THOSE SAMPLES THAT WILL LATER
TRANSFORM TO CARCINOMA AS
COMPARED TO CONTROL.
AND YOU CAN SEE FOR BOTH AKT AND
THE PATHWAY, CAN YOU SEE THE
TRANSFORMING SAMPLES WOULD SHOW,
HIGHER FREQUENCY COMPARED TO THE
CONTROL ADEN O CARCINOMA
SAMPLES, SO YES IN THAT, AND
THESE 2 PATHWAYS, MIGHT BE ABLE
TO PREDICT FOR THE
TRANSFORMATION.
THEN THERE IS THE TRANSCRIPTOMIC
DATA COMPARED TO THE SAMPLES
THAT TRANSFORM TO THE
PRETRANSFORMATION SPECIMENS, AND
WE OBSERVE A NUMBER OF PATHWAYS
THAT WE HAVE PREVIOUSLY
REPORTED, INCLUDING UPREGULATION
OF CELL CYCLE, DNA REPAIR GENES,
END METASTASIS, AKT
ENTHUSIASMERIN MYC, BUT WE WERE
ABLE TO DORPH AT THE ATOMIC
LEVEL, THAT THESE ARE COMPAT
WIBL WITH THE PATHWAY ACTIVATION
CONSISTENT WITH THE GENOMIC DATA
I JUST SHARED.
SO WE WANT TO HAVE A DEEPER LOOK
INTO THESE PATHWAYS BECAUSE IT
WAS SURPRISING WE FIEBD IT
ACTIVATED IN SQUAMOUS CARCINOMA
SO WE PERFORM LIKE AN
INTEGRATION OF MUTATION AND
TRANSCUE TAINIC DATA, AND YOU
CAN SEE THIS TRANSFORM SQUAMOUS,
WITH THE PERMITATION AND DE NOVO
SQUAMOUS WITH THE WILD-TYPE AND
HERE IN THE ROWS HERE YOU CAN
SEE THE OCCURRENCE OF DIFFERENT
MUTATIONS IN THE DIFFERENT YEENS
IN THE PATHWAY AND HERE CAN YOU
SEE THE ENRICHMENT FOR SAMPLE, 4
DIFFERENT SIGNATURES THAT HAVE
BEEN RELATED TO RB1
INACTIVATION.
SO AS YOU CAN SEE HERE, FOR MOST
OF THE SAMPLES THAT HAVE
MUTATIONS IN 1 OR SEVERAL
MEMBERS OF THE PATHWAY, WE SEE
ENRICHMENT IN RB PATHWAY IN THE
PHENOTYPE.
BUT WE WERE ABLE TO SEE THAT
MANY SAMPLES DIDN'T HAVE ANY
MUTATIONS OR ALTERATIONS IN THIS
PATHWAY WAS SHOWING US, WELL,
ENRICHMENT FOR INACTIVATION OF
RB1.
SUGGESTING THAT THERE MIGHT BE
MECHANISMS BEYOND MECHANICAL
TRANSFORM EGGS FOR TRANSFOR THE
PURPOSING TUMORS, AND THEN WE
DECIDE TO HAVE A LOOK AT THE
SUCCESS OF SAMPLES FOR WHICH WE
HAVE MUCH PREAND POST
TRANSFORMATION, AND AS YOU CAN
SEE, IN MOST OF THE CASES, THERE
WAS AN ENRICHMENT, IN THE
TRANSCRIPTOMIC SIGNATURE,
RELATED TO EVERYONE IN
ACTIVATION, IN THE SQUAMOUS POST
TRANSFORMATION THAT'S COMPARED
TO THE PRETRANSFORMATION OF THE
CARCINOMA.
AND WE ALSO WERE ABLE TO
VALIDATE THIS AT THE PROTEIN
LEVEL, BY THE PUBLICLY AVAILABLE
COHORTS, OF PROTEIN DATA FROM
THE ADENEE CARCINOMA AND
SQUAMOUS CARCINOMA WHERE AGAIN,
WE SEE ENRICHMENT IN PROTEIN
EXPRESSION SIGNATURES THAT ARE
RELATED TO RB1 INACTIVATION.
THEN AS THIS DATA WAS VERY
ENTICING WE WOULD LIKE
[INDISCERNIBLE] FUNCTIONALLY SO
WE CAME BACK TO THE MODEL THAT
WE PREVIOUSLY PUBLISHED WHERE WE
TOOK THE CARCINOMA CELL LINES
AND WE OVEREXPRESS NKT TO INDUCE
CERTAIN DEGREE OF TRANSFORMATION
TO SQUAMOUS.
AND WE DECIDE TO ADD THE EXTRA
VARIABLE OF RB PATHWAY
ACTIVATION INTO DIFFERENT
FLAVORS.
ONE OF THEM WILL BE BY KNOCKING
OUT DIRECTLY RB, AND OTHER 1
KNOCKING OUT CDKN2 AB, WHO'S
ACTIVATION RESULS THE SAME INTO
RB1 ACTIVATION, SO 2 DIFFERENT
WAYS OF DOING THE SAME THING.
THESE CELL LINES, AND THEN WE
PUT IN MICE AGAIN AND THEN
DRIVEN WITH [INDISCERNIBLE], AND
THE TUMORS RESPOND FOR LONG AND
THEY TAKE THEIR TIME TO RELAPSE,
YOU SEE THAT EACH OF THE TUMORS,
WE'VE [INDISCERNIBLE] AND MYC
TOGETHER OR NOT WITH A PATHWAY
ACTIVATION WHERE, INITIALLY
RESISTANT TO THE
[INDISCERNIBLE].
IN IMPORTANTLY WHEN WE COLLECTED
THESE TUMORS AND WE ANALYZED
THEM FOR THE EXPRESSION OF
AGAIN, ADEN O CARCINOMA AS
EXPRESSION MARKERS, AS YOU CAN
SEE HERE IN BC9, WE OBSERVE
INCREASED EXPRESSION IN P40 AND
CK5/6 AND THIS WAS FURTHER
INHANSED WHEN ON TOP OF MYC NKT
WE WOULD ENACTIVATE RB, AND
VARIOUS LEVELS WERE OBSERVED FOR
THE [INDISCERNIBLE], WHERE WE
WERE ABLE TO SEE DOWN REGULATION
OF THE MARKERS OF REGULATION OF
[INDISCERNIBLE], AND THEN
UPREGULATION OF THE P40, WHICH
WAS HIGHER IN THE TUMORS WITH
RB1 ACTIVATION, AND THIS ALSO
SUGGESTS THAT THIS ROLE HAS A
DRIVING OR POTENTIALLY HAS A
SQUAMOUS TRANSFORMATION EMPLOY
AND HERE YOU HAVE REPRESENTATIVE
IMAGES WHERE AGAIN, YOU CAN SEE
THE DOWN REGULATION OF TTF 1 AND
[INDISCERNIBLE] AND THEY
COMPLETE INDUCTION FROM 0 TO
IMPORTANT PERCENTAGE OF CELLS
EXPRESSING SQUAMOUS MARKERS.
