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>> OKAY, GOOD AFTERNOON.

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I'M VERY PLEASED TO BE HERE.

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I AM VALL, EXECUTIVE EDITOR OF

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THE SCIENCE JOURNALS AND I AM

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DELIGHTED TO WELCOME YOU TO THE

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12th ANNUAL,A AAS MARTIN AND

7
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ROSE WACHTEL CANCER RESEARCH

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AWARDS CEREMONY.

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AND I'M SORRY I HAVE TO READ MY

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NOTES TO REMEMBER THAT.

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SO THIS CEREMONY RECOGNIZES

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EARLY CAREER CANCER RESEARCHERS

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FOR OUTSTANDING KRIEWKS TO THE

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FIELD.

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AND THIS YEAR WE'RE DELIGHTED TO

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HONOR ALVARRO VILLENUA, AND I

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WILL SAY NO MORE ABOUT HIM

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BECAUSE HE WILL GET INTRODUCED

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LATER BUT I TELL YOU A LITTLE

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BIT ABOUT TODAY'S AWARD, IT WAS

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MADE POSSIBLE BY AT THE QUESTION

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OF MORE THAN $1 MILLION IN

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MARTIN WACHTEL, MR. WACHTEL

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WANTED TO ESTABLISH AN ENDOWMENT

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TO RECOGNIZE A AAS MEMBER WHO

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HAS   PERFORMED OUTSTANDING WORK

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IN THE FIELD OF CANCER RESEARCH.

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MR. WACHTEL WAS A BUSINESS MAN

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WHO RAISED ALBINO MICE AND RATS

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FOR MEDICAL RESEARCH, SO HE HAD

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THAT INVOLVEMENT IN MEDICAL

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RESEARCH AND HE WAS A FIRM

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BELIEVER IN THE POWER OF

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SCIENTIFIC RESEARCH TO BENEFIT

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MANKIND AND WANTED TO USE HIS

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WEALTH TO SUPPORT AND RECOGNIZE

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THOSE IN THE MEDICAL COMMUNITY

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WHOSE WORK HAS THE GREATEST

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IMPACT AND THAT'S WHAT BRINGS US

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HERE TODAY.

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AND WHY DID HE WANT THIS PERSON

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TO BE A MEMBER OF AAAS, AND HE

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SELECTED THE PLACE TO ESTABLISH

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THE PRIZE BECAUSE HE THOUGHT IT

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HAD A LONG AND DISTINGUISHED

46
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HISTORY OF REPRESENTING ALL THE

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SCIENCES.

48
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HOPEFULLY MOST OF YOU KNOW AAAS,

49
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BUT IT'S 175 YEAR-OLD NONPROFIT

50
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ORGANIZATION AND OUR MISSION IS

51
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BASED ON THE SAME PRINCIPLE THAT

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00:02:04,219 --> 00:02:06,621
DROVE MR. WACHTEL'S BUSINESS AND

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PHILANTHROPY.

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WE BELIEVE THAT SCIENCE AND

55
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TECHNOLOGY ARE THE KEY TO

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SOLVING THE GREATEST CHALLENGES

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THAT FACE OUR WORLD AND TO

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PROVIDING A BETTER LIFE FOR ALL.

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THE ASSOCIATION IS COMMITTED TO

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SERVING SOCIETY BY ADVANCING

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SCIENCE THROUGH INITIATIVES THAT

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ENHANCE EDUCATION, ENHANCE

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INTERNATIONAL COLLABORATION, AND

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ALSO CHAMPION SCIENCE ON CAPITOL

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HILL, SO, AAAS IS DOING MANY

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THINGS TO PROMOTE SORT OF THE

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SCIENCE IN SOCIETY ABOUT MAYBE,

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00:02:36,217 --> 00:02:39,420
MANY IN THIS ROOM KNOW AAAS

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00:02:39,420 --> 00:02:41,456
BETTER BECAUSE IN ADDITION TO

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00:02:41,456 --> 00:02:42,257
BEING THE LARGEST

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MULTIDISCIPLINARY SCIENCE AND

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ENGINEERING SOCIETY, WITH

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120,000 MEMBERS, TRIPLE AAAS

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PUBLISHES SCIENCE MAGAZINE ALONG

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WITH THE SIBLING JOURNALS,

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SCIENCE TRANSLATIONAL MEDICINE,

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WHICH ORGANIZED THE PRIZE THAT

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00:02:57,739 --> 00:03:01,943
WE'RE HERE FOR TODAY, SCIENCE

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00:03:01,943 --> 00:03:03,244
SIGNALING, SCIENCE ADVANCES,

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SCIENCE ROBOTICS AND SCIENCE

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IMMUNOLOGY.

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00:03:06,381 --> 00:03:10,351
AND NOW I WOULD LIKE TO

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RECOGNIZE THOSE WHO DID ALL THE

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WORK ON THIS PRIZE,

85
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[INDISCERNIBLE] WHO'S TRANSITION

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SCIENCE MEDICINE AND ASSOCIATE

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EDITORS COURT ME MELLOW WHO IS

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ALSO HERE AND DOROTHY HOLBERG,

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WHO FOR A VERY GOOD REASON CAN'T

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BE HERE TODAY BECAUSE SHE JUST

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GAVE BIRTH LITERALLY, JUST.

92
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SO GIVEN HIS HISTORY OF WORKING

93
00:03:35,643 --> 00:03:37,779
WITH NIH RESEARCHERS, I'M SURE

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00:03:37,779 --> 00:03:39,280
THAT MR. WACHTEL WOULD BE

95
00:03:39,280 --> 00:03:40,415
PARTICULARLY PLEASED TO KNOW

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THAT WE ARE NOW COLLABORATING

97
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WITH THE NIH IN THE PRESENTATION

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00:03:45,520 --> 00:03:46,421
OF THIS AWARD.

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00:03:46,421 --> 00:03:49,424
I WANT TO ACKNOWLEDGE JULIA

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LAMB, CRYSTAL RIVERA, AND ANKLE

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STUBS-DIGS OF THE NCI FOR ALL

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THEIR HEALTH AND NOW HERE TO

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00:03:55,797 --> 00:03:58,433
REPRESENT IS NCI IS THE

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CO-DIRECTOR OF THE CENTER FOR

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00:04:00,702 --> 00:04:02,003
CANCER RESEARCH DR. JAMES GULLY

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AND THANK YOU JAMES FOR YOUR

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ROLE IN MAKING TODAY'S EVENT A

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SUCCESS.

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[ APPLAUSE ]

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>> WELL, THANK YOU SO MUCH
AND

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YOU KNOW I JUST WANT TO SAY, I

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THINK WE ALL ENJOY A SUCCESS

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STORY BECAUSE TODAY D

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R. ALVARO QUINTANAL-VIWELL,

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LALONGA WILL GIVE US SUCH A

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STORY.

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GOOD AFTERNOON I'M THE ACTING

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DIRECTOR FOR THE CENTER FOR

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CANCER EXPRCH ON BEHALF OF

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DR. CAROL FIELD, MY FELLOW

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CO-DIRECTOR AND ON BEHALF ALSO

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OF DR. DEBORAH CITRON, WHO IS

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THE SCIENTIFIC DIRECTOR FOR

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CLINICAL RESEARCH AND MYSELF, WE

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WANT TO WELCOME YOU TO THE

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CENTER FOR CANCER RESEARCH GRAND

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ROUNDS.

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WE'RE DELIGHTED TO 7 AS THE HOST

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FOR THIS TENTH ANNUAL AAAS

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00:05:01,329 --> 00:05:03,698
MARTIN AND ROSE WACHTEL AWARD

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LECTURE, SO I WILL KEEP MY

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WELCOME REMARKS VERY SHORT.

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I JUST WANT TO TALK A LITTLE BIT

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ABOUT 1 OF THE GOALS IN THE

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NATIONAL CANCER PLAN THAT

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DR. RATHANALL LAID OUT.

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SO IN THE CANCER PLAN, SHE LAYS

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OUT 8 GOAL ANDS 1 OF THOSE

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EMPOWERING GOALS AND THE GOAL OF

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OPTIMIZING THE WORKFORCE.

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SO IN THE CENTER FOR CANCER

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RESEARCH WE REALLY BELIEVE THAT

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OUR MOST VALUABLE RESOURCE IS

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OUR PERSONNEL AND AMONG OUR

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DIVERSE AND ILLUSTRIOUS FACULTY

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AND STAFF 1 GROUP I'M KEENLY

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INTERESTED IN NURTURING IS OUR

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JOWNG INVESTIGATORS.

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SEE, THIS GROUP OF BRIGHT

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VISIONARIES, THEIR IDEAS WELL

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PROPEL US TO A BILLIANT FUTURE.

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THEIR THOUGHTS ARE FULL OF

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TOMORROW'S HOPE AND POSSIBILITY

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SAYS GIVING RISE TO FUNDAMENTAL

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DISCOVERIES THAT WILL ENABLE NEW

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DIRECTIONS AND ALSO NEILD CANCER

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THERAPIES OF TOMORROW, TODAY.

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SO IN A FEW SHORT MINUTES, I

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WILL HEAR A SCIENTIFIC STORY

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THAT EMBODIES THESE ASPIRATIONS.

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SO AFTER THE PRESENTATION OF THE

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AWARD TO

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DR. QUINANAL-VILLALONGA, I JUST

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LOVE SAYING THAT NAME, I INVITE

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TO YOU SIT BACK, RELAX AND ENJOY

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THIS INTERESTING STORY HE WILL

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SHARE THROUGH HIS KEY NOTE

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ADDRESS.

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[ APPLAUSE ]

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>> THANK YOU DR. GULLY.

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GOOD AFTERNOON AND THANK YOU ALL

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FOR JOINING US HERE TODAY, I'M

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MESSRS. SMITH AND I'M THE EDITOR

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OF TRANSLATIONAL MEDICINE WHO

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HOST THIS IS PRIZE WITH NYI AND

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WE'RE DELIGHTED TO DO SO THIS

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YEAR AGAIN.

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THE MISSION OF SCIENCE

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TRANSLATIONAL MEDICINE IS TO

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PROMOTE HUMAN HEALTH BY

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PROVIDING AN INTERDISCIPLINARY

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FORUM FOR BIOMEDICAL RESEARCHERS

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AROUND THE GLOBE, IN SCIENCE,

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MEDICINE AND ENGINEERING.

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SCIENCE TRANSLATIONAL MEDICINE

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IS DELIGHTED TO BE COORDINATING

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THE 12th ANNUAL WACHTEL AWARD

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ON BEHALF OF,A AAS, AND

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RECOGNIZING A LEADER EARLY

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CAREER SCIENTIST IN THE FIELD OF

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CANCER RESEARCH.

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I WOULD LIKE TO THANK OUR

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DISTINGUISHED JUDGING PANEL

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ELENOIRA [INDISCERNIBLE] FROM

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JOHN HOPKINS UNIVERSITY,

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[INDISCERNIBLE] FROM

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MASSACHUSETTS GENERAL HOSPITAL

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AND YOU'LL UNIVERSITY, AND

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[INDISCERNIBLE] FROM DUKE

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UNIVERSITY AND NOW WITHOUT

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FURTHER ADO, I WILL HAND OVER TO

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COURTNEY, ASSOCIATE EDITOR OF

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TRANSLATIONAL SCIENCE MEDICINE,

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WHO WILL INTRODUCE THIS YEAR'S

205
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WACHTEL PRIZE WINNER.

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>> HELLO, IT IS WITH
IMRAIT

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PLEASURE THAT I AM ABLE TO BROUS

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OUR 12th ANNUAL A,A AS MARTIN

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AND ROSE RESEARCH AWARD WINNER.

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THIS YEAR'S WIN SERIES POINTS

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DR. ALVARO QINTANAL-VILLA LONGA,

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PREVIOUSLY CO DIRECTOR AND LAB

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DIRECTOR AT SLOAN KETTERRING WHO

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IS NOW THE DIRECTOR AT AFT

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RAZENECA, DURING HIS TIME AT

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SLOAN KETTERRING, HE WORKED ON

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TUMOR PLASTICITY AND HOW LUNG

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TUMORS IN PARTICULAR CAN UNDERGO

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TRANSDIFFERENTIATION AND DEVELOP

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DRUG RESISTANCE, AND HOW THIS

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PLASTICITY CAN BE TARGETED.

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HE'S HERE TODAY TO TELL US MORE

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ABOUT HIS GROUND BREAKING WORK.

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ALVARO, CAN YOU PLEASE JOIN ME?

225
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AS THE RECIPIENT OF THE AAAS

226
00:08:52,093 --> 00:08:53,594
WACHTEL PRIZE, PLEASE ACCEPT

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THIS PLAQUE, IT HAS AAAS MARTIN

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AND ROSE WACHTEL RESEARCH AWARD

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PRESENTED TO

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ALVARO YUINAANAN-VILLALONGA, FOR

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OUTSTANDING RESEARCH IN THE

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FIELD OF CANCER WORK BY AN

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INVESTIGATOR. 

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KD--SALLY ARK PLAWZ

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[ APPLAUSE ] 

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IN,A DITION ALVARO'S ESSAY WAS

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PUBLISHED ON WEDNESDAY FOR HIS

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GROUND BREAKING WORK IN THIS

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WEEK'S ISSUE OF TRANSLATIONAL

241
00:09:33,668 --> 00:09:34,602
SCIENCE MEDICINE AND IS

242
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AVAILABLE IN HARD COPY AT THE

243
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TOP OF THE YOU AUDITOR YOWM FOR

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ANYONE THAT WOULD LIKE TO GIVE

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IT A READ.

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TODAY'S WEBINAR IS BEING

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RECORDED FOR THE A,A AS

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ARCHIVES, AFTER COMPLETION OF

249
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THE TALK, THERE WILL BE 15

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MINUTES AVAILABLE FOR QUESTIONS

251
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AND ANSWERS FROM THE AUDIENCE SO

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PLOAZ COME UP TO THE 2

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MICROPHONES AND WITHOUT FURTHER

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ADO, I WOULD INVITE THE DOCTOR

255
00:09:56,891 --> 00:09:57,992
TO DELIVER HIS AWARD LECTURE AND

256
00:09:57,992 --> 00:10:00,961
TELL US MORE ABOUT HIS EXCITING

257
00:10:00,961 --> 00:10:02,830
RESEARCH ON UNDERSTANDING

258
00:10:02,830 --> 00:10:04,265
PLASTICITY AS A RESISTANCE TO

259
00:10:04,265 --> 00:10:09,770
CANCER THR --THERAPY.

260
00:10:09,770 --> 00:10:10,104
[ APPLAUSE ]

261
00:10:10,104 --> 00:10:11,772
>> THANK YOU SO MUCH FOR
THE

262
00:10:11,772 --> 00:10:13,641
INTRODUCTION AND THANK YOU SO

263
00:10:13,641 --> 00:10:16,043
MUCH TO THE SCIENCE

264
00:10:16,043 --> 00:10:16,977
TRANSLATIONAL MEDICINE COMMITTEE

265
00:10:16,977 --> 00:10:19,046
AND THE SCIENTIFIC COMMITTEE FOR

266
00:10:19,046 --> 00:10:22,883
MAKING ME HONOR TO RECEIVE THIS

267
00:10:22,883 --> 00:10:27,755
AWARD, AND I MUST CONFESS, I

268
00:10:27,755 --> 00:10:29,490
WHEN I RECEIVED THE INFORMATION

269
00:10:29,490 --> 00:10:31,392
ON THE AWARD, I THOUGHT IT WAS A

270
00:10:31,392 --> 00:10:33,427
SPAM E-MAIL, AND I STILL TODAY I

271
00:10:33,427 --> 00:10:34,895
CAN'T BELIEVE I WAS HONORED WITH

272
00:10:34,895 --> 00:10:36,297
THIS AWARD SO I WOULD LIKE TO

273
00:10:36,297 --> 00:10:38,666
THANK YOU SO MUCH FOR THAT

274
00:10:38,666 --> 00:10:39,967
E-MAIL NOT BEING SPAM.