THEN WE DECIDE TO STUDY THESE
MARKERS AT THE SINGLE CELL
LEVELS AND THEN FOR TRANSCRIPT
OF THIS, AND AS YOU SEE HERE,
THIS IS THE CONTROL UNTREATED,
CONDITION, WE WERE SURPRISED TO
SEE IT WAS ACTUALLY LIKE
[INDISCERNIBLE], THESE ARE THE
PLOT, THAT BASICALLY ASSIGN EACH
OF THE CELLS, FOR CARCINOMA,
LIKE SQUAMOUS OR LIKE SMALLING
CELL AND AS CAN YOU SEE HERE IN
THIS CASE, THE CELLS CLUSTER
BETWEEN THE ADEN O CARCINOMA AND
SQUAMOUS PHENOTYPE, SO YES, IN
THAT, THERE'S SOMEY DID GROW OF
THE HETEROGENEITY AT THE
TRANSCRIPTOMIC LEVEL, PRESSING
ALREADY IN THE CONTROL SAMPLES.
AND YOU CAN SEE THAT WHEN WE
TREAT WITH THE OSIMETRINIB,
SUGGESTS THAT MAYBE IT TRIGGERED
FARTHER OUT HERE.
THEN WHEN WE OVEREXPRESS MYC, WE
SEE THE EFFECT, WE SEE THE CELL
DISPLAYS CLOSER TOWARDS THE
PHENOTYPE, BUT THIS RESOURCE,
LIKE OUR FARTHER ENHANCED AND WE
TREAT THESE TUMORS WITH
OSITINIB, AND THESE CELLS ARE
REALLY MOVING TOWARDS THE
SQUAMOUS CORNER AND THESE WERE
MORE STRONGLY OBSERVED IN THE
MODEL WITH MYC, AND EARLY
ACTIVATION WHERE AGAIN, CAN YOU
SEE DISPLACEMENT OF THE CELLS
TOWARDS THE SQUAMOUS CORNER, AND
HERE YOU CAN SEE LIKE THE
STRONGEST PHENOTYPES HERE WHERE
REALLY THE STRONGER PATIENT OF
CELLS THAT LOOK LIKE CARCINOMA
AND THEY TEND TO CLUSTER MORE ON
THE SQUAMOUS CORNER AS WELL.
AND WE PERFORMED SOME
ANALYSIS, BASICALLY STUDIED THE
GENES IN THE GENE SIGNATURES
THAT CHANGE OUT OF THE
TRAJECTORY FROM THE ADEN O
CARCINOMA STATE TO THE SQUAMOUS
STATE AND AS YOU CAN SEE HERE,
DURING THAT TRAJECTORY, OF
COURSE, WE OBSERVE DOWN
REGULATION OF ADEN O CARCINOMA
MARKERS AND INDUCTION OF
SQUAMOUS MARKERS, BUT WHEN WE
HAD A LOOK AT THE SIGNATURES, WE
OBSERVED THAT UNDER THE
DIRECTORY AGAIN, WE HAVE ENRICH
OF OF MYC, BECAUSE WE'RE
OVEREXPRESSING THIS PATHWAY SO
IF WE DIDN'T SEE THEM, THAT
WOULD BE BAD.
BUT WE ALSO OBSERVED
UPREGULATION OF A NUMBER OF
PATHWAYS THAT WITH THE COMPLEX,
AND THE WEAK SIGNALING THAT WE
DETECTED TO BE UPREGULATED IN
THE SPECIMENS, SO YOU SEE THE
SMALLS ARE REALLY MIMICKING WHAT
HAPPENS IN THE CLINICAL
SPECIMEN.
VERY SIMILARLY FOR THE OTHER
MODEL, THE 1 WHERE WE ACTIVATE
RB TO KNOCK OUT [INDISCERNIBLE],
YOU SEE THAT AGAIN, KNOCKING OUT
THESE 2 GENES WOULD LIKE MAKE
THE CELLS TRANSITION TO A MORE
LIKE PLASTIC STATE OR MORE
[INDISCERNIBLE] PLACE.
AND THEN THIS WILL BE PROBABLY
LIKE THE MOST EXTREME PHENOTYPE,
CAN YOU SEE THAT WHEN ON TOP OF
ACTIVATION OF THESE GENES TO
WHERE, TOGETHER WITH MYC, AKT,
AND WE SEE THE CELLS RECLUSTER
VERY STRONGLY IN THE SQUAMOUS
CORNER.
AND THE STUDY ANALYSIS HAD THIS
MODEL WERE VERY SIMILAR TO A
PRODUCED 1, AGAIN WE OBSERVE THE
DOWN REGULATION OF ADEN O
MARKERS AND UPREGULATION OF
SQUAMOUS MARKERS AND AGAIN A
SIMILAR TRANSCRIPTOMIC PROFILE
IN TERPS OF GENE SIGNATURES WITH
MYC INDUCE AS WELL AS A NUMBER
OF PATHWAYS WE SEE UPREGULATE
INDEED THE CLINICAL SPECIMENS
UNDER GOING THE SQUAMOUS
TRANSFORMATION.
ONE THING THAT WAS SURPRISING IN
THESE IS THAT COMPLETE E
UNEXECKED WHEN WE HAD A LOOK
THEA THE EXPRESSION OF EGFR, IT
SEEMS TO BE UPREGULATED FOR THE
TRANSFORMATION, WHICH IS MORE OR
LESS LIKE THE OPPOSITE WHAT WE
WOULD EXPECT.
SO WE DECIDE TO ARE A LOOK AT
THAT A LITTLE DEEPER AND AGAIN,
LIKE GROUPING, THE DIFFERENT
CONDITIONS OF THE ADEN O
CARCINOMA IN SQUAMOUS HERE, AND
PLOTTING TOGETHER, THE LEVELS OF
METHYLATION IN THE PROMOTER AND
THE BODY, AS WELL AS EXPRESSION
LEVEL OF MRNA, AND REASON FOR
SIGNATURES, THAT ARE RELATED TO
ACTIVATION, WE UNDERSTAND THERE
WAS NOT A LOT OF VERYIATION
BETWEEN ADEN O CARC NOAMS TOWARD
THE TRANSITION TO SQUAMOUS CELL
AND CARCINOMA SO JUST IN THAT
THERE'S NOT REALLY A DOWN
REGULATION OF EGFR OR EGFR
SIGNALING DURING THE SQUAMOUS
CELL TRANSFORMATION BUT WHAT
HAPPENS IN THE SMALL CELL
TRANSFORMATION WHERE THE SMALL
CELL IS COME PLETELY ABROGATED
AND WE WERE ABLE TO SEE THIS
AGAIN BY FOCUSING ON THE SETTING
ON THE MARCH PREAND POST
TRANSFORMATION SPECIMENS, CAN
YOU SEE IN MANY OF THESE CASES,
SIGNALING OF EGFR, OR AT LEAST
THE TRANSCRIPTOMIC LEVEL
ENRICHMENT FOR YEEN SIGNATURES
FOR GENEACIVATION ARE ACTUALLY
ENRICHED FOR IN THE SQUAMOUS
TUMORS AS COMPARED TO THE
TRANSFORMATION SPECIMEN.
AND WE HAVE SOME PRELIMINARY
[INDISCERNIBLE] DATA ON
CARCINOMAS WHERE WE OBSERVED THE
SAME THING.
THIS ACTUALLY HIGHER EXPRESS OF
EGFR SOMEHOW IN SQUAMOUS TOOL AS
COMPARED TO THE ADEN O CARCINOMA
AND THIS IS SOMETHING WE'RE
HAVING A LOOK SPONTANEOUS
ACTIVITY FARTHER DOWN.
THEN SOMETHING THAT WAS EQUALLY
SURPRISING WHEN WE REALIZE
AGAIN, THESE TRAJECTORY AND THIS
IS OUR PRECLINICAL FORMATION
WHICH IS THAT THE TIARAS RADIO
SEEN KINASE FOR WHICH INHIBITORS
ARE ABLE IN THE CLINIC WAS ALSO
UPREGULATED DURING THE PROCESS
OF TRANSFORMATION IN BOTH
MODELS, SO WE DECIDE TO CHECK
WHETHER APART FROM OUR PRIVILEGE
OF THE EXPRESSION OF THE
[INDISCERNIBLE] KINASE, WE WERE
ABLE TO SEE ENRICHMENT IN
SIGNATURES RELATED TO
METASIGNALLING AND THAT SEEMED
TO BE THE CASE IN BOTH MODELS.
SO WE DECIDE TO PARTICIPATE ON
THIS LEVEL IN THE THESE THAT ARE
RELATED TO WHAT WE HAVE HERE,
ALL OF THEM SHOWED HIGH EXPRESS
OF MYC, SO WE DECIDE TO TRY
INHIBITING MET TO SEE IF THAT
WILL BE INTERESTING TO BE A
THERAPEUTIC APPROACH IN THESE
MODELS.
AND THIS WAS TRANSITIONED
TOWARDS THE PHENOTYPE WITH THE
[INDISCERNIBLE] AND YOU CAN SEE
HERE THE COMBINATION OF
OSMERTINIB, AND WHEN WE TREATED
2 OTHER TUMORS THAT WERE PDF
MUTATION CASES AFTER
TRANSFORMATION TO SQUAMOUS, YOU
CAN SEE THAT THE COMBINATION OF
OSIMERTINIB, AND CRIZOTINIB,
WORKED BETTER THAN OTHER
THERAPEUTICS.
A SUMMARY OF THIS PART OF THE
TALK IS THAT THIS FEATURE OF
SQUAMOUS CELL TRANSFORMATION AND
ALSO SQUAMOUS TUMORS IN GENERAL,
GENOMIC ALTERATIONS IN THE RB
ENACTIVATED PATHWAY MAY INCREASE
RISK OF TRANSFORMATION SO WE
HAVE AT LEAST A HINT TO KIND OF
PREDICT WHICH PATIENTS MIGHT
HAVE HIGHER RISK OF
TRANSFORMATION, WE SEE THE
INACTIVATION MAY HAVE A ROLE IN
PLASTICITY IN THE
[INDISCERNIBLE] TRANSFORMATION
AND WE SEE THAT EGFR SIGNALING
IS NOT SUPPRESSED DURING
TRANSFORMATION UNLIKE WHAT WE
OBSERVE INDEED NE
TRANSFORMATION, WE WOULD LIKE TO
CONTINUE TREATING THESE TUMORS
WITH OSITNINB AFTER OUR
RESEARCH, AND OUR MET TARGET
SEEMS TO BE WORKING NICELY IN
COMBINATION OF OSITINIB.
AND THEN THE LAST PART OF THE
TALK WILL BE 2 SMALL WORKS THAT
WE HAVE IDENTIFIED 2 DIFFERENT
THERAPEUTIC TARGETS THAT MIGHT
BE ABLE TO PREVENT SMALL CELL OR
[INDISCERNIBLE] TRANSFORMATION.
THE FIRST 1 IS EXPORTING 1 WHICH
WE DORPH DURING THE SCREEN IN
THE PREVIOUS PROGEC, EXPORTING
WOB IS A CLEAR EXPORTER LOCATED
IN THE NUCLEUS AND IT EXPORTS
PROTEINS AND MRNAs FROM THE
CYTOSTUDIES
CYTOSOL, AND THIS HAS GAINED A
LOT OF ATTENTION IN CANCER
RESEARCH AND ALSO THE REAP WHY
THEY HAVE DEVELOPED DIFFERENT
INHIBITORS, 1 OF THEM EVEN
APPROVED FOR CLINICAL USE IN THE
SETTING OF MEDICAL DIAGNOSIS SO
IT MAKES THESE TARGETS PRETTY
PROMISING.
WE OBSERVED THAT EXPRESSION OF
EXPORTING 1 WAS HIGHEST IN SMALL
CELL AS COMPARED TO ALL TUMOR
TYPE, AND WE HAD THE OTHER
PROTEIN LEVEL COMPARING NONSMALL
CELL LUNG CANCER, WE PRVED NOT
ONLY THAT EXPORTING 1 IS MORE
HIGHLY EXPRESSED IN SMALL CELL,
BUT ALSO THAT IT IS CONSISTENTLY
HIGHY EXPRESSED IN ALL TUMORS
ARK ASSESSESSED.
SO WE DECIDE TO TEST THESE SMALL
CELL TRANSFORMATION AND AGAIN WE
DO THIS CONFORMED TO THE
CARCINOMA, TRANSFORMS MORE CELL
AND THEN DE NOVO SMALL CELL AND
AS CAN YOU SEE HERE THERE WAS AN
UPREGULATION OF EXPORTING 1
DURING THE PROCESS OF
TRANSFORMATION EMPLOY AND WERE
ABLE TO DO THIS AGAIN AT THE
PROTEIN LEVEL, AND AGAIN WE WERE
OBSERVING INCREASE EXPRESSION OF
EXPORTING 1 DURING THE PROCESS
OF TRANSFORMATION.
AND IN THIS TRANSFORMATION TO
SMALL CELL TUMORS AND ALSO IN
THE PROCESS WE [INDISCERNIBLE]
WE WANTED TO TEST WHETHER
EXPORTING 1 MIGHT BE ALSO
UPREGULATED IN THE SETTING AND
AS YOU CAN SEE HERE THESE 2
PUBLICLY AVAILABLE COHORTS THOSE
ADEN O CARCINOMA WERE SHOWING
HIGH EXPRESSION OF EXPORTING 1
AND WHEN WE COMPARED THE
EXPRESSION OF ADEN O CARCINOMA
VERSUS THE [INDISCERNIBLE]
TUMORS WE SAID AGAIN THAT IT WAS
UPREGULATED IN THE SETTING.
ABLE TO FIND THIS OTHER PROTEIN
LEVEL, SHOWING THAT SHOWING HIGH
EXPRESSION LEVELS OF EXPORTING
[INDISCERNIBLE] CARCINOMAS.
BUT I THINK THAT MOST
INTERESTING FINDING OF THIS
SLIDE IS THAT IN LUNG ADEN O
CARCINOMA EXPORTING 1 WAS
ALREADY UPREGULATED IN
TRANSFORMING CARCINOMA BEFORE IT
WOULD TRANSITION TOWARDS SMALL
CELL.
INDICATING THAT EXPORTING 1 OR
MIGHT BE UPREGULATED IN THE
EARLY STAGES OF TRANSFORMATION.
AND YOU CAN ATTEST THAT WHEN WE
WENT BACK TO THE MOST INITIAL
MOLECULAR EVENTS THAT RECORD THE
TRANSFORMATION THAT ARE IN THERE
WITH 3 AND RB1.