275
00:10:39,967 --> 00:10:41,502
AND I WOULD LIKE TO TALK TO YOU

276
00:10:41,502 --> 00:10:43,938
ABOUT WHAT I HAVE LEARNED DURING

277
00:10:43,938 --> 00:10:46,507
MY 6 YEARS AT MEMORIAL SLOAN

278
00:10:46,507 --> 00:10:47,975
KETTERRING IN NEW YORK ON

279
00:10:47,975 --> 00:10:48,309
PLASTICITY.

280
00:10:48,309 --> 00:10:58,753
THESE ARE MY DISCLOSURES.

281
00:10:59,320 --> 00:11:00,187
ANOTHER THING RELATED TO THE

282
00:11:00,187 --> 00:11:00,588
WORK TODAY.

283
00:11:00,588 --> 00:11:04,125
AND I WOULD LIKE TO START BY

284
00:11:04,125 --> 00:11:05,392
MAKING A BRIEF INTRODUCTION

285
00:11:05,392 --> 00:11:07,027
ABOUT LUNG CANCER, LUNG CANCER

286
00:11:07,027 --> 00:11:11,365
CAN BE DIVIDED INTO DIFFERENT

287
00:11:11,365 --> 00:11:13,100
SUBTYPES, THEY ACCOUNT FOR

288
00:11:13,100 --> 00:11:16,270
AROUND 15% OF CASES AND THEN

289
00:11:16,270 --> 00:11:18,139
NONSMALL CELL LUNG CANCER THAT

290
00:11:18,139 --> 00:11:24,879
CAN BE SUBDIVIDED INTEREST MORE

291
00:11:24,879 --> 00:11:27,314
TYPES LIKE LUNG SQUAMOUS CELL

292
00:11:27,314 --> 00:11:29,250
CARCINOMA OR LARGE CELL

293
00:11:29,250 --> 00:11:32,419
CARCINOMA WHICH ARE MUCH MORE

294
00:11:32,419 --> 00:11:32,686
PROMINENT.

295
00:11:32,686 --> 00:11:37,992
THEY PRESENT DIFFERENT MOLECULAR

296
00:11:37,992 --> 00:11:39,827
IMPLICATIONS.

297
00:11:39,827 --> 00:11:41,762
FOR EXAMPLE, LUNG CARCINOMAS

298
00:11:41,762 --> 00:11:43,264
HAVE IDENTIFIED DIFFERENT DRIVER

299
00:11:43,264 --> 00:11:45,065
SET OF PATIENTS THAT ARE

300
00:11:45,065 --> 00:11:47,101
AMENABLE FOR TARGETED THERAPY

301
00:11:47,101 --> 00:11:48,969
AND THESE [INDISCERNIBLE] IN THE

302
00:11:48,969 --> 00:11:53,140
MEDICINE ERA HAS RESHAPED THE

303
00:11:53,140 --> 00:11:57,645
WAY WE TREAT LUNG CARCINOMA IN

304
00:11:57,645 --> 00:11:57,912
PATIENTS.

305
00:11:57,912 --> 00:11:59,780
FOR SQUAMOUS CELL WE HAVE

306
00:11:59,780 --> 00:12:04,785
TARGETING SYSTEMIED POTENTIALLY

307
00:12:04,785 --> 00:12:07,421
TARGETABLE THERAPY, BUT UP TO

308
00:12:07,421 --> 00:12:10,658
TILL NOW THEY HAVE BEEN TREATED

309
00:12:10,658 --> 00:12:11,625
WITH CHEMO THERAPY.

310
00:12:11,625 --> 00:12:13,027
AND UP TILL NOW IT WAS PRETTY

311
00:12:13,027 --> 00:12:15,796
MUCH A BLACK HOLE, WE KNOW THESE

312
00:12:15,796 --> 00:12:19,133
TUMORS ARE CHARACTERIZED BY THE

313
00:12:19,133 --> 00:12:19,633
[INDISCERNIBLE] TUMOR

314
00:12:19,633 --> 00:12:23,103
SUPPRESSORS AND THEY ARE VERY

315
00:12:23,103 --> 00:12:24,605
HARD TO TARGET FARM CO

316
00:12:24,605 --> 00:12:25,906
LONGICALLY SO BASICALLY THERE'S

317
00:12:25,906 --> 00:12:31,178
NOTHING OR NO MATCH AVAILABLE

318
00:12:31,178 --> 00:12:33,247
FOR THE SQUAMOUS CELL TUMORS.

319
00:12:33,247 --> 00:12:37,618
AND YOU CAN SEE THE SURVIVAL FOR

320
00:12:37,618 --> 00:12:39,787
HOW PRECISION MEDICINE HAS

321
00:12:39,787 --> 00:12:41,255
CONVERTED THE WAY WE TREATED

322
00:12:41,255 --> 00:12:41,522
PATIENTS.

323
00:12:41,522 --> 00:12:43,090
YOU CAN SEE HERE THAT COMPARED

324
00:12:43,090 --> 00:12:45,593
TO THE PREVIOUS STANDARD OF CARE

325
00:12:45,593 --> 00:12:46,560
BEFORE TARGETED THERAPY, CHEMO

326
00:12:46,560 --> 00:12:48,662
THERAPY, YOU CAN SEE THE EDFRI

327
00:12:48,662 --> 00:12:51,498
IN THIS CASE FOR PATIENTS WITH A

328
00:12:51,498 --> 00:12:52,766
MUTATION, EDFR, REALLY THAT'S

329
00:12:52,766 --> 00:12:57,371
WAY BETTER THAN CHEMO THERAPY.

330
00:12:57,371 --> 00:12:59,373
THE PROBLEM IS THAT EVEN IF MOST

331
00:12:59,373 --> 00:13:01,208
OF THE TUMORS RESPOND VERY

332
00:13:01,208 --> 00:13:06,213
NICELY TO THIS THERAPY AND THE

333
00:13:06,213 --> 00:13:07,381
TUMOR REALLY SHRINKS, THE

334
00:13:07,381 --> 00:13:08,649
RESPONSE IS ONLY SUSTAINED FOR

335
00:13:08,649 --> 00:13:14,488
SO LONG AND THEN THE PATIENT

336
00:13:14,488 --> 00:13:16,056
RELAPSES AND WE TART THERAPY.

337
00:13:16,056 --> 00:13:17,091
THERE ARE VARIOUS NUMBERS OF

338
00:13:17,091 --> 00:13:20,361
WAYS IN WHICH A TUMOR CAN BECOME

339
00:13:20,361 --> 00:13:21,295
RESISTANT TO TARGETED THERAPY

340
00:13:21,295 --> 00:13:22,763
LIKE FOR EXAMPLE, ADDITIONAL

341
00:13:22,763 --> 00:13:24,431
MUTATIONS IN THE

342
00:13:24,431 --> 00:13:26,700
[INDISCERNIBLE], OR ACTIVATION

343
00:13:26,700 --> 00:13:28,102
FOR THE ONCOGENES KNOWN

344
00:13:28,102 --> 00:13:29,303
ONCOGENES IN THE CARCINOMA, THEN

345
00:13:29,303 --> 00:13:31,405
WE HAVE A PART OF THE

346
00:13:31,405 --> 00:13:32,106
[INDISCERNIBLE] THAT WE DON'T

347
00:13:32,106 --> 00:13:33,841
KNOW HOW THEY BOTTOM RESISTANT

348
00:13:33,841 --> 00:13:35,876
AND THEN A SMALL PROPORTION

349
00:13:35,876 --> 00:13:38,979
AROUND 15% OF TUMORS THAT

350
00:13:38,979 --> 00:13:39,747
UNDERGO HISTORICAL TRANSFORM

351
00:13:39,747 --> 00:13:41,582
EGG, PLEENING WHEN WE HAD A LOOK

352
00:13:41,582 --> 00:13:44,184
AT THESE TUMORS AFTER

353
00:13:44,184 --> 00:13:47,354
PROGRESSION, THEY LOOK LIKE A

354
00:13:47,354 --> 00:13:48,022
DIFFERENT TUMOR TYPE.

355
00:13:48,022 --> 00:13:51,025
AND JUST TO INTRODUCE PLASTICITY

356
00:13:51,025 --> 00:13:53,861
[INDISCERNIBLE] TRANSFORMATION

357
00:13:53,861 --> 00:13:57,264
DURING DEVELOPMENT, WILL ACQUIRE

358
00:13:57,264 --> 00:13:59,333
DIFFERENT MOLECULAR ALTERATIONS,

359
00:13:59,333 --> 00:14:01,168
LIKE FOR EXAMPLE, ADEN O

360
00:14:01,168 --> 00:14:04,872
CARCINOMA, AND THEN ALSO

361
00:14:04,872 --> 00:14:05,673
ADDITIONAL [INDISCERNIBLE]

362
00:14:05,673 --> 00:14:06,840
HETEROGENEITY IN THE TUMOR AND

363
00:14:06,840 --> 00:14:08,008
THESE CAN BE DIFFERENT CLONES

364
00:14:08,008 --> 00:14:11,712
THAT HAVE DIFFERENT MUTATIONS.

365
00:14:11,712 --> 00:14:13,914
IF WE SUBMIT THE TUMOR TO A

366
00:14:13,914 --> 00:14:16,150
SELECTIVE PRESSURE, LIKE FOR

367
00:14:16,150 --> 00:14:17,284
EXAMPLE, TARGETED THERAPY, THERE

368
00:14:17,284 --> 00:14:19,720
MIGHT BE CLONES THAT MIGHT BE

369
00:14:19,720 --> 00:14:21,522
PARTICULARLY RESISTANT TO THE

370
00:14:21,522 --> 00:14:25,059
TREATMENT, LIKE MAYBE THEY HAVE

371
00:14:25,059 --> 00:14:26,327
A MUTATION THAT FIRST RESIST THE

372
00:14:26,327 --> 00:14:27,394
TREATMENT, AND IF WE CONTINUE

373
00:14:27,394 --> 00:14:28,329
THE PRESSURE OF THE TREATMENT,

374
00:14:28,329 --> 00:14:29,730
IN THE END THAT CLONE WILL

375
00:14:29,730 --> 00:14:34,835
OVERTAKE THE TUMOR AND WILL RIDE

376
00:14:34,835 --> 00:14:36,670
THE RESISTANCE THERAPY HOWEVER

377
00:14:36,670 --> 00:14:39,306
IN SOME CASES, THAT TARGET MAY

378
00:14:39,306 --> 00:14:41,709
BE EPIGENETIC AND THEN MIGHT BE

379
00:14:41,709 --> 00:14:42,776
CLONE THAD ARE PARTICULARLY

380
00:14:42,776 --> 00:14:44,378
DIFFERENTIATED OR PLASTIC AND

381
00:14:44,378 --> 00:14:46,213
THEY MIGHT BE   PERMISSIVE FOR

382
00:14:46,213 --> 00:14:47,715
DIFFERENTIATION AND THEY MAY

383
00:14:47,715 --> 00:14:49,383
TRANSITION AND CHANGE TO

384
00:14:49,383 --> 00:14:49,917
SOMETHING ELSE.

385
00:14:49,917 --> 00:14:53,420
AND THIS CAN BE FOR EXAMPLE, A

386
00:14:53,420 --> 00:14:56,824
DIFFERENT STORY OF LUNG CANCER

387
00:14:56,824 --> 00:15:00,694
LIKE SQUAMOUS CARCINOMA OR ALSO

388
00:15:00,694 --> 00:15:01,328
[INDISCERNIBLE] CARCINOMA, AND

389
00:15:01,328 --> 00:15:03,464
THEN AT THIS POINT WE WILL HAVE

390
00:15:03,464 --> 00:15:05,532
A [INDISCERNIBLE] TUMOR AS PART

391
00:15:05,532 --> 00:15:06,800
OF THE CARCINOMA REGULAR

392
00:15:06,800 --> 00:15:08,802
HISTOLOGY AND THEN OUR SECOND

393
00:15:08,802 --> 00:15:11,572
COMPONENT THAT MAY BE SQUAMOUS

394
00:15:11,572 --> 00:15:13,340
OR SMALL CELL AND IF WE CONTINUE

395
00:15:13,340 --> 00:15:13,874
SELECTIVE PRESSURE OF THE

396
00:15:13,874 --> 00:15:15,676
TREATMENT WHICH IS BASICALLY

397
00:15:15,676 --> 00:15:17,978
TARGETING THE ADEN O CARCINOMA,

398
00:15:17,978 --> 00:15:19,480
WILL POTENTIALLY DEPLETE THIS

399
00:15:19,480 --> 00:15:21,081
COMPONENT AND AT THE TIME OF

400
00:15:21,081 --> 00:15:22,583
PROGRESSION WILL DETECT THIS

401
00:15:22,583 --> 00:15:24,351
FULLY OR MOSTLY FULLY

402
00:15:24,351 --> 00:15:25,819
DIFFERENTIATED TUMOR THAT SHOWS

403
00:15:25,819 --> 00:15:30,691
A DIFFERENT HISTORY TO THE REAL

404
00:15:30,691 --> 00:15:30,924
1.

405
00:15:30,924 --> 00:15:32,659
AND THIS OF COURSE IN MANY

406
00:15:32,659 --> 00:15:34,061
DIFFERENT SETTINGS AND MANY CAN

407
00:15:34,061 --> 00:15:34,795
[INDISCERNIBLE] IN SETTINGS

408
00:15:34,795 --> 00:15:38,432
WHERE THERE'S NO TREME, I GUESS

409
00:15:38,432 --> 00:15:40,367
SPONTANEOUSLY, BUT THE CONCRETE

410
00:15:40,367 --> 00:15:41,635
MOLECULAR BACKGROUND, WHAT HAS

411
00:15:41,635 --> 00:15:45,806
BEEN THE MOST EXTENSIVE STORY IS

412
00:15:45,806 --> 00:15:46,507
IN [INDISCERNIBLE] CARCINOMA,

413
00:15:46,507 --> 00:15:49,043
WHERE UP TO 9% OF THE TUMORS AT

414
00:15:49,043 --> 00:15:51,712
THE MOMENT OF PROGRESSION WITH

415
00:15:51,712 --> 00:15:52,813
[INDISCERNIBLE] THE TARGETED

416
00:15:52,813 --> 00:15:57,484
THERAPY THEY RELAPSE AS SQUAMOUS

417
00:15:57,484 --> 00:15:59,019
CARCINOMA AND 14% OF THE TUMORS

418
00:15:59,019 --> 00:15:59,820
RELAPSE FOR SMALL CELL.

419
00:15:59,820 --> 00:16:02,823
AND IT ALSO HAPPENS IN A

420
00:16:02,823 --> 00:16:03,891
DIFFERENT SETTING,

421
00:16:03,891 --> 00:16:04,925
[INDISCERNIBLE] RECEPTOR

422
00:16:04,925 --> 00:16:05,626
INDEPENDENT OF THE CARCINOMA,

423
00:16:05,626 --> 00:16:07,961
WHERE UP TO 30% OF TUMORS

424
00:16:07,961 --> 00:16:09,696
RELAPSE AND THEY ARE

425
00:16:09,696 --> 00:16:10,898
[INDISCERNIBLE] CARCINOMA WITH

426
00:16:10,898 --> 00:16:14,601
THE TARGETED THERAPY IN THIS

427
00:16:14,601 --> 00:16:17,104
CASE [INDISCERNIBLE].