WE HAD THE EXPRESSION OF
EXPORTING 1 IN 3 DIFFERENT
PUBLICLY AVAILABLE COHORTS, 2 OF
THE CARCINOMA AND 1 OF THE
[INDISCERNIBLE] CARCINOMA AND WE
DECIDE THE TUMORS BETWEEN THOSE
THAT HAD WILD-TYPE
[INDISCERNIBLE] 1 AND THOSE THAT
HAD MUTATIONS IN BOTH GENES AND
AS YOU CAN SEE HERE
CONSISTENTLY, WE OBSERVE
INCREASED EXPRESSION OF
EXPORTING 1 IN THOSE TUMORS THAT
HAD MUTATIONS OF RB1, SO THIS
RESOURCE SUGGESTS THAT VERY
EARLY IN THE TRANSFORMATION
PROCESS, RIGHT AFTER THE
ACQUISITION OF THE DAY
ACTIVATION RB1, EXPORTING 1 MAY
BE UPREGULATED AND WE WANT TO
VALIDATE THIS IN PRECLINICAL
MODELS WITH THE PROCESS OF THE
CARCINOMA LINE, AND BOTH OF THEM
WILD-TYPE AND [INDISCERNIBLE] 1,
SO WE INDUCE KNOCK OUT OF PD3
AND/OR RB1 AND OBSERVED THAT THE
CELL LINES WERE BOTH
[INDISCERNIBLE] RB1 WERE NOT OUT
AND SHOWED UPREGULATION OF
EXPORTS 1 AND NOT ONLY
UPREGULATION BUT INCREASE INDEED
SENSITIVITY TO THE EXPORTED 1
INHIBITORS, AS CAN YOU SEE HERE
FOR ADEN O CARCINOMA CELL LINE
AND 2 ADEN O CARCINOMA CELL
LINES, THOSE WITH THE DOUBLE
KNOCK OUT [INDISCERNIBLE] WERE
SHOWING INCREASED SENSITIVITY TO
THE CONCENTRATIONAL
[INDISCERNIBLE] INHIBIT ON ARE
AND SO YES THIS UP ON
ACTIVATION, YOU NOT ONLY GET
UPREGULATION, BUT ALSO THE TUMOR
CELLS HAVE BECOME MORE DEPENDENT
ON IT.
AND THIS PROVIDED A RATIONAL TO
INHIBIT EXPORTING 1S AS A MEANS
TO PREVENT LIKE THIS HURDLE, FOR
SMALL CELL TRANSFORMATION.
SO WE LEVERAGED THE CARCINOMA TO
CARCINOMA IN VIVO, THIS IS 2
PROCESS OF THE CARCINOMA CELL
LINES WHERE WE WILL INDUCE P53
AND RB1 KNOCK OUT AND THEN TREAT
THEM WITH TARGETED THERAPY IN
THIS CASE [INDISCERNIBLE].
AND INDUCE [INDISCERNIBLE]
CARCINOMA IN VIVO, SO AS CAN YOU
SEE HERE FOR BOTH OF THE MODELS,
THE COMBINATION OF THE TARGETED
THERAPY, AND EXPORTED INHIB
THORS THOR WAS OUT PERFORMER
THE EFFICACY TO ANY OF THE OTHER
THERAPY AREAS AND MOST
IMPORTANT, WE COLLECTED THESE
TUMORS, AT END POINT, AS CAN YOU
SEE HERE, WHEN WE HAD A LOOK AT
THE EXPRESSION OF THE MARKERS
[INDISCERNIBLE], FOR BOTH OF
THEM ARE SUSPECTED THAT THIS
WOULD TRIGGER THAT OCCURRENCE OF
CELLS THAT WE'RE SHOWING IN THE
PHENOTYPE, HOWEVER IN THE
COMBINATION TREATMENT, WE DIDN'T
SEE ANY OF THIS SUGGESTING THAT
THIS COMBINATION IS NOT ONLY
ABLE TO EXTEND THE RESPONSE OF
TARGETED THERAPY BUT ALSO TO
PREVENT OR AT LEAST DELAY THE
TRANSFORMATION.
AND THERE'S NOT REALLY A SMALL
TRANSFORMATION IN THE LUNG BUT
WE HAVE 1 INTERESTING PDX IN THE
LAB THAT SHOWED MIXED PHENOTYPE
COP BIENED NONSMALL CELL AND
SMALL CELL, AND A MODEL WITH
EGFR FERM ENATION AND OAIVE THEE
THAT WAS MOSTLY SMALL CELL AS
CAN YOU SEE HERE WITH ONLY LIKE
[INDISCERNIBLE] CARC NOAM ACIN
THIS CELL WE EXPERIENCE THE CELL
OF TARGETED THERAPY TOGETHER
WITH [INDISCERNIBLE], WAS OUT
PERFORMING DELAYING TUMOR GROWTH
IN THE OTHER 2 ARMS.
IN THIS CASE WE COLLECT THE
TUMORS AND WE HAVE A LOOK AT
THEM, WE SAID THERE WAS NO
REGRESSION OF THAT FEIGN TYPE
SUGGEST THAT THAT MAY INTERFERE
WITH THE [INDISCERNIBLE] BECAUSE
IT HAS NOT AFTER IT HAS
OCCURRED.
AND IN ORDER TO FIND A MECHANISM
BY WHICH INHIBITION OF
[INDISCERNIBLE] WAS PREVENTING
TRANSFORMATION, WE LEVERAGED
SOME TRANSCRIPTOMIC DATA ON THE
MODELS AND WE OBSERVE THAT
CANNED WHAT WILL TRIGGER THE
EXPRESSION OF SOX 2, WHICH IS A
FACTOR [INDISCERNIBLE] WHICH IS
KNOWN TO BE ESSENTIAL FOR
TRANSFORMATION TO OCCUR.
SO WE OBSERVED THAT THIS
[INDISCERNIBLE] FURTHER WAS
UPREGULATED WITH [INDISCERNIBLE]
BUT THEN WAS SUPPRESSED IN THE
COMBINATION TREATMENT.
AND WE BELIEVE THIS AS WELL AT
THE PROTEIN LEVEL, CAN YOU SEE
THAT FOR BOTH PROSTATE AND
[INDISCERNIBLE] MODELS, TARGETED
THERAPY WOULD INCREASE THE
EXPRESSION OF SOX 2 THAT WAS
REPRESSED IN THE TUMORS.
SO IN ORDER TO PROVE THE SOX 2
WAS REALLY, THE MECHANISM HERE,
WE PREFER SOME RESCUE
EXPERIMENTS BY OVEREXPRESSING
SOX 2 AND AS YOU CAN SEE HERE,
THIS IS THE CONTROL CELL LINE,
THAT SHOW LIKE LOW LEVEL OF
EXPRESSION OF NEURONAL MARKERS
AND DRIVERRING EXPRESSION OF AR,
AND WITHIN [INDISCERNIBLE] WE
SEE THE OPPOSITE FINE O TYPE, WE
SEE THE [INDISCERNIBLE] OF THE
CARCINOMA AR, AND WE WOULD EXEC
AND AS SHOWN BEFORE WHEN WE
TREAT THESE CELLS WITH THE
COMBINATION OF [INDISCERNIBLE],
WE HAVE SET [INDISCERNIBLE] TO
THE PHENOTYPE AGAIN, AGAIN NO
OTHER FEATURES AND
UPREGULATIONAL OF THE DRIVER,
BUT IF WE TREAT WITH THE
COMBINATION BUT ALSO OVEREXPRESS
SOX 2, WE PARTIALLY RESCUE THIS
TRANSFORMATION FEIGNEE TYPE
CHARACTERIZED BY THE EXPRESSION
OF THE MARKERS SO IN THAT SOX 2
DOWN REGULATION BY EXPORTING 1
INHIBITION IS REALLY THE REASON
WHY WE ARE PREVENTING
TRANSFORATION HERE.
AND AS A CONCLUSION WE HAVE THIS
DIAGRAM WHERE WE OBSERVE THE
ACTIVATION IN RB1 WHICH IS EARLY
IN TRANSFORMATION PROCESS, WE
TART TO OBSERVE UPREGULATION OF
EXPORTING 1 AND UPON TREATMENT
WITH [INDISCERNIBLE] THERAPY WE
GIVE UPREGULATION OF PROTEIN 1
TOGETHER WITH SOX 2 WHICH IS
ESSENTIAL FOR TRANSFORMATION AND
THAT WHY WE GET TRANSFORMATION,
HOWEVER WITH TARGETED THERAPY WE
HAVE THE INHIBITOR AND WE SEE
THE SOX EXPRESSION DECREASED AND
THAT PREVENTS TRANSFORMATION
[INDISCERNIBLE].
AND THE LAST PART OF THE TALK
WILL BE ABOUT A DIFFERENT
THERAPEUTIC TARGET THAT'S EVEN
MORE POTENT.
THIS IS C67 AND WE IDENTIFY IT
IN CRISPR SCREEN, AND IT IS A
PROTEIN THAT IS RESPONSIBLE TO
INITIATE DNA REPLICATION AND
USELESS BEEN INVOLVED IN
[INDISCERNIBLE] COHESION AND
ALSO [INDISCERNIBLE].
AND IT'S AN INTERESTING TARGET
BECAUSE THERE'S ALREADY
INHIBITORS THAT ARE
[INDISCERNIBLE] TESTING AND HAVE
ALREADY SHOWN PROMISING RESULTS
IN TERMS OF EFFICACY.
WE EXPRESS THE EXPRESSION OF 67
IN OUR CLINICAL SPECIMENS
UNDERGOING TRANSFORATION BOTH IN
THE LUNG AND PROSTATE AND AND AS
YOU CANY HERE--AS YOU CAN SEE
HERE, WE HAVE THIS COMPARED TO
LUNG AND PROOF THE EAT TUMORS,
AND WE WERE TRANSFORMING
CARCINOMAS SUGGIESTING AGAIN
THAL UPREGULATION
[INDISCERNIBLE] IN THE
TRANSFORMATION PROCESS AND
SIMILARLY TO WHAT WE OBSERVE FOR
EXPORTING 1 WHEN WE HAVE A LUCK
AT THIS PUBLICLY AVAILABLE
COHORTS, AGAIN, 2 IN LUNG AND 1
IN THE PROSTATE, BUT THOSE WITH
THE MUTATION SHOWING INCREASED
EXPRESSION OF CA-C7.
AND AGAIN, THE CELL LINES WHERE
WE WOULD ENACTIVATE, WERE
SHOWING INCREED IN SENSITIVITY
TO [INDISCERNIBLE] WHICH IS THE
C67 INHIBITORS AGAIN, SUGGESTING
THAT [INDISCERNIBLE] 1
ACTIVATION DON'T ONLY LEAD TO
INCREASED EXPRESSION OF IT BAH
ALSO INCREASED DEPENNENCY,
AGAIN, THIS PROVIDED A RATIONAL
TO INHIBIT C67, ALSO TO INHIBIT
TRANSFORMATION, AND IN THIS
CASE, THE RESULTS WERE EVEN MORE
STRIKING.
WE WERE LIKE ALL TUMORS
DISAPPEAR NOTHING 1 OF THE
MODELS WHERE WE TREATED WITH THE
COMBINATION, AND YOU CAN SEE
AGAIN, THAT EVEN IN THIS CASE,
LIKE THE TUMOR AND THE
DEVELOPMENT RESISTANCE, THAT
RESPONSE TO TARGETED THERAPY WAS
VERY DRAMATICALLY EXTENDED OVER
TIME.
AND WHEN WE ANALYZED THE TUMORS
OF THE EARLY MODEL FOR WHICH THE
COMBINATION TUMORS SURVIVE, AND
WE HAD A LOOK AT THE EXPRESSION
OF THE MARKERS, YOU OBSERVED
THAT A SUSPECTED [INDISCERNIBLE]
TARGETED THERAPY WOULD INDUCE
THE EXPRESSION OF AN THE MARKERS
BUT THIS PHENOTYPE WAS CHANGED
IN THE [INDISCERNIBLE].
AND RESULT WAS COMPARED TO THE
CONTROL IT WAS SUPPRESSED WITH
THE ENZALUTAMID, AND WE WHEN WE
OBSERVE WITH AN INHIBITOR, WE
SEE THIS PHENOTYPE IS COMPARED
TO AND LED US TO THE CONTROL
CONDITION.
SO SUGJOAOF THE THANKSGIVING
COMBINATION MAY BE ABLE TO
REALLY SUPPRESS [INDISCERNIBLE]
TRANSFORMATION.
IN ORDER TO LOOK FOR THE
MECHANISM FOR THIS, WE OBSERVED
THAT ENZALUTAHAD MID WOULD
INHIBIT MYC, AND ALSO
[INDISCERNIBLE] AS WE MENTIONED
AND WE OBSERVED THAT SIMILARLY
IS A INHIBITOR WOULD ABROGATE
THE EXPRESSION OF MYC IN BOTH
MODELS OF TRANSFORMATION THAT WE
TESTED.
AND AFTER HAVING A LOOK AT THE
EXPRESSION LEVELS OF THE MRNA OF
MYC, WE SAID THERE WERE REALLY
NO DIFFERENCES SUGGIESTING THAT
THE DOWN REGULATION OF MYC WAS
NOT DUE TO TRANSCRIPTIONAL
CHANGES BUT RATHER POST
TRANSLATIONAL MODIFICATIONS SO
WE KNEW THAT MYC WAS MOSTLY
[INDISCERNIBLE] IN THE
PROTEOSOME, SO WE DECIDE TO
STUDY THE ACTIVATION OF THE
PROTEOSOME IN CELL LINES WHERE
C-CELL WAS INHIBITED.
SO WHAT WE OBSERVE IS THAT IN 2
DIFFERENT CELL LINES, 1 FROM THE
LUNG AND 1 FROM THE PROOF
THEASTY, WHEN YOU INHIBIT C67
EITHER BY USING CANNED WHAT OR
BY KNOCKING OUT C67 BY
IDENTIFICATION, WE OBSERVED IT
WAS INCREASED ACTIVATION OF THE
PROTEIN COMPLEXIOSOME.
SO WE SUGGIEST THAD THIS
ACTIVATION OF THE PROTEIN
COMPLEXIOSOME, AND WE OBSERVED
THAT IN THE CONTROL THERE WAS NO
SIGNIFICANT EXPRESSION OF
NEURONAL MARKERS, TARGETED
THERAPY WOULD INDUCE THE
EXPRESSION OF THESE MARKERS,
TREATMENT WITH THIS PHENOTYPE
BUT THEN WHEN WE WOULD
OVEREXPRESS AN [INDISCERNIBLE]
MYC THAT IS RESISTANT TO THE
[INDISCERNIBLE] PROTEOSOME, AND
THIS IS THE MECHANISM BY WHICH
C87 IS PREVENTING
TRANSFORMATION, SO BASICALLY, IT
INCREASES THE GENE, AND
ULTIMATELY LEADING TO
TRANSFORMATION BUT WHEN WE
COMBINE TARGETED THERAPY WITH A
INHIBITORS WE OVERACTIVATE THE
PROTEOSOME, AND WE INTEGRATE MYC
AND THE CELLS TRANSFORM AND THEY
BASICALLY ARE ABLE TO RESPOND TO
TARGETED THERAPY FOR A LONGER
TIME AND POTENTIALLY UNDER GO
[INDISCERNIBLE] RESISTANCE THAT
WAS PROBABLY LESS AGGRESSIVE
THAN SMALL CELL TRANSFORMATION.