428
00:16:17,104 --> 00:16:19,640
SO, BASIC FEATURES ABOUT

429
00:16:19,640 --> 00:16:21,108
HISTORICAL TRANSFORMATION, FIRST

430
00:16:21,108 --> 00:16:22,943
[INDISCERNIBLE] SMALL CELL

431
00:16:22,943 --> 00:16:24,111
TRANSFORMATION IS CHARACTERIZED

432
00:16:24,111 --> 00:16:25,245
BY THESE TUMORS EXPRESSION OF

433
00:16:25,245 --> 00:16:28,782
THE DRIVER GENE, IN THIS CASE,

434
00:16:28,782 --> 00:16:31,218
EDFR, YOU CAN SEE IN THIS

435
00:16:31,218 --> 00:16:33,320
MATCHED BIOPSY OR EXPRESSLY IN

436
00:16:33,320 --> 00:16:35,722
PREAND POST RESISTANT ESPECIALLY

437
00:16:35,722 --> 00:16:37,357
WITH EDFI'S LOST AND THE

438
00:16:37,357 --> 00:16:45,099
EXPRESSION OF THE MARKERS LIKE

439
00:16:45,099 --> 00:16:48,135
AT THE [INDISCERNIBLE].

440
00:16:48,135 --> 00:16:49,403
THEY ALSO SHOW REGULAR SMALL

441
00:16:49,403 --> 00:16:51,572
CELL TUMORS HOWEVER WHEN YOU

442
00:16:51,572 --> 00:16:53,073
INDUCE ACTIVATION IN LUNG

443
00:16:53,073 --> 00:16:55,109
CARCINOMA THAT DOESN'T INDUCE

444
00:16:55,109 --> 00:16:57,344
TRANSFORMATION OR EVEN RESISTANT

445
00:16:57,344 --> 00:17:01,315
TO TARGETED THERAPY SO WITH THAT

446
00:17:01,315 --> 00:17:02,716
DIFFERENT REGULATIONS ARE

447
00:17:02,716 --> 00:17:05,419
REQUIRED FOR TRANSFORMATION TO

448
00:17:05,419 --> 00:17:07,221
OCCUR AND VERY IMPORTANTLY WE

449
00:17:07,221 --> 00:17:09,957
HAVE CELLS THAT ARE

450
00:17:09,957 --> 00:17:10,858
[INDISCERNIBLE] IN OUR YOU

451
00:17:10,858 --> 00:17:13,927
HADITANT DID WORSE ON THAT

452
00:17:13,927 --> 00:17:15,596
THERAPY AND THEY TEND TO RESPOND

453
00:17:15,596 --> 00:17:17,764
FOR SHORTER TIME AND HAVE

454
00:17:17,764 --> 00:17:19,299
INCREASED RISK FOR

455
00:17:19,299 --> 00:17:20,901
TRANSFORMATION, SO BASICALLY, WE

456
00:17:20,901 --> 00:17:22,669
ARE ABLE TO IDENTIFY THE SUBSET

457
00:17:22,669 --> 00:17:26,039
OF PATIENTS THAT ARE AT RISK OF

458
00:17:26,039 --> 00:17:26,907
TRANSFORMATION THERE.

459
00:17:26,907 --> 00:17:29,176
HOWEVER, EVEN THOUGH WE KNOW

460
00:17:29,176 --> 00:17:32,479
THESE PATIENTS ARE, WE DON'T

461
00:17:32,479 --> 00:17:33,881
REALLY HAVE ANY THERAPY TO

462
00:17:33,881 --> 00:17:35,182
PREVENT THE TRANSFORMATION AND

463
00:17:35,182 --> 00:17:38,452
ON THE SQUAMOUS SIDE, WE KNOW

464
00:17:38,452 --> 00:17:44,925
THEY BEAR LYE --BARELY DO, YOU

465
00:17:44,925 --> 00:17:46,426
SEE THE POSITIVE, NEGATIVE AND

466
00:17:46,426 --> 00:17:50,397
THEY INDUCE EXPRESSION OF

467
00:17:50,397 --> 00:17:52,099
JAMILLE REYNOLDSOUS MARKERS LIKE

468
00:17:52,099 --> 00:17:53,400
B40, AND WE KNOW ABOUT THE

469
00:17:53,400 --> 00:17:55,836
DRIVERS IN THIS PROCESS, WE

470
00:17:55,836 --> 00:17:57,037
CAN'T YET IDENTIFY THE PATIENTS

471
00:17:57,037 --> 00:17:59,306
OF HIGH RISK AND WE DON'T HAVE

472
00:17:59,306 --> 00:18:01,575
ANY THERAPIES AVAILABLE TO

473
00:18:01,575 --> 00:18:06,113
PREVAIL OR TREAT THIS

474
00:18:06,113 --> 00:18:07,614
TRANSFORMATION, SO THIS IS WITH

475
00:18:07,614 --> 00:18:10,050
AN ARK FILLIATE, SO THIS WILL BE

476
00:18:10,050 --> 00:18:11,785
DIVIDED INTO DIFFERENT WORKS

477
00:18:11,785 --> 00:18:14,288
THAT ILLUSTRATE IN THE LAST 6

478
00:18:14,288 --> 00:18:17,758
YEARS, AND THE FIRST 1 WILL BE

479
00:18:17,758 --> 00:18:19,426
FOCUSING ON THAT AND THE

480
00:18:19,426 --> 00:18:23,697
AVAILABILITY THAT WE HAVE FOUND

481
00:18:23,697 --> 00:18:26,900
BETWEEN THE ENDOCRINE AND

482
00:18:26,900 --> 00:18:27,501
SQUAMOUS CELL TRANSFORMATION.

483
00:18:27,501 --> 00:18:30,103
IN THIS WORK WE HAVE

484
00:18:30,103 --> 00:18:30,904
[INDISCERNIBLE] SPECIMENS

485
00:18:30,904 --> 00:18:31,705
UNDERGOING TRANSFORMATION IN

486
00:18:31,705 --> 00:18:35,209
THIS CASE IT WAS EDFI

487
00:18:35,209 --> 00:18:36,176
DIAGNOSTIC, IT IS REALLY

488
00:18:36,176 --> 00:18:38,245
DIFFICULT TO FIND PREAND POST

489
00:18:38,245 --> 00:18:39,279
TRANSFORMATION SAMPLES SO WE

490
00:18:39,279 --> 00:18:41,181
COULD ONLY FOCUS ON 1 DRIVER

491
00:18:41,181 --> 00:18:43,383
EDFR, SO WE TOOK 1 SAMPLE UNDER

492
00:18:43,383 --> 00:18:44,451
1 TRANSFORMATION THAT WE COULD

493
00:18:44,451 --> 00:18:48,522
LOCATE AND WHAT WE SEE WHEN WE

494
00:18:48,522 --> 00:18:50,090
WHAT WE FIRST   PERFORMED

495
00:18:50,090 --> 00:18:51,258
METHYLATION STUDIES IN THESE

496
00:18:51,258 --> 00:18:55,062
SAMPLES IS THAT WHEN WE COMPARE

497
00:18:55,062 --> 00:18:55,996
4 DIFFERENT CATEGORIES OF

498
00:18:55,996 --> 00:18:58,799
SAMPLES IN THIS CASE, ADEN O

499
00:18:58,799 --> 00:19:02,102
CARCINOMA, THAT NEVER TRANSFORMS

500
00:19:02,102 --> 00:19:04,705
THEN WE HAVE IN CLEAR BLUE, THE

501
00:19:04,705 --> 00:19:06,173
CARCINOMA THAT WOULD LATER

502
00:19:06,173 --> 00:19:08,709
TRANSFORM TO SMALL CELL, THEN

503
00:19:08,709 --> 00:19:10,110
HERE, TRANSFORMS MORE CELLS

504
00:19:10,110 --> 00:19:11,845
PREVIOUSLY OF THE CARCINOMA, AND

505
00:19:11,845 --> 00:19:13,146
THEN THE SMALL CELL WHICH IS

506
00:19:13,146 --> 00:19:15,215
LIKE SMALL CELLS THAT WERE NEVER

507
00:19:15,215 --> 00:19:16,316
WITH THE CARCINOMA BEFORE, AS

508
00:19:16,316 --> 00:19:19,519
YOU CAN SEE HERE, IN THESE LIKE

509
00:19:19,519 --> 00:19:22,055
BCA CLUSTER, THAT BASICALLY

510
00:19:22,055 --> 00:19:23,890
CLUSTERS, THE SAMPLES ACCORDING

511
00:19:23,890 --> 00:19:25,192
TO SIMILARITIES IN THE

512
00:19:25,192 --> 00:19:26,627
METHYLATION PROFILE, YOU CANEE

513
00:19:26,627 --> 00:19:30,097
THERE'S A BIG OVERLAP BETWEEN

514
00:19:30,097 --> 00:19:32,532
THE TRANSFORMAD SMALL CELL WITH

515
00:19:32,532 --> 00:19:34,368
THE ADENO CARCINOMA AND THEN THE

516
00:19:34,368 --> 00:19:36,903
SMALL CELL AND THE CLASSES

517
00:19:36,903 --> 00:19:37,137
DIFFER.

518
00:19:37,137 --> 00:19:40,407
AND IF WE HAVE A LOOK AT THE

519
00:19:40,407 --> 00:19:41,608
SQUAMOUS TRANSFORMATION SAMPLE,

520
00:19:41,608 --> 00:19:43,176
WE SAW VERY DIFFERENT BUT

521
00:19:43,176 --> 00:19:46,580
SIMILAR RESULTS, YOU CAN SEE THE

522
00:19:46,580 --> 00:19:47,547
TRANSFORMATION THIS BINK

523
00:19:47,547 --> 00:19:50,183
OVERLAPS WITH THE ADEN O

524
00:19:50,183 --> 00:19:52,319
CARCINOMAs WHILE DE NOVO

525
00:19:52,319 --> 00:19:53,720
[INDISCERNIBLE] CLASS

526
00:19:53,720 --> 00:19:54,288
DIFFERENTLY.

527
00:19:54,288 --> 00:19:57,157
SO THIS RESULT SUGGESTS THAT THE

528
00:19:57,157 --> 00:19:58,759
TRANSFORMAD TUMORS, OR TO SMALL

529
00:19:58,759 --> 00:20:01,228
CELL RETAIN BOTH SCALE AT THE

530
00:20:01,228 --> 00:20:02,863
EPIIMENETTIC FEATURES WITH THE

531
00:20:02,863 --> 00:20:04,464
CARCINOMA, SO YOU SEE THEY MIGHT

532
00:20:04,464 --> 00:20:09,002
HAVE A DIFFERENT BIOLOGY AND

533
00:20:09,002 --> 00:20:11,638
POTENTIALLY DIFFERENT THERAPY

534
00:20:11,638 --> 00:20:11,905
ABILITIES.

535
00:20:11,905 --> 00:20:21,415
THEP WE TRY TO LEVERAGE THE DATA

536
00:20:21,415 --> 00:20:22,716
TO ESTABLISH THE TRANSFORMATION

537
00:20:22,716 --> 00:20:25,218
AND WE TODAYED BODIES THAT WERE

538
00:20:25,218 --> 00:20:27,621
IN THE PROCESS OF

539
00:20:27,621 --> 00:20:29,690
[INDISCERNIBLE] OR MAUL CELL.

540
00:20:29,690 --> 00:20:34,061
WE FOUND REASSURING PALGT WAYS

541
00:20:34,061 --> 00:20:35,228
SO INCREASED PHENOTYPE WHICH WAS

542
00:20:35,228 --> 00:20:37,664
SUSPECTED AND OF COURSE NEURON

543
00:20:37,664 --> 00:20:40,367
DIFFERENTIATION IN SOAZ CELLS

544
00:20:40,367 --> 00:20:43,036
UNDERGOING NEURAL

545
00:20:43,036 --> 00:20:44,671
DIFFERENTIATION, BECAUSE AS WE

546
00:20:44,671 --> 00:20:46,973
KNOW EGFR IS REPRESSED WITH THE

547
00:20:46,973 --> 00:20:48,141
TRANSFORMATION TO SMALL CELL,

548
00:20:48,141 --> 00:20:50,210
BUT THEN WE WILL SURPRISED TO

549
00:20:50,210 --> 00:20:52,846
FIND THIS ACTUALLY DIFFERENT

550
00:20:52,846 --> 00:20:56,917
PATHWAYS THAT ARE CONVERGENTLY

551
00:20:56,917 --> 00:20:58,985
UPREGULATED IN THE

552
00:20:58,985 --> 00:21:01,154
[INDISCERNIBLE] INCLUDING REPAIR

553
00:21:01,154 --> 00:21:02,989
CYCLE, THE [INDISCERNIBLE]

554
00:21:02,989 --> 00:21:10,530
COMPLEX HAS BEEN WITH

555
00:21:10,530 --> 00:21:11,832
PLASTICITY; AND WE ALSO HAD DOWN

556
00:21:11,832 --> 00:21:14,334
REGULATION OF A NUMBER OF

557
00:21:14,334 --> 00:21:17,037
PATHWAYS THAT WERE LINKED TO

558
00:21:17,037 --> 00:21:17,771
IMMUNE RESPONSE SUGGESTING THAT

559
00:21:17,771 --> 00:21:20,073
SOME OF THE TRANSFORMATION MAY

560
00:21:20,073 --> 00:21:26,146
UNDERGO SOME SORT OF ANTITUMOR

561
00:21:26,146 --> 00:21:27,080
IMMUNE SUPPRESSION.

562
00:21:27,080 --> 00:21:31,218
AND LASTLY WE OBSERVED SAMPLES

563
00:21:31,218 --> 00:21:35,088
INCLUDING UPREGULATION OF

564
00:21:35,088 --> 00:21:35,956
[INDISCERNIBLE] AND SIGNALING.

565
00:21:35,956 --> 00:21:38,358
THIS DATA LED US TO THINK TO A

566
00:21:38,358 --> 00:21:40,227
POTENTIAL MODEL WHERE ADEN O

567
00:21:40,227 --> 00:21:42,729
CARCINOMA BEFORE TRANSFORMATION

568
00:21:42,729 --> 00:21:43,430
MAY UNDERGO AN INTERMEDIARY

569
00:21:43,430 --> 00:21:44,865
STATE THAT IS CHARACTERIZED BY

570
00:21:44,865 --> 00:21:47,067
THE SUPPRESSION OF UMPIRESUNE

571
00:21:47,067 --> 00:21:48,001
RESPONSE AND UPREGULATION OF

572
00:21:48,001 --> 00:21:49,069
THESE PATHWAYS THAT WERE

573
00:21:49,069 --> 00:21:51,571
PREVIOUSLY MENTION EXCLUDE THEN

574
00:21:51,571 --> 00:21:53,073
THESE POTENTIAL, INTERMEDIATE

575
00:21:53,073 --> 00:21:55,809
PLASTIC STATE MAY ULTIMATELY

576
00:21:55,809 --> 00:21:58,445
UNDERGO TRANSDIFFERENTIATION TO

577
00:21:58,445 --> 00:22:00,113
A GIVING FATE ACCORDING TO THE

578
00:22:00,113 --> 00:22:01,581
OCCURRENCE OF ADDITIONAL

579
00:22:01,581 --> 00:22:06,787
MUTATIONS THAT MAY PUSH TOWARDS

580
00:22:06,787 --> 00:22:08,822
A PARTICULAR PHASE THEREFORE

581
00:22:08,822 --> 00:22:10,223
EXAMPLE THE [INDISCERNIBLE]

582
00:22:10,223 --> 00:22:10,924
SIGNALING TRANSFORMATION EMPLOY

583
00:22:10,924 --> 00:22:15,295
BUT WE TRY TO FOCUS ON 2

584
00:22:15,295 --> 00:22:17,831
MOLECULAR FACTORS ATK SIGNALS

585
00:22:17,831 --> 00:22:21,101
AND NYC BECAUSE THEY BOTH LEAD

586
00:22:21,101 --> 00:22:23,437
TO CANCELING STEM PLASTICITY SO

587
00:22:23,437 --> 00:22:25,539
WEY DECIDED TO SEE IF THESE

588
00:22:25,539 --> 00:22:26,807
WOULD BE TRANSFORMATION DRIVERS

589
00:22:26,807 --> 00:22:29,476
AS L. SO TO DO THAT WE TOOK THE

590
00:22:29,476 --> 00:22:32,345
MUTANT, IN THE CARCINOMA LINES

591
00:22:32,345 --> 00:22:36,817
AND WE OVEREXPRESS MYC AND

592
00:22:36,817 --> 00:22:37,984
[INDISCERNIBLE] AKT, AND THEN WE

593
00:22:37,984 --> 00:22:41,288
PUT THESE TUMORS INTO MICE AND

594
00:22:41,288 --> 00:22:45,459
WE [INDISCERNIBLE] WITH THERAPY

595
00:22:45,459 --> 00:22:46,693
IN THIS CASE, [INDISCERNIBLE].