AND AS A TAKE HOME MESSAGE,
[INDISCERNIBLE] BUT IT IS WHAT
IT IS.
SO WE OBSERVED THAT POTENTIALLY,
ADEN O CARCINOMA MAY UNDERGO
INTERMEDIARY STATE THAT IS MORE
PLASTIC AND TARGETED THERAPY MAY
BE ABLE TO INTIEWS THIS STATE
TOGETHER WITH THE OCCURRENCE OF
DIFFERENT MOLECULAR ALTERATIONS,
THISITATE IS CHARACTERIZED BY
SUPPRESSIONAL IMMUNE RESPONSE
AND UPREGULATION PATHWAYS LIKE
AKT AND MYC AND THEN
ADDITIONALLY OTHER ALTERATIONS
MAY LEAD TO DIFFERENT FATE.
BUT AGAIN THIS IS NOT USUALLY AS
EASY AS IT SEEMS.
ADEN O CARCINOMA LOOK
[INDISCERNIBLE] CARCINOMA AND
YOU SEE SOME DEGREE OF THE
UNITY; THESE INCREASE
TRANSCRIPTOMIC HETEROGENEITY,
EVEN THOUGH THEY LOOK LIKE
SQUAMOUS CELL CARCINOMA OR
[INDISCERNIBLE], AND WE SEE THE
INCREASED [INDISCERNIBLE] IN THE
PROFILES AND MAYBE THESE
ADDITIONAL MOLECULAR
[INDISCERNIBLE] PUSH TOWARDS SO
IT MAY MAKE THAT THE CELLS WE
THINK ALL THAT MAY MAKE BRIEF
SPECIFIC PHENOTYPE IN THIS CASE,
IN THIS CASE, SQUAMOUS SORE
SMALL CELL, IN THE CASE OF
SQUAMOUS SARS INFECTION NOAMA,
IT SEEMS THAT AKT INHIBITION OR
MYC MAY BE ABLE TOW PREVEBT
TRANSORMATION TO SQUAMOUS AND IN
THE CASE OF SMALL CELL,
[INDISCERNIBLE] MIGHT BE
INTERESTING THERAPEUTIC TARGETS
FOR THIS.
AND VERY IMPORTANT, SINCE THAT
MUTATION IS AKT AND AB
PATHWAY,--RB PATHWAY MAY BE ABLE
TO PREDICT THOSE PATIENTS THAT
ARE HIGH RISK TO SQUAMOUS.
SO WITH THAT I WOULD LIKE TO
ACKNOWLEDGE ALL MY AMAZING LAB
MEMBERS AND COLLABORATORS FROM
MSK AND THE BROAD.
AND ALSO PATIENTS AND FAMILIES
FOR THEIR CONSENTING TO SHARE
THEIR CLINICAL SPECIMENS FOR US
TO DO TUMOR ANALYSIS AND TO MY
FRIENDS FAMILY AND MENTORS
INCLUDING [INDISCERNIBLE] THAT
CAME HERE FOR SUPPORT AND OF
COURSE ALL THE FUNDING SOURCES.
SO HAPPY TO TAKE ANY QUESTIONS,
THANK YOU SO MUCH FOR YOUR
ATTENTION. .
[ APPLAUSE ]
>> THANKS A LOT THAT WAS QUITE A
TOUR DEFORCE, AND I HAD A COUPLE
QUESTIONS ABOUT THE LAST PART.
YOU KNOW I HAVE AN INTEREST IN
NEUROENDOCRINE TRANSFORMATION,
YOU, IN THE MODELS WHERE YOU
ACTUALLY TREATED THE TUMORS,
SOME OF THE COMBINATIONS
ACTUALLY SHOWED VERY GOOD
ESPECIALLY EXPORT INHIBITOR FOR
LIKE 77 DAYS BUT THEN YOU HAD
RELAPSE, AND YOU IMPLICATED THAT
THE RELAPSE THROUGH MODELING
WITH SOX 2, DID YOU SEE SOX 2
REEXPRESSION IN THE RELAPSED
TUMORS FROM THAT--THOSE
EXPERIMENTS?
>> WE DIDN'T SPECIFICALLY HAVE A
LOOK AT THAT BUT WE HAVE STUDIED
THAT THOSE TUMORS BECAUSE WHEN
WE ANALYZE THE TUMORS FOR
ENDOCRINE MARKERS THOSE WERE AT
END POINT SO THEY WOULD REGROW
AND THEY WERE NOT REALLY SHOWING
ENDOCRINE PHENOTYPE SO I WOULD
ASSUME THAT SOX MIGHT NOT HAVE
BEEN ON OVEREXPRESSED BUT WE
DIDN'T REALLY HAVE A LOOK AT IT.
>> OKAY, BECAUSE I JUST THINK
THAT IF THE MODEL IS PREDICTING
WHAT WOULD GO ON IN THE PATIENT
YOU KNOW YOU MAY BE ABLE TO SEE
IT JUST BY THE TREATMENTS YOU
GIVE.
THE RESISTANCE WOULD GIVE YOU
CLUES AS TO WHAT WOULD RELAPSE.
>> EXACTLY.
IT WOULD BE INTERESTING TO LOOK
AT THOSE TUMORS AND SEE HOW THEY
BECAME A RESISTANT.
>> AND I HAVE A GENERAL QUESTION
THAT YOU CAN ANSWER AT THE END
OF THE SCIENTIFIC QUESTIONS,
YOU'VE HAD AN EXTREMELY
SUCCESSFUL YOU KNOW TRAINING
EXPERIENCE AND WHAT DID YOU
KNOWLEDGE WAS THE KEY TO YOUR
SUCCESS?
>> SO I THINK I WAS LACKING NOT
TO LIKE LAND IN A LAB WHERE
THERE WERE A LOT OF RESOURCES.
WE WERE VERY SPOILED, WE
WOULDN'T DO OUR IN VIVO SPRMS
OURSELVES, FOR EXAMPLE, LIKE
[INDISCERNIBLE], SO THAT WAS
[INDISCERNIBLE] SOMETHING ELSE
AND THAT'S HOW MANY IN OUR LAB
LOOKED TO BE MORE PRODUCTIVE.
THERE'S NO REAL SECRET, I AM
ABLE TO TAKE SEVERAL APPROACH AT
THE SAME TIME IF YOU CAN DO THAT
THAT'S ALWAYS A GOOD IDEA
BECAUSE IF YOU PUT YOUR EGGS
ONLY IN 1 BASK, IF THAT DOESN'T
WORK THEN YOU'RE SCREWED BUT YOU
HAVE A FEW THEN, PARTICULARLY
SOME PLAN B, SOMETHING THAT'S
GOING TO BE PUBLICKED NO MATTER
WHAT, SO MAYBE LESS RISK, LOWER
REWARD BUT GETS YOU A PAPER,
THAT'S NIGHT TO HAVE THAT AS A
BACK UP PLAN.