596
00:22:46,693 --> 00:22:47,961
YOU CAN SEE HERE IN GRAY, YOU

597
00:22:47,961 --> 00:22:49,596
CAN SEE THE EXPRESSING TUMORS IN

598
00:22:49,596 --> 00:22:51,298
THE ABSENCE OF THE TARGETED

599
00:22:51,298 --> 00:22:52,999
THERAPY THEY WOULD GROW THE SAME

600
00:22:52,999 --> 00:22:56,169
BBUT THEN WE WHEN WE TREAT THEM

601
00:22:56,169 --> 00:22:58,138
WITH [INDISCERNIBLE], WE THOSE

602
00:22:58,138 --> 00:23:01,441
THOSE TUMORS ARE REABLE TO

603
00:23:01,441 --> 00:23:04,077
RELAPSE SIGNIFICANTLY EARLIER

604
00:23:04,077 --> 00:23:07,380
THAN THOSE WITHOUT MYC, AND AKT,

605
00:23:07,380 --> 00:23:10,317
SO SUGGIEST THAGOREAN THEY WERE

606
00:23:10,317 --> 00:23:12,219
RESISTANT TO THERAPY.

607
00:23:12,219 --> 00:23:13,753
BUT MOST IMPORTANTLY WHEN WE

608
00:23:13,753 --> 00:23:15,655
COLLECTED THESE TUMORS AND

609
00:23:15,655 --> 00:23:17,157
ANALYZED EXPRESSION OF

610
00:23:17,157 --> 00:23:18,625
DIAGNOSTIC AND SQUAMOUS MARKERS,

611
00:23:18,625 --> 00:23:22,796
WHAT WE OBSERVE IS THAT IN THE

612
00:23:22,796 --> 00:23:24,531
CONTROL, TUMORS WITH THE

613
00:23:24,531 --> 00:23:26,566
SEMANTIS SHRIMP NIB, WE

614
00:23:26,566 --> 00:23:28,301
DEPARTMENT GET ANY EXPRESSION OF

615
00:23:28,301 --> 00:23:29,703
THESE MARKERS, HOWEVER IN THOSE

616
00:23:29,703 --> 00:23:37,978
TUMORS THAT ARE EXPRESSING MYC

617
00:23:37,978 --> 00:23:41,314
AND AKT, AND THESE RESULTS WERE

618
00:23:41,314 --> 00:23:42,382
LIKE FATHERRER POTENTIATED TO

619
00:23:42,382 --> 00:23:44,050
WORK WITH THOSE, SO IN THAT

620
00:23:44,050 --> 00:23:45,752
TARGETING SYSTEMIED THERAPY WERE

621
00:23:45,752 --> 00:23:51,958
LIKE FARTHER PROMOTE OR AT LEAST

622
00:23:51,958 --> 00:23:53,059
ENRICH FOR TRANSFORMATION.

623
00:23:53,059 --> 00:23:54,861
THEN WE DORPHED THAT WITHIN OUR

624
00:23:54,861 --> 00:23:57,364
PREVIOUS PLATFORM, THERE WAS A

625
00:23:57,364 --> 00:23:59,466
DIFFERENT PDX THAT WAS A

626
00:23:59,466 --> 00:24:01,201
DIFFERENT CARCINOMA THAT WHEN

627
00:24:01,201 --> 00:24:03,703
TREATED WITH [INDISCERNIBLE] IT

628
00:24:03,703 --> 00:24:05,372
WOULD SHOW SENSITIVITY BUT

629
00:24:05,372 --> 00:24:06,172
EVENTUALLY BECOME RESISTANT AND

630
00:24:06,172 --> 00:24:08,842
AT THE MOMENT OF RESISTANCE IT

631
00:24:08,842 --> 00:24:10,577
WILL SHOW A SQUAMOUS TYPE

632
00:24:10,577 --> 00:24:11,878
PHENOTYPE, AND THIS WAS

633
00:24:11,878 --> 00:24:12,712
CHARACTERIZED BY THE DOWN

634
00:24:12,712 --> 00:24:15,715
REGULATION OF THE MARKER TTF1

635
00:24:15,715 --> 00:24:17,350
AND UPREGULATION OF B40 AND 5 OR

636
00:24:17,350 --> 00:24:20,787
6, AND WE DECIDE TO LEVERAGE

637
00:24:20,787 --> 00:24:22,556
THIS MODEL AS A TRANSFORMATION

638
00:24:22,556 --> 00:24:25,225
AND WE DECIDE TO TRY DIFFERENT

639
00:24:25,225 --> 00:24:26,126
THERAPEUTIC APPROACHES TO SEE

640
00:24:26,126 --> 00:24:28,361
WHETHER IT WILL BE ABLE TO LIKE

641
00:24:28,361 --> 00:24:32,699
BASICALLY PREVENT THIS

642
00:24:32,699 --> 00:24:33,233
TRANSFORMATION TO OCCUR.

643
00:24:33,233 --> 00:24:36,670
BUT WE ALSO TREATED THESE

644
00:24:36,670 --> 00:24:38,171
[INDISCERNIBLE] WITH A

645
00:24:38,171 --> 00:24:39,706
COMBINATION OF [INDISCERNIBLE]

646
00:24:39,706 --> 00:24:41,975
TARGETED THERAPY AND 1 INHIBITOR

647
00:24:41,975 --> 00:24:45,178
OF AKT, WITH [INDISCERNIBLE], WE

648
00:24:45,178 --> 00:24:47,714
OBSERVE THAT THE TUMORS WOULD

649
00:24:47,714 --> 00:24:48,748
RESPOND TO THERAPY MUCH STRONGLY

650
00:24:48,748 --> 00:24:51,251
AND THEY WILL SHOW LIKE

651
00:24:51,251 --> 00:24:52,652
DRAMATICALLY EXTEND THE RESPONSE

652
00:24:52,652 --> 00:24:56,623
TO THERAPY, SO THIS WOULD ALSO

653
00:24:56,623 --> 00:24:57,257
SUGGIEST THAT THIS

654
00:24:57,257 --> 00:24:59,159
[INDISCERNIBLE] MIGHT BE A

655
00:24:59,159 --> 00:25:03,663
THERAPEUTIC APPROACH FOR TUMORS

656
00:25:03,663 --> 00:25:05,265
THAT EXPERIENCE REGIONAL

657
00:25:05,265 --> 00:25:06,633
TRANSFORMATION, AND THESE IS IN

658
00:25:06,633 --> 00:25:08,034
LINE WITH A SCIENCE PAPER FROM

659
00:25:08,034 --> 00:25:10,203
THE [INDISCERNIBLE] LAB WHERE

660
00:25:10,203 --> 00:25:11,271
THEY ARE STUDYING CROSS

661
00:25:11,271 --> 00:25:12,706
FORMATION FROM THE ADENEE

662
00:25:12,706 --> 00:25:15,108
CARCINOMA TO SMALL CELL AND THEY

663
00:25:15,108 --> 00:25:18,078
HAVE DISCOVERED THAT LUNG ADIN O

664
00:25:18,078 --> 00:25:20,313
CARCINOMA MAY UNDERGO

665
00:25:20,313 --> 00:25:21,481
[INDISCERNIBLE] PLASTIC STATE

666
00:25:21,481 --> 00:25:23,116
THAT [INDISCERNIBLE] THE COMEGZ

667
00:25:23,116 --> 00:25:25,118
OF MYC AND AKT TO TRANSITION TO

668
00:25:25,118 --> 00:25:28,421
A DIFFERENT PHENOTYPE IN THIS

669
00:25:28,421 --> 00:25:29,322
CASE SMALL CELL.

670
00:25:29,322 --> 00:25:31,424
SO CONCLUSIONS FROM THIS PART IS

671
00:25:31,424 --> 00:25:35,362
THAT TRANSFORMED TUMORS SEEM TO

672
00:25:35,362 --> 00:25:37,998
RETAIN BOTH SCALE FEATURES FROM

673
00:25:37,998 --> 00:25:40,000
THE PREVIOUS ADEN O CARCINOMA

674
00:25:40,000 --> 00:25:41,267
STATE AND THEN WE CAN

675
00:25:41,267 --> 00:25:43,403
DISTINGUISH THEM FROM THE NOVEL

676
00:25:43,403 --> 00:25:45,372
TUMORS, WE SEE THERE'S A NUMBER

677
00:25:45,372 --> 00:25:47,340
OF PATHWAYS THAT ARE

678
00:25:47,340 --> 00:25:48,508
CONVERGENTLY DISREGULATED BOTH

679
00:25:48,508 --> 00:25:50,143
IN THE BRAIN AND SQUAMOUS

680
00:25:50,143 --> 00:25:52,846
TRANSFORMATION AND WE SEE THAT

681
00:25:52,846 --> 00:25:55,882
THE INDUCTION OF NYC SIGNALING,

682
00:25:55,882 --> 00:25:59,953
THE SQUAMOUS TYPE IN THE ADEN'S

683
00:25:59,953 --> 00:26:02,722
CARCINOMA IN VIVO MODELS.

684
00:26:02,722 --> 00:26:06,626
THE SECOND PART OF STORY AND

685
00:26:06,626 --> 00:26:12,132
THIS IS THE PUBLISHED DATA, AND

686
00:26:12,132 --> 00:26:12,866
THERE'S MANY SDN EDITORS IN THE

687
00:26:12,866 --> 00:26:19,906
ROOM AND IT'S ABOUT THE ROLE OF

688
00:26:19,906 --> 00:26:21,508
RB-PATHWAY INACTIVATION IN

689
00:26:21,508 --> 00:26:23,043
SQUAMOUS TRANSFORMATION, SO

690
00:26:23,043 --> 00:26:24,110
RB PATHWAY HAS BEEN LINKED TO

691
00:26:24,110 --> 00:26:25,712
THE SMALL CELL ACTIVATION,

692
00:26:25,712 --> 00:26:26,880
BECAUSE THEY'RE PRETTY MUCH

693
00:26:26,880 --> 00:26:28,848
HALLMARKS OF SMALL CELL TUMORS

694
00:26:28,848 --> 00:26:30,116
AND HERE WE PROVIDE EVIDENCE

695
00:26:30,116 --> 00:26:31,651
THAT IT MOOT BE LINKED TO

696
00:26:31,651 --> 00:26:37,223
PLASTICITY IN GENERAL AND ALSO

697
00:26:37,223 --> 00:26:38,224
TO SQUAMOUS TRANSFORMATION.

698
00:26:38,224 --> 00:26:40,126
SO FOR THIS PROJECT, WE TRY TO

699
00:26:40,126 --> 00:26:41,961
DO AN APPROACH THAT WAS PRETTY

700
00:26:41,961 --> 00:26:43,596
SIMILAR TO THE PREVIOUS 1 AGAIN,

701
00:26:43,596 --> 00:26:46,433
WE ALSO TRY TO DO

702
00:26:46,433 --> 00:26:47,600
CHARACTERIZATION OF TUMORS

703
00:26:47,600 --> 00:26:48,334
UNDERGOING SQUAMOUS CELL

704
00:26:48,334 --> 00:26:50,136
TRANSFORMATION BUT IN THIS CASE,

705
00:26:50,136 --> 00:26:56,309
WE FOCUS ONLY ON E, HOPING THAT

706
00:26:56,309 --> 00:26:57,143
BY DECREASING THE

707
00:26:57,143 --> 00:26:58,211
HETEROGENERRITY OF THE SAMPLES

708
00:26:58,211 --> 00:27:00,046
WE COULD SEE SIGNALS THAT WE

709
00:27:00,046 --> 00:27:04,050
WERE OVERLOOKING IN THE PREVIOUS

710
00:27:04,050 --> 00:27:04,284
PROJECT.

711
00:27:04,284 --> 00:27:06,052
WHICH PARTICULARLY WE COLLECTED

712
00:27:06,052 --> 00:27:08,588
CONTROLS OF CARCINOMAS THAT WERE

713
00:27:08,588 --> 00:27:09,055
NEVER TRANSFORMED,

714
00:27:09,055 --> 00:27:09,989
[INDISCERNIBLE] THAT WERE NEVER

715
00:27:09,989 --> 00:27:14,427
BEFORE, AND THEN SOME SAMPLES

716
00:27:14,427 --> 00:27:16,362
THAT UNDERWENT TRANSFORMATION.

717
00:27:16,362 --> 00:27:18,064
AND WE BERNEA DEET FORMED A

718
00:27:18,064 --> 00:27:22,235
COLLABORATION AT THE ELF OF

719
00:27:22,235 --> 00:27:26,406
GENOMICS, METHYLATION, RNASEQ

720
00:27:26,406 --> 00:27:29,275
TOGETHER WITH [INDISCERNIBLE].

721
00:27:29,275 --> 00:27:30,777
WHEN WE UNDER GO THE

722
00:27:30,777 --> 00:27:32,145
TRANSFORMATION, THE FIRST THING

723
00:27:32,145 --> 00:27:33,680
WE NOTICE WAS THAT THERE WAS A

724
00:27:33,680 --> 00:27:36,249
HIGH FREQUENCY OF HIGH MUTATIONS

725
00:27:36,249 --> 00:27:37,650
OR BRINGING MEMBERS OF THE

726
00:27:37,650 --> 00:27:38,585
PATHWAY, CONSISTENT WITH THE

727
00:27:38,585 --> 00:27:41,020
DATA I'VE SHOWN BEFORE, LINKING

728
00:27:41,020 --> 00:27:43,289
NEGATIVE PATHWAY TO SQUAMOUS

729
00:27:43,289 --> 00:27:44,357
TRANSFORMATION BUT WE WERE

730
00:27:44,357 --> 00:27:46,392
OBSERVED TO FIND ALSO THAT THERE

731
00:27:46,392 --> 00:27:47,127
WERE VERY FREE RADICALS QUEPT

732
00:27:47,127 --> 00:27:49,863
MUTATIONS IN THE RB PATHWAY AS

733
00:27:49,863 --> 00:27:50,663
WELL.

734
00:27:50,663 --> 00:27:54,567
IN THE END, WHEN WE COMPARE THE

735
00:27:54,567 --> 00:27:56,302
FREQUENCY OF MUTATIONS IN THESE

736
00:27:56,302 --> 00:27:58,538
FROM THE RB AND NEGATIVE PATHWAY

737
00:27:58,538 --> 00:28:00,440
BETWEEN ADEN O CARCINOMA AND

738
00:28:00,440 --> 00:28:03,343
SQUAMOUS CARCINOMA FIRST IN THAT

739
00:28:03,343 --> 00:28:04,511
THIS COHORT IS AVAILABLE, CAN

740
00:28:04,511 --> 00:28:08,114
YOU SEE THAT ACTUALLY DENOVAE

741
00:28:08,114 --> 00:28:09,949
SQUAMOUS CARCINOMA ARE ENRICHED

742
00:28:09,949 --> 00:28:12,018
FROM THE [INDISCERNIBLE] OF BOTH

743
00:28:12,018 --> 00:28:13,987
PATHWAYS AND BASED ON THESE

744
00:28:13,987 --> 00:28:16,156
RESULTS WE CAN OBSERVE

745
00:28:16,156 --> 00:28:17,323
[INDISCERNIBLE] WHERE WE COMPARE

746
00:28:17,323 --> 00:28:19,592
THE ADEN O CARCINOMA AND JAMILLE

747
00:28:19,592 --> 00:28:21,294
REYNOLDSOUS WITH A MIXTURE OF

748
00:28:21,294 --> 00:28:22,262
[INDISCERNIBLE] AND COMOPPOSITE

749
00:28:22,262 --> 00:28:23,096
BEHAVIORIAL PHENOTYPENTS AND

750
00:28:23,096 --> 00:28:24,697
SQUAMOUS CARCINOMA.

751
00:28:24,697 --> 00:28:31,471
YOU CAN SEE AGAIN THAT THERE'S

752
00:28:31,471 --> 00:28:33,239
AN ENRICHMENT IN THESE PATHWAYS

753
00:28:33,239 --> 00:28:35,441
FOR THE RB PATHWAY, SUGGESTING

754
00:28:35,441 --> 00:28:37,010
THAT THESE 2 PATHWAYS MAY BE

755
00:28:37,010 --> 00:28:38,611
SPECIFICALLY LINKED TO THE

756
00:28:38,611 --> 00:28:40,113
SQUAMOUS CELL TRANSFORMATION BUT

757
00:28:40,113 --> 00:28:44,417
MAYBE JUST SQUAMOUS TUMORS.

758
00:28:44,417 --> 00:28:46,619
AND THEN, SEEING THIS ENRICHMENT

759
00:28:46,619 --> 00:28:48,822
MUTATIONS IN POAGHT BOTH

760
00:28:48,822 --> 00:28:50,190
PATHWAYS IN SAMPLES UNDERGOING

761
00:28:50,190 --> 00:28:52,659
TRANSFORMATION, WE DECIDE TO SEE

762
00:28:52,659 --> 00:28:53,860
WHETHER THESE MUTATIONS MAY HAVE

763
00:28:53,860 --> 00:28:58,364
THE POTENTIAL TO PREDICT TUMORS

764
00:28:58,364 --> 00:28:59,432
FOR HIGH TRANSFORMATION TO

765
00:28:59,432 --> 00:29:01,000
SQUAMOUS, SO IT WAS TO COMPARE

766
00:29:01,000 --> 00:29:03,303
THE FREQUENCY OF MUTATIONS IN

767
00:29:03,303 --> 00:29:07,273
THE DIFFERENT  GENES IN EACH OF

768
00:29:07,273 --> 00:29:08,575
THE PATHWAYS FOR SAMPLES THAT

769
00:29:08,575 --> 00:29:13,546
WERE LATER GOING TO TRANSFORM AS

770
00:29:13,546 --> 00:29:14,147
SQUAMOUS CARCINOMA,

771
00:29:14,147 --> 00:29:16,049
[INDISCERNIBLE], IN GREAT,

772
00:29:16,049 --> 00:29:18,051
VERSUS A COHORT OF NEVER

773
00:29:18,051 --> 00:29:19,686
TRANSFORMING THE CARCINOMA IN

774
00:29:19,686 --> 00:29:20,753
BLACK AND AS CAN YOU SEE HERE

775
00:29:20,753 --> 00:29:23,656
MANY OF THESE MUTATIONS SHOW

776
00:29:23,656 --> 00:29:25,925
LIKE ENRICHMENT FREQUENCY, IN

777
00:29:25,925 --> 00:29:28,661
THOSE SAMPLES THAT WILL LATER

778
00:29:28,661 --> 00:29:29,762
TRANSFORM TO CARCINOMA AS

779
00:29:29,762 --> 00:29:31,097
COMPARED TO CONTROL.

780
00:29:31,097 --> 00:29:34,267
AND YOU CAN SEE FOR BOTH AKT AND

781
00:29:34,267 --> 00:29:36,202
THE PATHWAY, CAN YOU SEE THE

782
00:29:36,202 --> 00:29:40,006
TRANSFORMING SAMPLES WOULD SHOW,

783
00:29:40,006 --> 00:29:41,841
HIGHER FREQUENCY COMPARED TO THE

784
00:29:41,841 --> 00:29:43,409
CONTROL ADEN O CARCINOMA

785
00:29:43,409 --> 00:29:45,845
SAMPLES, SO YES IN THAT, AND

786
00:29:45,845 --> 00:29:47,881
THESE 2 PATHWAYS, MIGHT BE ABLE

787
00:29:47,881 --> 00:29:53,953
TO PREDICT FOR THE

788
00:29:53,953 --> 00:29:54,320
TRANSFORMATION.

789
00:29:54,320 --> 00:29:56,522
THEN THERE IS THE TRANSCRIPTOMIC

790
00:29:56,522 --> 00:29:57,957
DATA COMPARED TO THE SAMPLES

791
00:29:57,957 --> 00:30:00,593
THAT TRANSFORM TO THE

792
00:30:00,593 --> 00:30:01,327
PRETRANSFORMATION SPECIMENS, AND

793
00:30:01,327 --> 00:30:02,729
WE OBSERVE A NUMBER OF PATHWAYS

794
00:30:02,729 --> 00:30:06,499
THAT WE HAVE PREVIOUSLY

795
00:30:06,499 --> 00:30:07,567
REPORTED, INCLUDING UPREGULATION

796
00:30:07,567 --> 00:30:15,141
OF CELL CYCLE, DNA REPAIR GENES,

797
00:30:15,141 --> 00:30:17,343
END METASTASIS, AKT

798
00:30:17,343 --> 00:30:19,712
ENTHUSIASMERIN MYC, BUT WE WERE

799
00:30:19,712 --> 00:30:21,547
ABLE TO DORPH AT THE ATOMIC

800
00:30:21,547 --> 00:30:22,615
LEVEL, THAT THESE ARE COMPAT

801
00:30:22,615 --> 00:30:24,517
WIBL WITH THE PATHWAY ACTIVATION

802
00:30:24,517 --> 00:30:27,887
CONSISTENT WITH THE GENOMIC DATA

803
00:30:27,887 --> 00:30:28,288
I JUST SHARED.

804
00:30:28,288 --> 00:30:30,189
SO WE WANT TO HAVE A DEEPER LOOK

805
00:30:30,189 --> 00:30:31,391
INTO THESE PATHWAYS BECAUSE IT

806
00:30:31,391 --> 00:30:33,693
WAS SURPRISING WE FIEBD IT

807
00:30:33,693 --> 00:30:34,961
ACTIVATED IN SQUAMOUS CARCINOMA

808
00:30:34,961 --> 00:30:37,330
SO WE   PERFORM LIKE AN

809
00:30:37,330 --> 00:30:42,969
INTEGRATION OF MUTATION AND

810
00:30:42,969 --> 00:30:47,240
TRANSCUE TAINIC DATA, AND YOU

811
00:30:47,240 --> 00:30:49,008
CAN SEE THIS TRANSFORM SQUAMOUS,

812
00:30:49,008 --> 00:30:52,845
WITH THE PERMITATION AND DE NOVO

813
00:30:52,845 --> 00:30:54,113
SQUAMOUS WITH THE WILD-TYPE AND

814
00:30:54,113 --> 00:30:55,882
HERE IN THE ROWS HERE YOU CAN

815
00:30:55,882 --> 00:30:57,850
SEE THE OCCURRENCE OF DIFFERENT

816
00:30:57,850 --> 00:30:58,785
MUTATIONS IN THE DIFFERENT YEENS

817
00:30:58,785 --> 00:31:00,219
IN THE PATHWAY AND HERE CAN YOU

818
00:31:00,219 --> 00:31:03,323
SEE THE ENRICHMENT FOR SAMPLE, 4

819
00:31:03,323 --> 00:31:04,290
DIFFERENT SIGNATURES THAT HAVE

820
00:31:04,290 --> 00:31:06,492
BEEN RELATED TO RB1

821
00:31:06,492 --> 00:31:06,826
INACTIVATION.

822
00:31:06,826 --> 00:31:09,162
SO AS YOU CAN SEE HERE, FOR MOST

823
00:31:09,162 --> 00:31:10,563
OF THE SAMPLES THAT HAVE

824
00:31:10,563 --> 00:31:11,998
MUTATIONS IN 1 OR SEVERAL

825
00:31:11,998 --> 00:31:16,736
MEMBERS OF THE PATHWAY, WE SEE

826
00:31:16,736 --> 00:31:19,973
ENRICHMENT IN RB PATHWAY IN THE

827
00:31:19,973 --> 00:31:20,239
PHENOTYPE.

828
00:31:20,239 --> 00:31:21,841
BUT WE WERE ABLE TO SEE THAT

829
00:31:21,841 --> 00:31:23,743
MANY SAMPLES DIDN'T HAVE ANY

830
00:31:23,743 --> 00:31:25,478
MUTATIONS OR ALTERATIONS IN THIS

831
00:31:25,478 --> 00:31:28,581
PATHWAY WAS SHOWING US, WELL,

832
00:31:28,581 --> 00:31:32,118
ENRICHMENT FOR INACTIVATION OF

833
00:31:32,118 --> 00:31:32,285
RB1.

834
00:31:32,285 --> 00:31:37,023
SUGGESTING THAT THERE MIGHT BE

835
00:31:37,023 --> 00:31:38,157
MECHANISMS BEYOND MECHANICAL

836
00:31:38,157 --> 00:31:39,559
TRANSFORM EGGS FOR TRANSFOR THE

837
00:31:39,559 --> 00:31:40,526
PURPOSING TUMORS, AND THEN WE

838
00:31:40,526 --> 00:31:42,495
DECIDE TO HAVE A LOOK AT THE

839
00:31:42,495 --> 00:31:44,263
SUCCESS OF SAMPLES FOR WHICH WE

840
00:31:44,263 --> 00:31:45,331
HAVE MUCH PREAND POST

841
00:31:45,331 --> 00:31:47,066
TRANSFORMATION, AND AS YOU CAN

842
00:31:47,066 --> 00:31:49,736
SEE, IN MOST OF THE CASES, THERE

843
00:31:49,736 --> 00:31:52,839
WAS AN ENRICHMENT, IN THE

844
00:31:52,839 --> 00:31:53,373
TRANSCRIPTOMIC SIGNATURE,

845
00:31:53,373 --> 00:31:54,707
RELATED TO EVERYONE IN

846
00:31:54,707 --> 00:31:56,275
ACTIVATION, IN THE SQUAMOUS POST

847
00:31:56,275 --> 00:31:57,343
TRANSFORMATION THAT'S COMPARED

848
00:31:57,343 --> 00:31:59,779
TO THE PRETRANSFORMATION OF THE

849
00:31:59,779 --> 00:32:00,046
CARCINOMA.

850
00:32:00,046 --> 00:32:01,180
AND WE ALSO WERE ABLE TO

851
00:32:01,180 --> 00:32:03,349
VALIDATE THIS AT THE PROTEIN

852
00:32:03,349 --> 00:32:05,918
LEVEL, BY THE PUBLICLY AVAILABLE

853
00:32:05,918 --> 00:32:07,687
COHORTS, OF PROTEIN DATA FROM

854
00:32:07,687 --> 00:32:09,222
THE ADENEE CARCINOMA AND

855
00:32:09,222 --> 00:32:11,491
SQUAMOUS CARCINOMA WHERE AGAIN,

856
00:32:11,491 --> 00:32:13,359
WE SEE ENRICHMENT IN PROTEIN

857
00:32:13,359 --> 00:32:14,994
EXPRESSION SIGNATURES THAT ARE

858
00:32:14,994 --> 00:32:22,168
RELATED TO RB1 INACTIVATION.

859
00:32:22,168 --> 00:32:24,670
THEN AS THIS DATA WAS VERY

860
00:32:24,670 --> 00:32:26,172
ENTICING WE WOULD LIKE

861
00:32:26,172 --> 00:32:26,839
[INDISCERNIBLE] FUNCTIONALLY SO

862
00:32:26,839 --> 00:32:29,442
WE CAME BACK TO THE MODEL THAT

863
00:32:29,442 --> 00:32:30,643
WE PREVIOUSLY PUBLISHED WHERE WE

864
00:32:30,643 --> 00:32:32,378
TOOK THE CARCINOMA CELL LINES

865
00:32:32,378 --> 00:32:34,914
AND WE OVEREXPRESS NKT TO INDUCE

866
00:32:34,914 --> 00:32:37,617
CERTAIN DEGREE OF TRANSFORMATION

867
00:32:37,617 --> 00:32:38,718
TO SQUAMOUS.

868
00:32:38,718 --> 00:32:40,586
AND WE DECIDE TO ADD THE EXTRA

869
00:32:40,586 --> 00:32:42,188
VARIABLE OF RB PATHWAY

870
00:32:42,188 --> 00:32:43,189
ACTIVATION INTO DIFFERENT

871
00:32:43,189 --> 00:32:43,423
FLAVORS.

872
00:32:43,423 --> 00:32:46,025
ONE OF THEM WILL BE BY KNOCKING

873
00:32:46,025 --> 00:32:53,332
OUT DIRECTLY RB, AND OTHER 1

874
00:32:53,332 --> 00:32:55,668
KNOCKING OUT CDKN2 AB, WHO'S

875
00:32:55,668 --> 00:32:58,404
ACTIVATION RESULS THE SAME INTO

876
00:32:58,404 --> 00:32:59,272
RB1 ACTIVATION, SO 2 DIFFERENT

877
00:32:59,272 --> 00:33:04,710
WAYS OF DOING THE SAME THING.

878
00:33:04,710 --> 00:33:05,978
THESE CELL LINES, AND THEN WE

879
00:33:05,978 --> 00:33:11,184
PUT IN MICE AGAIN AND THEN

880
00:33:11,184 --> 00:33:12,685
DRIVEN WITH [INDISCERNIBLE], AND

881
00:33:12,685 --> 00:33:13,886
THE TUMORS RESPOND FOR LONG AND

882
00:33:13,886 --> 00:33:16,122
THEY TAKE THEIR TIME TO RELAPSE,

883
00:33:16,122 --> 00:33:20,193
YOU SEE THAT EACH OF THE TUMORS,

884
00:33:20,193 --> 00:33:21,327
WE'VE [INDISCERNIBLE] AND MYC

885
00:33:21,327 --> 00:33:24,030
TOGETHER OR NOT WITH A PATHWAY

886
00:33:24,030 --> 00:33:27,333
ACTIVATION WHERE, INITIALLY

887
00:33:27,333 --> 00:33:28,668
RESISTANT TO THE

888
00:33:28,668 --> 00:33:29,035
[INDISCERNIBLE].

889
00:33:29,035 --> 00:33:30,203
IN IMPORTANTLY WHEN WE COLLECTED

890
00:33:30,203 --> 00:33:31,437
THESE TUMORS AND WE ANALYZED

891
00:33:31,437 --> 00:33:36,042
THEM FOR THE EXPRESSION OF

892
00:33:36,042 --> 00:33:38,044
AGAIN, ADEN O CARCINOMA AS

893
00:33:38,044 --> 00:33:39,412
EXPRESSION MARKERS, AS YOU CAN

894
00:33:39,412 --> 00:33:44,083
SEE HERE IN BC9, WE OBSERVE

895
00:33:44,083 --> 00:33:46,652
INCREASED EXPRESSION IN P40 AND

896
00:33:46,652 --> 00:33:49,388
CK5/6 AND THIS WAS FURTHER

897
00:33:49,388 --> 00:33:53,259
INHANSED WHEN ON TOP OF MYC NKT

898
00:33:53,259 --> 00:33:54,994
WE WOULD ENACTIVATE RB, AND

899
00:33:54,994 --> 00:33:56,963
VARIOUS LEVELS WERE OBSERVED FOR

900
00:33:56,963 --> 00:33:59,699
THE [INDISCERNIBLE], WHERE WE

901
00:33:59,699 --> 00:34:02,535
WERE ABLE TO SEE DOWN REGULATION

902
00:34:02,535 --> 00:34:05,538
OF THE MARKERS OF REGULATION OF

903
00:34:05,538 --> 00:34:07,707
[INDISCERNIBLE], AND THEN

904
00:34:07,707 --> 00:34:08,808
UPREGULATION OF THE P40, WHICH

905
00:34:08,808 --> 00:34:12,378
WAS HIGHER IN THE TUMORS WITH

906
00:34:12,378 --> 00:34:17,583
RB1 ACTIVATION, AND THIS ALSO

907
00:34:17,583 --> 00:34:20,253
SUGGESTS THAT THIS ROLE HAS A

908
00:34:20,253 --> 00:34:22,555
DRIVING OR POTENTIALLY HAS A

909
00:34:22,555 --> 00:34:23,589
SQUAMOUS TRANSFORMATION EMPLOY

910
00:34:23,589 --> 00:34:26,058
AND HERE YOU HAVE REPRESENTATIVE

911
00:34:26,058 --> 00:34:27,460
IMAGES WHERE AGAIN, YOU CAN SEE

912
00:34:27,460 --> 00:34:30,897
THE DOWN REGULATION OF TTF 1 AND

913
00:34:30,897 --> 00:34:33,166
[INDISCERNIBLE] AND THEY

914
00:34:33,166 --> 00:34:35,001
COMPLETE INDUCTION FROM 0 TO

915
00:34:35,001 --> 00:34:42,909
IMPORTANT PERCENTAGE OF CELLS

916
00:34:42,909 --> 00:34:43,576
EXPRESSING SQUAMOUS MARKERS.