>> THANK YOU.
NTHANK YOU VERY MUCH FOR YOUR
TALK.
I'M ELAINE JAFFE, I WORK ON
LYMPHOMA NOT LUNG CANCER BUT
I'VE ALSO BEEN INTERESTED IN
TRANSDIFFERENTIATION AND LINEAGE
PLASTICITY AND MAINLY B-CELL
LYMPHOMAS WHICH CAN UNDERGO
TRANSFORMATIONS FOR ACIDIC TUMOR
ONS AND IN THE LYMPHOMAS WE'VE
STUDIED, YOU CAN--WE CAN SEE
TRANSDIFFERENTIATION EVEN BEFORE
ANY THERAPY SO IT'S NOT
NECESSARILY DRIIVE BY THERAPY,
SUGGESTING THAT THE CELLS THAT
PROMOTE THAT ARE LAWYER THERE,
AND ACTUALLY IN SOME STUDIES YOU
CAN SHOW THAT PARTICULARLY IN
FOLLICULAR LYMPHOMA, THE
IMENETTIC PROFILE OF THE
TRANSDIFFERENTIATED CELL, IS
ACTUALLY CLOSELY RELATED TO A
BONE MARROW STEM CELL, SO IT WAS
PROBABLY THERE VERY EARLY IN
TUMOR INITIATION AND I WONDER IF
YOU'VE SEEN ANYTHING LIKE THAT,
MODEL IN THE LUNG TUMORS?
>> SO WE DO SEE MANY CASES WITH
TRANSFORMATION, OF COURSE
SPONTANEOUSLY WITHOUT TREATMENT,
AND THOSE CASES ARE ADEN O
SQUAMOUS TUMORS AND A SQUAMOUS
COMPONENT BUT ALSO COMBINE ADEN
O SMALL CELL TUMORS, SO IT'S
DEFINITELY OCCURRED AND WE'VE
ALSO LIST THOSE TUMORS FOR OUR
ANALYSIS BECAUSE IT'S HARD TO
GET THIS PREAND POST
TRANSFORMATION SAMPLES AND IN
THE END, I THINK THAT WHAT
TRANSFORMATION IS THE SERIOUS OF
MOLECULAR EVENTS AND THOSE MAY
OCCUR IN THE [INDISCERNIBLE]
TREATMENT.
IT IS TRUE THAT AS FAR AS WE
HAVE SEEN OUR MODELS, THE
TARGETED THERAPY, BASICALLY
POTENTIATING OR ACCELERATES
TRANSFORMATION BASICALLY BY
INHIBITING THE MOLECULAR
PATHWAYINGS THAT DETERMINE THE
ADEN O CARCINOMA STATE, BUT THAT
DOESN'T MEAN THAT THERE'S OTHER
MEANS BY WHICH THOSE PATHWAYS
MIGHT BE DOWN REGULATED SO
BASICALLY, I THINK THAT X,
Y,-POTENTIAL WILL GIVE YOU A
DIFFERENT TUMOR IF THEY DMR
WHATEVER CONTEXT, NO MATTER
WHETHER IT'S A STEM SOLE OR
CARCINOMA.
>> THANK YOU.
>> HI, TELENT TELE--EXCELLENT I
HAVE 2 QUESTIONS FOR YOU, THE
FIRST QUESTION IS WHAT DO YOU
SEE PLASTICITY IN THE SENSE,
WHAT DETBREE, I SHOULD SAY DO
YOU SEE HETEROGENEITY IN THE
PLASTICITY THAT YOU SEE WHERE,
YOU KNOW YOU'RE SHOWING US LIKE
DEFINITELY KIND OF A LINEAR
TRANSFORMATION, IT'S PROBABLY
NOT LINEAR, IT'S CIRCULAR, BUT
ANYWAY, HAPPENING, CIRCULAR
LITTLE BALL HAPPENING OVER TIME,
BUT TO WHAT EXTENT ARE THERE
DIFFERENCES WITHIN THE CELL
POPULATIONS THAT YOU'VE EXAMINED
IN THAT WAY, AND THEN I WILL GET
TO MY SECOND QUESTION.
>> SO WE HAVEN'T HAD A LOOK AT
THE [INDISCERNIBLE] YET, WE ARE
DOING THAT NOW, I THINK OUR
SPECIMEN IS IN TRANSFORM EGG, SO
THESE ARE THE IMMUNO DEFICIENT
MODELS BUT WE HAVE SOME VERY
INTERESTING IMAGES WHERE WE SEE
FOR EXAMPLE, A COMBINED ADEN O
SMALL CELL TUMORS, YOU SEE THAT
THE CARCINOMA PORTION IS FILL
WIDE IMMUNE CELLS AND THEN THE
LITTLE SPACE THAT IS SMALL IS
COMPLETELY EMPTY, SO I BEING I
WAS DISCUSSING THAT PREVIOUSLY
LIKE, THIS TRANSFORMATION MAY
GIVE US HINTS ABOUT HOW SMALL
CELL FOR EXAMPLE IS ABLE TO LIKE
REPRESS THE [INDISCERNIBLE] OF
IMMUNE CELLS OR THE IMMUNO
PHENOTYPE BECAUSE DURING THIS
PROCESS OF TRANSFORMATION, YOU
SEE THAT THERE'S A LOT OF
PATHWAYS THAT ARE DRIVEN TO
IMMUNE PATHWAYS TO SUPPRESS BUT
WE DONT KNOW YET HOW THAT
HAPPENS.
>> RIGHT.
SO MY SECOND QUESTION IS RELATED
TO THAT SO NORMALLY WE SPEND A
LOT OF TIME IN MY LAB AND WE
THINK ABOUT TUMOR AND
MICROENVIRONMENT CROSS TALK AND
HOW THEY'RE SHAPING BUT THE
OTHER MICROENVIRONMENT IS THE
MICROENVIRONMENT OF THE TUMOR
CELL POPULATION, SO I'M TALKING
ABOUT IF WE WERE THE TUMOR AND
WE WERE ALL TUMOR CELLS IN HERE,
I AM VERY DIFFERENT THAN PICK
ANYBODY ELSE BECAUSE I'M VERY
DIFFERENT THAN ANYBODY ELSE
HERE, EVERYBODY'S DIFFERENT THAB
EVERYBODY ELSE, THAT'S ITS OWN
LITTLE MICROENVIRONMENT, AND
EVERYBODY THINKS OF IT AS VERY
ANTAGONISTIC I WOULD SAY LIKE
SURVIVAL OF THE FITTEST, LIKE I
WILL GET A GRANT THEREFORE THIS
PERSON'S NOT GOING TO--THAT'S A
JOKE BECAUSE OBVIOUS 3 THAT'S
NOT HAPPENING.
[LAUGHTER]
BUT ANYWAY, SOMEBODY EVERY THERE
MAY NOT GET A GRANT BUT MAYBE
IT'S WHEN I GET THE GRANT, HE
LOOKS REAL GOOD AND THEN HE WILL
GET THE NEXT GRANT, SO THERE'S
COOPERATIVITY WITH THE
MICROENVIRONMENT THAT COULD
HAPPEN EVEN AMONG THE TUMOR, AND
PEOPLE DON'T THINK OF THE
MICROENVIRONMENT THIS WAY BUT
IT'S THE SAME BIOLOGY.