917
00:34:43,576 --> 00:34:45,778
THEN WE DECIDE TO STUDY THESE

918
00:34:45,778 --> 00:34:47,480
MARKERS AT THE SINGLE CELL

919
00:34:47,480 --> 00:34:49,448
LEVELS AND THEN FOR TRANSCRIPT

920
00:34:49,448 --> 00:34:50,550
OF THIS, AND AS YOU SEE HERE,

921
00:34:50,550 --> 00:34:52,985
THIS IS THE CONTROL UNTREATED,

922
00:34:52,985 --> 00:34:54,053
CONDITION, WE WERE SURPRISED TO

923
00:34:54,053 --> 00:34:57,590
SEE IT WAS ACTUALLY LIKE

924
00:34:57,590 --> 00:34:59,058
[INDISCERNIBLE], THESE ARE THE

925
00:34:59,058 --> 00:35:03,362
PLOT, THAT BASICALLY ASSIGN EACH

926
00:35:03,362 --> 00:35:05,598
OF THE CELLS, FOR CARCINOMA,

927
00:35:05,598 --> 00:35:06,566
LIKE SQUAMOUS OR LIKE SMALLING

928
00:35:06,566 --> 00:35:08,501
CELL AND AS CAN YOU SEE HERE IN

929
00:35:08,501 --> 00:35:10,369
THIS CASE, THE CELLS CLUSTER

930
00:35:10,369 --> 00:35:12,605
BETWEEN THE ADEN O CARCINOMA AND

931
00:35:12,605 --> 00:35:13,839
SQUAMOUS PHENOTYPE, SO YES, IN

932
00:35:13,839 --> 00:35:17,176
THAT, THERE'S SOMEY DID GROW OF

933
00:35:17,176 --> 00:35:18,444
THE HETEROGENEITY AT THE

934
00:35:18,444 --> 00:35:19,178
TRANSCRIPTOMIC LEVEL, PRESSING

935
00:35:19,178 --> 00:35:20,713
ALREADY IN THE CONTROL SAMPLES.

936
00:35:20,713 --> 00:35:24,750
AND YOU CAN SEE THAT WHEN WE

937
00:35:24,750 --> 00:35:30,122
TREAT WITH THE OSIMETRINIB,

938
00:35:30,122 --> 00:35:36,195
SUGGESTS THAT MAYBE IT TRIGGERED

939
00:35:36,195 --> 00:35:37,797
FARTHER OUT HERE.

940
00:35:37,797 --> 00:35:39,999
THEN WHEN WE OVEREXPRESS MYC, WE

941
00:35:39,999 --> 00:35:42,435
SEE THE EFFECT, WE SEE THE CELL

942
00:35:42,435 --> 00:35:44,971
DISPLAYS CLOSER TOWARDS THE

943
00:35:44,971 --> 00:35:48,541
PHENOTYPE, BUT THIS RESOURCE,

944
00:35:48,541 --> 00:35:51,644
LIKE OUR FARTHER ENHANCED AND WE

945
00:35:51,644 --> 00:35:55,214
TREAT THESE TUMORS WITH

946
00:35:55,214 --> 00:35:58,084
OSITINIB, AND THESE CELLS ARE

947
00:35:58,084 --> 00:35:59,885
REALLY MOVING TOWARDS THE

948
00:35:59,885 --> 00:36:01,854
SQUAMOUS CORNER AND THESE WERE

949
00:36:01,854 --> 00:36:05,091
MORE STRONGLY OBSERVED IN THE

950
00:36:05,091 --> 00:36:06,492
MODEL WITH MYC, AND EARLY

951
00:36:06,492 --> 00:36:07,860
ACTIVATION WHERE AGAIN, CAN YOU

952
00:36:07,860 --> 00:36:09,829
SEE DISPLACEMENT OF THE CELLS

953
00:36:09,829 --> 00:36:11,364
TOWARDS THE SQUAMOUS CORNER, AND

954
00:36:11,364 --> 00:36:14,667
HERE YOU CAN SEE LIKE THE

955
00:36:14,667 --> 00:36:16,068
STRONGEST PHENOTYPES HERE WHERE

956
00:36:16,068 --> 00:36:17,236
REALLY THE STRONGER PATIENT OF

957
00:36:17,236 --> 00:36:18,771
CELLS THAT LOOK LIKE CARCINOMA

958
00:36:18,771 --> 00:36:21,107
AND THEY TEND TO CLUSTER MORE ON

959
00:36:21,107 --> 00:36:24,944
THE SQUAMOUS CORNER AS WELL.

960
00:36:24,944 --> 00:36:26,812
AND WE   PERFORMED SOME

961
00:36:26,812 --> 00:36:28,514
ANALYSIS, BASICALLY STUDIED THE

962
00:36:28,514 --> 00:36:30,783
GENES IN THE GENE SIGNATURES

963
00:36:30,783 --> 00:36:32,685
THAT CHANGE OUT OF THE

964
00:36:32,685 --> 00:36:34,086
TRAJECTORY FROM THE ADEN O

965
00:36:34,086 --> 00:36:35,254
CARCINOMA STATE TO THE SQUAMOUS

966
00:36:35,254 --> 00:36:37,923
STATE AND AS YOU CAN SEE HERE,

967
00:36:37,923 --> 00:36:39,225
DURING THAT TRAJECTORY, OF

968
00:36:39,225 --> 00:36:41,727
COURSE, WE OBSERVE DOWN

969
00:36:41,727 --> 00:36:43,362
REGULATION OF ADEN O CARCINOMA

970
00:36:43,362 --> 00:36:45,464
MARKERS AND INDUCTION OF

971
00:36:45,464 --> 00:36:46,265
SQUAMOUS MARKERS, BUT WHEN WE

972
00:36:46,265 --> 00:36:49,302
HAD A LOOK AT THE SIGNATURES, WE

973
00:36:49,302 --> 00:36:50,503
OBSERVED THAT UNDER THE

974
00:36:50,503 --> 00:36:53,272
DIRECTORY AGAIN, WE HAVE ENRICH

975
00:36:53,272 --> 00:36:54,674
OF OF MYC, BECAUSE WE'RE

976
00:36:54,674 --> 00:36:55,408
OVEREXPRESSING THIS PATHWAY SO

977
00:36:55,408 --> 00:36:57,476
IF WE DIDN'T SEE THEM, THAT

978
00:36:57,476 --> 00:36:58,377
WOULD BE BAD.

979
00:36:58,377 --> 00:36:59,912
BUT WE ALSO OBSERVED

980
00:36:59,912 --> 00:37:02,281
UPREGULATION OF A NUMBER OF

981
00:37:02,281 --> 00:37:03,949
PATHWAYS THAT WITH THE COMPLEX,

982
00:37:03,949 --> 00:37:06,018
AND THE WEAK SIGNALING THAT WE

983
00:37:06,018 --> 00:37:07,720
DETECTED TO BE UPREGULATED IN

984
00:37:07,720 --> 00:37:10,356
THE SPECIMENS, SO YOU SEE THE

985
00:37:10,356 --> 00:37:11,657
SMALLS ARE REALLY MIMICKING WHAT

986
00:37:11,657 --> 00:37:14,527
HAPPENS IN THE CLINICAL

987
00:37:14,527 --> 00:37:14,794
SPECIMEN.

988
00:37:14,794 --> 00:37:15,895
VERY SIMILARLY FOR THE OTHER

989
00:37:15,895 --> 00:37:19,031
MODEL, THE 1 WHERE WE ACTIVATE

990
00:37:19,031 --> 00:37:20,132
RB TO KNOCK OUT [INDISCERNIBLE],

991
00:37:20,132 --> 00:37:22,501
YOU SEE THAT AGAIN, KNOCKING OUT

992
00:37:22,501 --> 00:37:24,804
THESE 2 GENES WOULD LIKE MAKE

993
00:37:24,804 --> 00:37:29,175
THE CELLS TRANSITION TO A MORE

994
00:37:29,175 --> 00:37:30,609
LIKE PLASTIC STATE OR MORE

995
00:37:30,609 --> 00:37:31,277
[INDISCERNIBLE] PLACE.

996
00:37:31,277 --> 00:37:33,245
AND THEN THIS WILL BE PROBABLY

997
00:37:33,245 --> 00:37:34,547
LIKE THE MOST EXTREME PHENOTYPE,

998
00:37:34,547 --> 00:37:36,615
CAN YOU SEE THAT WHEN ON TOP OF

999
00:37:36,615 --> 00:37:39,018
ACTIVATION OF THESE GENES TO

1000
00:37:39,018 --> 00:37:41,554
WHERE, TOGETHER WITH MYC, AKT,

1001
00:37:41,554 --> 00:37:43,322
AND WE SEE THE CELLS RECLUSTER

1002
00:37:43,322 --> 00:37:47,727
VERY STRONGLY IN THE SQUAMOUS

1003
00:37:47,727 --> 00:37:48,094
CORNER.

1004
00:37:48,094 --> 00:37:50,730
AND THE STUDY ANALYSIS HAD THIS

1005
00:37:50,730 --> 00:37:52,298
MODEL WERE VERY SIMILAR TO A

1006
00:37:52,298 --> 00:37:54,734
PRODUCED 1, AGAIN WE OBSERVE THE

1007
00:37:54,734 --> 00:37:57,103
DOWN REGULATION OF ADEN O

1008
00:37:57,103 --> 00:37:58,804
MARKERS AND UPREGULATION OF

1009
00:37:58,804 --> 00:38:01,107
SQUAMOUS MARKERS AND AGAIN A

1010
00:38:01,107 --> 00:38:01,941
SIMILAR TRANSCRIPTOMIC PROFILE

1011
00:38:01,941 --> 00:38:04,944
IN TERPS OF GENE SIGNATURES WITH

1012
00:38:04,944 --> 00:38:06,412
MYC INDUCE AS WELL AS A NUMBER

1013
00:38:06,412 --> 00:38:08,481
OF PATHWAYS WE SEE UPREGULATE

1014
00:38:08,481 --> 00:38:10,649
INDEED THE CLINICAL SPECIMENS

1015
00:38:10,649 --> 00:38:12,518
UNDER GOING THE SQUAMOUS

1016
00:38:12,518 --> 00:38:12,885
TRANSFORMATION.

1017
00:38:12,885 --> 00:38:15,588
ONE THING THAT WAS SURPRISING IN

1018
00:38:15,588 --> 00:38:17,022
THESE IS THAT COMPLETE E

1019
00:38:17,022 --> 00:38:17,990
UNEXECKED WHEN WE HAD A LOOK

1020
00:38:17,990 --> 00:38:21,093
THEA THE EXPRESSION OF EGFR, IT

1021
00:38:21,093 --> 00:38:23,129
SEEMS TO BE UPREGULATED FOR THE

1022
00:38:23,129 --> 00:38:23,963
TRANSFORMATION, WHICH IS MORE OR

1023
00:38:23,963 --> 00:38:25,531
LESS LIKE THE OPPOSITE WHAT WE

1024
00:38:25,531 --> 00:38:26,165
WOULD EXPECT.

1025
00:38:26,165 --> 00:38:29,435
SO WE DECIDE TO ARE A LOOK AT

1026
00:38:29,435 --> 00:38:31,904
THAT A LITTLE DEEPER AND AGAIN,

1027
00:38:31,904 --> 00:38:33,339
LIKE GROUPING, THE DIFFERENT

1028
00:38:33,339 --> 00:38:34,740
CONDITIONS OF THE ADEN O

1029
00:38:34,740 --> 00:38:37,376
CARCINOMA IN SQUAMOUS HERE, AND

1030
00:38:37,376 --> 00:38:38,344
PLOTTING TOGETHER, THE LEVELS OF

1031
00:38:38,344 --> 00:38:41,280
METHYLATION IN THE PROMOTER AND

1032
00:38:41,280 --> 00:38:44,150
THE BODY, AS WELL AS EXPRESSION

1033
00:38:44,150 --> 00:38:48,254
LEVEL OF MRNA, AND REASON FOR

1034
00:38:48,254 --> 00:38:51,490
SIGNATURES, THAT ARE RELATED TO

1035
00:38:51,490 --> 00:38:53,292
ACTIVATION, WE UNDERSTAND THERE

1036
00:38:53,292 --> 00:38:55,394
WAS NOT A LOT OF VERYIATION

1037
00:38:55,394 --> 00:38:58,664
BETWEEN ADEN O CARC NOAMS TOWARD

1038
00:38:58,664 --> 00:39:00,599
THE TRANSITION TO SQUAMOUS CELL

1039
00:39:00,599 --> 00:39:03,002
AND CARCINOMA SO JUST IN THAT

1040
00:39:03,002 --> 00:39:05,571
THERE'S NOT REALLY A DOWN

1041
00:39:05,571 --> 00:39:08,340
REGULATION OF EGFR OR EGFR

1042
00:39:08,340 --> 00:39:10,209
SIGNALING DURING THE SQUAMOUS

1043
00:39:10,209 --> 00:39:11,343
CELL TRANSFORMATION BUT WHAT

1044
00:39:11,343 --> 00:39:13,612
HAPPENS IN THE SMALL CELL

1045
00:39:13,612 --> 00:39:14,680
TRANSFORMATION WHERE THE SMALL

1046
00:39:14,680 --> 00:39:16,549
CELL IS COME PLETELY ABROGATED

1047
00:39:16,549 --> 00:39:18,184
AND WE WERE ABLE TO SEE THIS

1048
00:39:18,184 --> 00:39:19,685
AGAIN BY FOCUSING ON THE SETTING

1049
00:39:19,685 --> 00:39:22,121
ON THE MARCH PREAND POST

1050
00:39:22,121 --> 00:39:22,822
TRANSFORMATION SPECIMENS, CAN

1051
00:39:22,822 --> 00:39:26,192
YOU SEE IN MANY OF THESE CASES,

1052
00:39:26,192 --> 00:39:29,862
SIGNALING OF EGFR, OR AT LEAST

1053
00:39:29,862 --> 00:39:31,130
THE TRANSCRIPTOMIC LEVEL

1054
00:39:31,130 --> 00:39:33,098
ENRICHMENT FOR YEEN SIGNATURES

1055
00:39:33,098 --> 00:39:34,366
FOR GENEACIVATION ARE ACTUALLY

1056
00:39:34,366 --> 00:39:36,735
ENRICHED FOR IN THE SQUAMOUS

1057
00:39:36,735 --> 00:39:39,638
TUMORS AS COMPARED TO THE

1058
00:39:39,638 --> 00:39:40,272
TRANSFORMATION SPECIMEN.

1059
00:39:40,272 --> 00:39:44,877
AND WE HAVE SOME PRELIMINARY

1060
00:39:44,877 --> 00:39:45,711
[INDISCERNIBLE] DATA ON

1061
00:39:45,711 --> 00:39:47,580
CARCINOMAS WHERE WE OBSERVED THE

1062
00:39:47,580 --> 00:39:48,781
SAME THING.

1063
00:39:48,781 --> 00:39:51,517
THIS ACTUALLY HIGHER EXPRESS OF

1064
00:39:51,517 --> 00:39:53,419
EGFR SOMEHOW IN SQUAMOUS TOOL AS

1065
00:39:53,419 --> 00:39:54,487
COMPARED TO THE ADEN O CARCINOMA

1066
00:39:54,487 --> 00:39:55,855
AND THIS IS SOMETHING WE'RE

1067
00:39:55,855 --> 00:40:01,160
HAVING A LOOK SPONTANEOUS

1068
00:40:01,160 --> 00:40:01,694
ACTIVITY FARTHER DOWN.

1069
00:40:01,694 --> 00:40:03,229
THEN SOMETHING THAT WAS EQUALLY

1070
00:40:03,229 --> 00:40:05,965
SURPRISING WHEN WE REALIZE

1071
00:40:05,965 --> 00:40:08,501
AGAIN, THESE TRAJECTORY AND THIS

1072
00:40:08,501 --> 00:40:10,269
IS OUR PRECLINICAL FORMATION

1073
00:40:10,269 --> 00:40:12,071
WHICH IS THAT THE TIARAS RADIO

1074
00:40:12,071 --> 00:40:13,606
SEEN KINASE FOR WHICH INHIBITORS

1075
00:40:13,606 --> 00:40:17,109
ARE ABLE IN THE CLINIC WAS ALSO

1076
00:40:17,109 --> 00:40:19,512
UPREGULATED DURING THE PROCESS

1077
00:40:19,512 --> 00:40:21,046
OF TRANSFORMATION IN BOTH

1078
00:40:21,046 --> 00:40:24,016
MODELS, SO WE DECIDE TO CHECK

1079
00:40:24,016 --> 00:40:24,984
WHETHER APART FROM OUR PRIVILEGE

1080
00:40:24,984 --> 00:40:26,819
OF THE EXPRESSION OF THE

1081
00:40:26,819 --> 00:40:27,786
[INDISCERNIBLE] KINASE, WE WERE

1082
00:40:27,786 --> 00:40:31,891
ABLE TO SEE ENRICHMENT IN

1083
00:40:31,891 --> 00:40:32,358
SIGNATURES RELATED TO

1084
00:40:32,358 --> 00:40:33,025
METASIGNALLING AND THAT SEEMED

1085
00:40:33,025 --> 00:40:38,864
TO BE THE CASE IN BOTH MODELS.

1086
00:40:38,864 --> 00:40:41,700
SO WE DECIDE TO PARTICIPATE ON

1087
00:40:41,700 --> 00:40:43,335
THIS LEVEL IN THE THESE THAT ARE

1088
00:40:43,335 --> 00:40:45,104
RELATED TO WHAT WE HAVE HERE,

1089
00:40:45,104 --> 00:40:47,406
ALL OF THEM SHOWED HIGH EXPRESS

1090
00:40:47,406 --> 00:40:53,345
OF MYC, SO WE DECIDE TO TRY

1091
00:40:53,345 --> 00:40:54,513
INHIBITING MET TO SEE IF THAT

1092
00:40:54,513 --> 00:40:59,084
WILL BE INTERESTING TO BE A

1093
00:40:59,084 --> 00:41:04,557
THERAPEUTIC APPROACH IN THESE

1094
00:41:04,557 --> 00:41:05,724
MODELS.

1095
00:41:05,724 --> 00:41:07,192
AND THIS WAS TRANSITIONED

1096
00:41:07,192 --> 00:41:10,062
TOWARDS THE PHENOTYPE WITH THE

1097
00:41:10,062 --> 00:41:14,867
[INDISCERNIBLE] AND YOU CAN SEE

1098
00:41:14,867 --> 00:41:17,670
HERE THE COMBINATION OF

1099
00:41:17,670 --> 00:41:20,973
OSMERTINIB, AND WHEN WE TREATED

1100
00:41:20,973 --> 00:41:24,543
2 OTHER TUMORS THAT WERE PDF

1101
00:41:24,543 --> 00:41:25,611
MUTATION CASES AFTER

1102
00:41:25,611 --> 00:41:26,245
TRANSFORMATION TO SQUAMOUS, YOU

1103
00:41:26,245 --> 00:41:36,789
CAN SEE THAT THE COMBINATION OF

1104
00:41:37,590 --> 00:41:40,025
OSIMERTINIB, AND CRIZOTINIB,

1105
00:41:40,025 --> 00:41:41,560
WORKED BETTER THAN OTHER

1106
00:41:41,560 --> 00:41:41,894
THERAPEUTICS.

1107
00:41:41,894 --> 00:41:45,297
A SUMMARY OF THIS PART OF THE

1108
00:41:45,297 --> 00:41:48,067
TALK IS THAT THIS FEATURE OF

1109
00:41:48,067 --> 00:41:49,768
SQUAMOUS CELL TRANSFORMATION AND

1110
00:41:49,768 --> 00:41:51,770
ALSO SQUAMOUS TUMORS IN GENERAL,

1111
00:41:51,770 --> 00:41:54,974
GENOMIC ALTERATIONS IN THE RB

1112
00:41:54,974 --> 00:41:56,141
ENACTIVATED PATHWAY MAY INCREASE

1113
00:41:56,141 --> 00:41:56,976
RISK OF TRANSFORMATION SO WE

1114
00:41:56,976 --> 00:41:58,944
HAVE AT LEAST A HINT TO KIND OF

1115
00:41:58,944 --> 00:42:01,213
PREDICT WHICH PATIENTS MIGHT

1116
00:42:01,213 --> 00:42:04,049
HAVE HIGHER RISK OF

1117
00:42:04,049 --> 00:42:05,351
TRANSFORMATION, WE SEE THE

1118
00:42:05,351 --> 00:42:08,287
INACTIVATION MAY HAVE A ROLE IN

1119
00:42:08,287 --> 00:42:09,588
PLASTICITY IN THE

1120
00:42:09,588 --> 00:42:10,222
[INDISCERNIBLE] TRANSFORMATION

1121
00:42:10,222 --> 00:42:12,925
AND WE SEE THAT EGFR SIGNALING

1122
00:42:12,925 --> 00:42:16,095
IS NOT SUPPRESSED DURING

1123
00:42:16,095 --> 00:42:18,397
TRANSFORMATION UNLIKE WHAT WE

1124
00:42:18,397 --> 00:42:19,031
OBSERVE INDEED NE

1125
00:42:19,031 --> 00:42:20,899
TRANSFORMATION, WE WOULD LIKE TO

1126
00:42:20,899 --> 00:42:25,070
CONTINUE TREATING THESE TUMORS

1127
00:42:25,070 --> 00:42:26,905
WITH OSITNINB AFTER OUR

1128
00:42:26,905 --> 00:42:30,009
RESEARCH, AND OUR MET TARGET

1129
00:42:30,009 --> 00:42:33,746
SEEMS TO BE WORKING NICELY IN

1130
00:42:33,746 --> 00:42:34,246
COMBINATION OF OSITINIB.

1131
00:42:34,246 --> 00:42:36,949
AND THEN THE LAST PART OF THE

1132
00:42:36,949 --> 00:42:39,051
TALK WILL BE 2 SMALL WORKS THAT

1133
00:42:39,051 --> 00:42:41,920
WE HAVE IDENTIFIED 2 DIFFERENT

1134
00:42:41,920 --> 00:42:42,955
THERAPEUTIC TARGETS THAT MIGHT

1135
00:42:42,955 --> 00:42:47,993
BE ABLE TO PREVENT SMALL CELL OR

1136
00:42:47,993 --> 00:42:48,794
[INDISCERNIBLE] TRANSFORMATION.

1137
00:42:48,794 --> 00:42:51,363
THE FIRST 1 IS EXPORTING 1 WHICH

1138
00:42:51,363 --> 00:42:53,065
WE DORPH DURING THE SCREEN IN

1139
00:42:53,065 --> 00:42:54,566
THE PREVIOUS PROGEC, EXPORTING

1140
00:42:54,566 --> 00:42:59,638
WOB IS A CLEAR EXPORTER LOCATED

1141
00:42:59,638 --> 00:43:02,741
IN THE NUCLEUS AND IT EXPORTS

1142
00:43:02,741 --> 00:43:05,377
PROTEINS AND MRNAs FROM THE

1143
00:43:05,377 --> 00:43:10,616
CYTOSTUDIES 

1144
00:43:10,616 --> 00:43:11,850
CYTOSOL, AND THIS HAS GAINED A

1145
00:43:11,850 --> 00:43:12,885
LOT OF ATTENTION IN CANCER

1146
00:43:12,885 --> 00:43:16,321
RESEARCH AND ALSO THE REAP WHY

1147
00:43:16,321 --> 00:43:17,990
THEY HAVE DEVELOPED DIFFERENT

1148
00:43:17,990 --> 00:43:21,226
INHIBITORS, 1 OF THEM EVEN

1149
00:43:21,226 --> 00:43:23,562
APPROVED FOR CLINICAL USE IN THE

1150
00:43:23,562 --> 00:43:25,064
SETTING OF MEDICAL DIAGNOSIS SO

1151
00:43:25,064 --> 00:43:29,535
IT MAKES THESE TARGETS PRETTY

1152
00:43:29,535 --> 00:43:29,802
PROMISING.

1153
00:43:29,802 --> 00:43:31,603
WE OBSERVED THAT EXPRESSION OF

1154
00:43:31,603 --> 00:43:34,339
EXPORTING 1 WAS HIGHEST IN SMALL

1155
00:43:34,339 --> 00:43:36,542
CELL AS COMPARED TO ALL TUMOR

1156
00:43:36,542 --> 00:43:40,679
TYPE, AND WE HAD THE OTHER

1157
00:43:40,679 --> 00:43:41,980
PROTEIN LEVEL COMPARING NONSMALL

1158
00:43:41,980 --> 00:43:44,383
CELL LUNG CANCER, WE PRVED NOT

1159
00:43:44,383 --> 00:43:45,884
ONLY THAT EXPORTING 1 IS MORE

1160
00:43:45,884 --> 00:43:47,686
HIGHLY EXPRESSED IN SMALL CELL,

1161
00:43:47,686 --> 00:43:50,923
BUT ALSO THAT IT IS CONSISTENTLY

1162
00:43:50,923 --> 00:44:01,433
HIGHY EXPRESSED IN ALL TUMORS

1163
00:44:02,935 --> 00:44:03,569
ARK ASSESSESSED.

1164
00:44:03,569 --> 00:44:05,771
SO WE DECIDE TO TEST THESE SMALL

1165
00:44:05,771 --> 00:44:08,173
CELL TRANSFORMATION AND AGAIN WE

1166
00:44:08,173 --> 00:44:10,275
DO THIS CONFORMED TO THE

1167
00:44:10,275 --> 00:44:12,511
CARCINOMA, TRANSFORMS MORE CELL

1168
00:44:12,511 --> 00:44:13,545
AND THEN DE NOVO SMALL CELL AND

1169
00:44:13,545 --> 00:44:16,515
AS CAN YOU SEE HERE THERE WAS AN

1170
00:44:16,515 --> 00:44:17,449
UPREGULATION OF EXPORTING 1

1171
00:44:17,449 --> 00:44:20,919
DURING THE PROCESS OF

1172
00:44:20,919 --> 00:44:21,787
TRANSFORMATION EMPLOY AND WERE

1173
00:44:21,787 --> 00:44:23,622
ABLE TO DO THIS AGAIN AT THE

1174
00:44:23,622 --> 00:44:26,925
PROTEIN LEVEL, AND AGAIN WE WERE

1175
00:44:26,925 --> 00:44:28,227
OBSERVING INCREASE EXPRESSION OF

1176
00:44:28,227 --> 00:44:33,432
EXPORTING 1 DURING THE PROCESS

1177
00:44:33,432 --> 00:44:35,534
OF TRANSFORMATION.

1178
00:44:35,534 --> 00:44:37,503
AND IN THIS TRANSFORMATION TO

1179
00:44:37,503 --> 00:44:38,904
SMALL CELL TUMORS AND ALSO IN

1180
00:44:38,904 --> 00:44:39,972
THE PROCESS WE [INDISCERNIBLE]

1181
00:44:39,972 --> 00:44:41,507
WE WANTED TO TEST WHETHER

1182
00:44:41,507 --> 00:44:44,176
EXPORTING 1 MIGHT BE ALSO

1183
00:44:44,176 --> 00:44:45,878
UPREGULATED IN THE SETTING AND

1184
00:44:45,878 --> 00:44:48,080
AS YOU CAN SEE HERE THESE 2

1185
00:44:48,080 --> 00:44:53,185
PUBLICLY AVAILABLE COHORTS THOSE

1186
00:44:53,185 --> 00:44:54,386
ADEN O CARCINOMA WERE SHOWING

1187
00:44:54,386 --> 00:44:56,255
HIGH EXPRESSION OF EXPORTING 1

1188
00:44:56,255 --> 00:44:59,124
AND WHEN WE COMPARED THE

1189
00:44:59,124 --> 00:45:01,393
EXPRESSION OF ADEN O CARCINOMA

1190
00:45:01,393 --> 00:45:02,995
VERSUS THE [INDISCERNIBLE]

1191
00:45:02,995 --> 00:45:05,364
TUMORS WE SAID AGAIN THAT IT WAS

1192
00:45:05,364 --> 00:45:07,866
UPREGULATED IN THE SETTING.

1193
00:45:07,866 --> 00:45:12,838
ABLE TO FIND THIS OTHER PROTEIN

1194
00:45:12,838 --> 00:45:14,473
LEVEL, SHOWING THAT SHOWING HIGH

1195
00:45:14,473 --> 00:45:17,810
EXPRESSION LEVELS OF EXPORTING

1196
00:45:17,810 --> 00:45:18,677
[INDISCERNIBLE] CARCINOMAS.

1197
00:45:18,677 --> 00:45:20,846
BUT I THINK THAT MOST

1198
00:45:20,846 --> 00:45:22,181
INTERESTING FINDING OF THIS

1199
00:45:22,181 --> 00:45:25,651
SLIDE IS THAT IN LUNG ADEN O

1200
00:45:25,651 --> 00:45:28,487
CARCINOMA EXPORTING 1 WAS

1201
00:45:28,487 --> 00:45:29,788
ALREADY UPREGULATED IN

1202
00:45:29,788 --> 00:45:31,490
TRANSFORMING CARCINOMA BEFORE IT

1203
00:45:31,490 --> 00:45:34,860
WOULD TRANSITION TOWARDS SMALL

1204
00:45:34,860 --> 00:45:35,694
CELL.

1205
00:45:35,694 --> 00:45:37,429
INDICATING THAT EXPORTING 1 OR

1206
00:45:37,429 --> 00:45:39,264
MIGHT BE UPREGULATED IN THE

1207
00:45:39,264 --> 00:45:40,966
EARLY STAGES OF TRANSFORMATION.

1208
00:45:40,966 --> 00:45:44,102
AND YOU CAN ATTEST THAT WHEN WE

1209
00:45:44,102 --> 00:45:47,739
WENT BACK TO THE MOST INITIAL

1210
00:45:47,739 --> 00:45:49,441
MOLECULAR EVENTS THAT RECORD THE

1211
00:45:49,441 --> 00:45:50,609
TRANSFORMATION THAT ARE IN THERE

1212
00:45:50,609 --> 00:45:52,144
WITH 3 AND RB1.