>> I SHOWED HERE OUR
[INDISCERNIBLE] STUDIES COMBINED
SMALL CELL AND AND AS YOU CAN
SEE, THE NONSMALL CELL
COMOPPOSITE BEHAVIORIAL
PHENOTYPE SENT MINIMAL, IT'S
LIKE AROUND 5% AND YOU HAVE THAT
PDX THAT IS PASSAGE OVER MANY
MICE, AND THAT NONNEURONAL
COMPONENT STAYS THERE, SO THAT
SUGGESTS THERE MY BE INTERACTION
BETWEEN THE CARCINOMA AND SMALL
CELL COMPONENTS AND THIS IS
ACTUALLY OTHER DATA IN SMALL
CELL TUMORS WHERE 2 DIFFERENT
POPULATIONS HAVE BEEN LIKE
IDENTIFIED AND 1 OF THEM THAT
YOU GO INVITRO AND IT LIKE
STICKS TO THE PLATE AND THE
OTHER 1 IS LIKE FLEETING AND THE
FLOATING 1 IS MORE NEUROI HAD
BEEN O KRIEN AND THE OTHER IS
MORE NEUROINDCOKRIEN AND ENT AND
THEY HAVE IDENTIFIED FOR
EXAMPLE, WHEN YOU LIKE--AND GRAB
THEM SEPARATELY, THE METABOLIC
POTENTIAL AND INDUCED, BUT WHEN
YOU GRAB THEM TOGETHER, THE
MOUSE IS FULL WITH METASTASIS.
AND THEY HAVE SEEN THAT 1 OF
THESE POPULATIONS,
[INDISCERNIBLE] IS ENRICHED FOR
RECEPTORS OF [INDISCERNIBLE],
WHILE THE OTHER EXPRESSES THE
LIGANDS SO THERE MUST BE A
RELATIONSHIP BETWEEN THEM BUT WE
DON'T KNOW, WE EXPLORE THAD IN
DETAIL.
>> WELL I CAN'T WAIT TO
COLLABORATE.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH FOR THE
TALK.
IT WAS A GREAT TAILBACK SO I'M
WAY BIOINFORMATICIAN, SO I HAVE
ALREADY, I MAY ALREADY HAVE MANY
QUESTIONS FOR YOU, SO MY FIRST
QUESTION IS THAT AS YOU HAVE
SAID THAT THE [INDISCERNIBLE]
TRANS DIFFERENTIATED
[INDISCERNIBLE] OR IS IT
UNIDIRECTIONAL OR URT, LUSC
TRANSFORM OR ALSO INTO YOUR
[INDISCERNIBLE] THAT WAS MY
FIRST QUESTION FOR YOU.
AND THE SECOND QUESTION IS THAT
AS YOU SAID, THERE'S GENOME IRK
ALTERATION IN THE RB PATHWAY AKT
WOULD HELP TO TRANSFORMATION
CANNED WHAT SO AS A
BIOINFORMATICIAN APPROACH, WHAT
KIND OF FEATURES OR DESSCRIPTORS
I'M LOOKING FOR SO I CAN PREDICT
OR DEVELOP A METHOD WHICH CAN
COULD TELL YOU THAT IS THE
PROBABILITY OF THE A CELL TO GET
[INDISCERNIBLE] AS
[INDISCERNIBLE]?
THOSE ARE 2 QUESTIONS.
[INDISCERNIBLE]
>> SO CAN YOU REPEAT YOUR FIRST
QUESTION, I'MORRY.
>> SO THE FIRST QUESTION IS ONCE
THE CELL GETS TRANSFORMED FROM
[INDISCERNIBLE], AND INTO
[INDISCERNIBLE], IT LOSES ITS
ABILITY TO BE TRANSFORMED FROM
[INDISCERNIBLE] TO SCLC, SO
THERE'S LIKE VERY RECENT DATA ON
THE PROCESS SETTING WHERE THEY
HAVE ANSWERED ANALYSIS TO WHAT I
HAVE SHOWN HERE AND THE ANALYSIS
FROM THE CARCINOMA TO THE SMALL
CELL, LIKE PHENOTYPES, THEY
OBSERVE THAT IN THE MIDDLE
THERE'S AN INCREASED PHENOTYPE
THAT MUST BE ASSOCIATED TO
[INDISCERNIBLE] CELL OR SQUAMOUS
TRANSCRIPTOMIC PROFILE.
SUGGEST NOTHING THIS MODEL I'M
SHOWING HERE THAT MIGHT BE AN
INTERMEDIATE, THAT MIGHT BE
SQUAMOUS CARCINOMA SO I DON'T
THINK IT'S LIKE A LINEAR
PROCESS, IT MIGHT BE IF LIKE AT
SOME POINT, CELLS REACH 1
CERTAIN STATE, THEY MIGHT GET
[INDISCERNIBLE] BUT FOR EXAMPLE,
LET'S SAY, TO BECOME SMALL CELL,
WE NEED MUTATIONS IN WHY, X OR
YX PATHWAYS AND IF THOSE ARE
[INDISCERNIBLE] MUTATION THAT IS
NOT REVERSIBLE THEN THEY MIGHT
GET [INDISCERNIBLE].
BUT THERE'S ALSO A POSSIBILITY
THERE MIGHT BE REALLY
DIFFERENTIATION TO PRESERVE THAT
AND WE HAD 1 INTERESTING PATIENT
IN MSK WHERE WE WOULD GET LIKE
LONGITUDINAL SAMPLES FROM THE
[INDISCERNIBLE], THIS WAS A
TRANSFORMATION CASE AND
EVERYTHING WE WOULD GET A NEW
SAMPLE FROM HER IN A DIFFERENT
TIME POINT IT WOULD LOOK LIKE A
[INDISCERNIBLE].
SO FIRST IT WOULD LOOK LIKE A
[INDISCERNIBLE] AND THEN WE
WOULD DO THE TEST AND THEN IT
WOULD BE ADEN O CARCINOMA AGAIN
SO I THINK THAT IT'S NOT LIKE A
LINEAR PROCESS, BUT IT MIGHT BE
IF ONCE THERE'S LIKE A GIVEN
STATE BY MUTATION IS NOT
REVERSIBLE.
>> THANK YOU VERY MUCH.
>> THANK YOU ALVARO FOR AN
AMAZING TALK AND CONGRATULATIONS
AGAIN ON WINNING THE SERIES
WACHTEL PRIZE.
A BIG THANK YOU TO THE AUDIENCE
BOTH IN PERSON AND VIRTUAL AND
PLEASE DO SPREAD THE WORD ABOUT
THIS AWARD THE 13th ANNUAL
WACHTEL PRIZE APPLICATION WILL
OPEN MIDSEPTEMBER OF THIS YEAR,
SO NEXT MONTH.
FOR IN-PERSON ATTENDEES I HOPE
YOU WILL STAY FOR LUNCH WHICH IS
READY FOR YOU IN THE FAES
TERRACE AND WE HAVE COPIES OF
HIS AWARD WINNING ESSAY WHICH
WAS JUST PUBLISHED ON SEM ON
WEDNESDAY AND YOU CAN FIND IT AS
YOU EXIT THE AUDITORIUM.
SO THANK YOU ALL.
[ APPLAUSE ]