1213
00:45:52,144 --> 00:45:54,112
WE HAD THE EXPRESSION OF

1214
00:45:54,112 --> 00:45:56,982
EXPORTING 1 IN 3 DIFFERENT

1215
00:45:56,982 --> 00:45:58,684
PUBLICLY AVAILABLE COHORTS, 2 OF

1216
00:45:58,684 --> 00:46:01,220
THE CARCINOMA AND 1 OF THE

1217
00:46:01,220 --> 00:46:02,921
[INDISCERNIBLE] CARCINOMA AND WE

1218
00:46:02,921 --> 00:46:04,656
DECIDE THE TUMORS BETWEEN THOSE

1219
00:46:04,656 --> 00:46:06,124
THAT HAD WILD-TYPE

1220
00:46:06,124 --> 00:46:08,093
[INDISCERNIBLE] 1 AND THOSE THAT

1221
00:46:08,093 --> 00:46:09,027
HAD MUTATIONS IN BOTH GENES AND

1222
00:46:09,027 --> 00:46:11,964
AS YOU CAN SEE HERE

1223
00:46:11,964 --> 00:46:12,898
CONSISTENTLY, WE OBSERVE

1224
00:46:12,898 --> 00:46:13,599
INCREASED EXPRESSION OF

1225
00:46:13,599 --> 00:46:15,901
EXPORTING 1 IN THOSE TUMORS THAT

1226
00:46:15,901 --> 00:46:19,271
HAD MUTATIONS OF RB1, SO THIS

1227
00:46:19,271 --> 00:46:20,405
RESOURCE SUGGESTS THAT VERY

1228
00:46:20,405 --> 00:46:21,740
EARLY IN THE TRANSFORMATION

1229
00:46:21,740 --> 00:46:23,442
PROCESS, RIGHT AFTER THE

1230
00:46:23,442 --> 00:46:26,678
ACQUISITION OF THE DAY

1231
00:46:26,678 --> 00:46:28,413
ACTIVATION RB1, EXPORTING 1 MAY

1232
00:46:28,413 --> 00:46:30,849
BE UPREGULATED AND WE WANT TO

1233
00:46:30,849 --> 00:46:32,684
VALIDATE THIS IN PRECLINICAL

1234
00:46:32,684 --> 00:46:34,553
MODELS WITH THE PROCESS OF THE

1235
00:46:34,553 --> 00:46:36,521
CARCINOMA LINE, AND BOTH OF THEM

1236
00:46:36,521 --> 00:46:37,723
WILD-TYPE AND [INDISCERNIBLE] 1,

1237
00:46:37,723 --> 00:46:42,661
SO WE INDUCE KNOCK OUT OF PD3

1238
00:46:42,661 --> 00:46:44,663
AND/OR RB1 AND OBSERVED THAT THE

1239
00:46:44,663 --> 00:46:47,532
CELL LINES WERE BOTH

1240
00:46:47,532 --> 00:46:49,801
[INDISCERNIBLE] RB1 WERE NOT OUT

1241
00:46:49,801 --> 00:46:50,936
AND SHOWED UPREGULATION OF

1242
00:46:50,936 --> 00:46:52,371
EXPORTS 1 AND NOT ONLY

1243
00:46:52,371 --> 00:46:55,173
UPREGULATION BUT INCREASE INDEED

1244
00:46:55,173 --> 00:46:56,275
SENSITIVITY TO THE EXPORTED 1

1245
00:46:56,275 --> 00:46:58,543
INHIBITORS, AS CAN YOU SEE HERE

1246
00:46:58,543 --> 00:47:01,580
FOR ADEN O CARCINOMA CELL LINE

1247
00:47:01,580 --> 00:47:03,081
AND 2 ADEN O CARCINOMA CELL

1248
00:47:03,081 --> 00:47:04,883
LINES, THOSE WITH THE DOUBLE

1249
00:47:04,883 --> 00:47:06,451
KNOCK OUT [INDISCERNIBLE] WERE

1250
00:47:06,451 --> 00:47:12,190
SHOWING INCREASED SENSITIVITY TO

1251
00:47:12,190 --> 00:47:12,658
THE CONCENTRATIONAL

1252
00:47:12,658 --> 00:47:13,558
[INDISCERNIBLE] INHIBIT ON ARE

1253
00:47:13,558 --> 00:47:15,861
AND SO YES THIS UP ON

1254
00:47:15,861 --> 00:47:18,297
ACTIVATION, YOU NOT ONLY GET

1255
00:47:18,297 --> 00:47:19,798
UPREGULATION, BUT ALSO THE TUMOR

1256
00:47:19,798 --> 00:47:21,833
CELLS HAVE BECOME MORE DEPENDENT

1257
00:47:21,833 --> 00:47:23,502
ON IT.

1258
00:47:23,502 --> 00:47:26,171
AND THIS PROVIDED A RATIONAL TO

1259
00:47:26,171 --> 00:47:27,973
INHIBIT EXPORTING 1S AS A MEANS

1260
00:47:27,973 --> 00:47:31,510
TO PREVENT LIKE THIS HURDLE, FOR

1261
00:47:31,510 --> 00:47:36,348
SMALL CELL TRANSFORMATION.

1262
00:47:36,348 --> 00:47:40,252
SO WE LEVERAGED THE CARCINOMA TO

1263
00:47:40,252 --> 00:47:42,087
CARCINOMA IN VIVO, THIS IS 2

1264
00:47:42,087 --> 00:47:44,089
PROCESS OF THE CARCINOMA CELL

1265
00:47:44,089 --> 00:47:46,625
LINES WHERE WE WILL INDUCE P53

1266
00:47:46,625 --> 00:47:48,493
AND RB1 KNOCK OUT AND THEN TREAT

1267
00:47:48,493 --> 00:47:51,897
THEM WITH TARGETED THERAPY IN

1268
00:47:51,897 --> 00:47:55,267
THIS CASE [INDISCERNIBLE].

1269
00:47:55,267 --> 00:47:56,468
AND INDUCE [INDISCERNIBLE]

1270
00:47:56,468 --> 00:47:57,636
CARCINOMA IN VIVO, SO AS CAN YOU

1271
00:47:57,636 --> 00:48:00,072
SEE HERE FOR BOTH OF THE MODELS,

1272
00:48:00,072 --> 00:48:02,441
THE COMBINATION OF THE TARGETED

1273
00:48:02,441 --> 00:48:04,309
THERAPY, AND EXPORTED INHIB

1274
00:48:04,309 --> 00:48:07,279
THORS THOR WAS OUT   PERFORMER

1275
00:48:07,279 --> 00:48:10,349
THE EFFICACY TO ANY OF THE OTHER

1276
00:48:10,349 --> 00:48:11,650
THERAPY AREAS AND MOST

1277
00:48:11,650 --> 00:48:13,852
IMPORTANT, WE COLLECTED THESE

1278
00:48:13,852 --> 00:48:15,721
TUMORS, AT END POINT, AS CAN YOU

1279
00:48:15,721 --> 00:48:18,223
SEE HERE, WHEN WE HAD A LOOK AT

1280
00:48:18,223 --> 00:48:21,626
THE EXPRESSION OF THE MARKERS

1281
00:48:21,626 --> 00:48:23,962
[INDISCERNIBLE], FOR BOTH OF

1282
00:48:23,962 --> 00:48:26,431
THEM ARE SUSPECTED THAT THIS

1283
00:48:26,431 --> 00:48:27,499
WOULD TRIGGER THAT OCCURRENCE OF

1284
00:48:27,499 --> 00:48:30,402
CELLS THAT WE'RE SHOWING IN THE

1285
00:48:30,402 --> 00:48:32,571
PHENOTYPE, HOWEVER IN THE

1286
00:48:32,571 --> 00:48:33,472
COMBINATION TREATMENT, WE DIDN'T

1287
00:48:33,472 --> 00:48:35,874
SEE ANY OF THIS SUGGESTING THAT

1288
00:48:35,874 --> 00:48:37,943
THIS COMBINATION IS NOT ONLY

1289
00:48:37,943 --> 00:48:40,178
ABLE TO EXTEND THE RESPONSE OF

1290
00:48:40,178 --> 00:48:41,446
TARGETED THERAPY BUT ALSO TO

1291
00:48:41,446 --> 00:48:49,755
PREVENT OR AT LEAST DELAY THE

1292
00:48:49,755 --> 00:48:50,122
TRANSFORMATION.

1293
00:48:50,122 --> 00:48:51,456
AND THERE'S NOT REALLY A SMALL

1294
00:48:51,456 --> 00:48:52,691
TRANSFORMATION IN THE LUNG BUT

1295
00:48:52,691 --> 00:48:54,626
WE HAVE 1 INTERESTING PDX IN THE

1296
00:48:54,626 --> 00:48:56,962
LAB THAT SHOWED MIXED PHENOTYPE

1297
00:48:56,962 --> 00:48:58,330
COP BIENED NONSMALL CELL AND

1298
00:48:58,330 --> 00:49:03,301
SMALL CELL, AND A MODEL WITH

1299
00:49:03,301 --> 00:49:04,836
EGFR FERM ENATION AND OAIVE THEE

1300
00:49:04,836 --> 00:49:07,439
THAT WAS MOSTLY SMALL CELL AS

1301
00:49:07,439 --> 00:49:09,908
CAN YOU SEE HERE WITH ONLY LIKE

1302
00:49:09,908 --> 00:49:10,909
[INDISCERNIBLE] CARC NOAM ACIN

1303
00:49:10,909 --> 00:49:13,345
THIS CELL WE EXPERIENCE THE CELL

1304
00:49:13,345 --> 00:49:14,646
OF TARGETED THERAPY TOGETHER

1305
00:49:14,646 --> 00:49:19,885
WITH [INDISCERNIBLE], WAS OUT 

1306
00:49:19,885 --> 00:49:21,353
PERFORMING DELAYING TUMOR GROWTH

1307
00:49:21,353 --> 00:49:22,554
IN THE OTHER 2 ARMS.

1308
00:49:22,554 --> 00:49:23,722
IN THIS CASE WE COLLECT THE

1309
00:49:23,722 --> 00:49:26,758
TUMORS AND WE HAVE A LOOK AT

1310
00:49:26,758 --> 00:49:30,429
THEM, WE SAID THERE WAS NO

1311
00:49:30,429 --> 00:49:33,198
REGRESSION OF THAT FEIGN TYPE

1312
00:49:33,198 --> 00:49:34,800
SUGGEST THAT THAT MAY INTERFERE

1313
00:49:34,800 --> 00:49:36,201
WITH THE [INDISCERNIBLE] BECAUSE

1314
00:49:36,201 --> 00:49:38,970
IT HAS NOT AFTER IT HAS

1315
00:49:38,970 --> 00:49:39,237
OCCURRED.

1316
00:49:39,237 --> 00:49:41,273
AND IN ORDER TO FIND A MECHANISM

1317
00:49:41,273 --> 00:49:42,941
BY WHICH INHIBITION OF

1318
00:49:42,941 --> 00:49:44,876
[INDISCERNIBLE] WAS PREVENTING

1319
00:49:44,876 --> 00:49:46,411
TRANSFORMATION, WE LEVERAGED

1320
00:49:46,411 --> 00:49:48,146
SOME TRANSCRIPTOMIC DATA ON THE

1321
00:49:48,146 --> 00:49:50,215
MODELS AND WE OBSERVE THAT

1322
00:49:50,215 --> 00:49:51,983
CANNED WHAT WILL TRIGGER THE

1323
00:49:51,983 --> 00:49:54,519
EXPRESSION OF SOX 2, WHICH IS A

1324
00:49:54,519 --> 00:49:55,353
FACTOR [INDISCERNIBLE] WHICH IS

1325
00:49:55,353 --> 00:49:58,890
KNOWN TO BE ESSENTIAL FOR

1326
00:49:58,890 --> 00:49:59,791
TRANSFORMATION TO OCCUR.

1327
00:49:59,791 --> 00:50:01,960
SO WE OBSERVED THAT THIS

1328
00:50:01,960 --> 00:50:03,962
[INDISCERNIBLE] FURTHER WAS

1329
00:50:03,962 --> 00:50:04,663
UPREGULATED WITH [INDISCERNIBLE]

1330
00:50:04,663 --> 00:50:07,732
BUT THEN WAS SUPPRESSED IN THE

1331
00:50:07,732 --> 00:50:08,800
COMBINATION TREATMENT.

1332
00:50:08,800 --> 00:50:10,802
AND WE BELIEVE THIS AS WELL AT

1333
00:50:10,802 --> 00:50:12,404
THE PROTEIN LEVEL, CAN YOU SEE

1334
00:50:12,404 --> 00:50:16,575
THAT FOR BOTH PROSTATE AND

1335
00:50:16,575 --> 00:50:17,275
[INDISCERNIBLE] MODELS, TARGETED

1336
00:50:17,275 --> 00:50:18,777
THERAPY WOULD INCREASE THE

1337
00:50:18,777 --> 00:50:20,278
EXPRESSION OF SOX 2 THAT WAS

1338
00:50:20,278 --> 00:50:23,148
REPRESSED IN THE TUMORS.

1339
00:50:23,148 --> 00:50:25,717
SO IN ORDER TO PROVE THE SOX 2

1340
00:50:25,717 --> 00:50:28,553
WAS REALLY, THE MECHANISM HERE,

1341
00:50:28,553 --> 00:50:31,823
WE PREFER SOME RESCUE

1342
00:50:31,823 --> 00:50:32,491
EXPERIMENTS BY OVEREXPRESSING

1343
00:50:32,491 --> 00:50:33,859
SOX 2 AND AS YOU CAN SEE HERE,

1344
00:50:33,859 --> 00:50:37,229
THIS IS THE CONTROL CELL LINE,

1345
00:50:37,229 --> 00:50:41,199
THAT SHOW LIKE LOW LEVEL OF

1346
00:50:41,199 --> 00:50:45,971
EXPRESSION OF NEURONAL MARKERS

1347
00:50:45,971 --> 00:50:48,039
AND DRIVERRING EXPRESSION OF AR,

1348
00:50:48,039 --> 00:50:49,641
AND WITHIN [INDISCERNIBLE] WE

1349
00:50:49,641 --> 00:50:51,543
SEE THE OPPOSITE FINE O TYPE, WE

1350
00:50:51,543 --> 00:50:53,278
SEE THE [INDISCERNIBLE] OF THE

1351
00:50:53,278 --> 00:50:56,915
CARCINOMA AR, AND WE WOULD EXEC

1352
00:50:56,915 --> 00:50:58,083
AND AS SHOWN BEFORE WHEN WE

1353
00:50:58,083 --> 00:51:01,052
TREAT THESE CELLS WITH THE

1354
00:51:01,052 --> 00:51:01,920
COMBINATION OF [INDISCERNIBLE],

1355
00:51:01,920 --> 00:51:04,055
WE HAVE SET [INDISCERNIBLE] TO

1356
00:51:04,055 --> 00:51:06,958
THE PHENOTYPE AGAIN, AGAIN NO

1357
00:51:06,958 --> 00:51:08,093
OTHER FEATURES AND

1358
00:51:08,093 --> 00:51:11,930
UPREGULATIONAL OF THE DRIVER,

1359
00:51:11,930 --> 00:51:15,133
BUT IF WE TREAT WITH THE

1360
00:51:15,133 --> 00:51:16,568
COMBINATION BUT ALSO OVEREXPRESS

1361
00:51:16,568 --> 00:51:19,504
SOX 2, WE PARTIALLY RESCUE THIS

1362
00:51:19,504 --> 00:51:20,438
TRANSFORMATION FEIGNEE TYPE

1363
00:51:20,438 --> 00:51:22,040
CHARACTERIZED BY THE EXPRESSION

1364
00:51:22,040 --> 00:51:25,010
OF THE MARKERS SO IN THAT SOX 2

1365
00:51:25,010 --> 00:51:27,913
DOWN REGULATION BY EXPORTING 1

1366
00:51:27,913 --> 00:51:28,980
INHIBITION IS REALLY THE REASON

1367
00:51:28,980 --> 00:51:32,184
WHY WE ARE PREVENTING

1368
00:51:32,184 --> 00:51:32,617
TRANSFORATION HERE.

1369
00:51:32,617 --> 00:51:35,287
AND AS A CONCLUSION WE HAVE THIS

1370
00:51:35,287 --> 00:51:37,155
DIAGRAM WHERE WE OBSERVE THE

1371
00:51:37,155 --> 00:51:39,457
ACTIVATION IN RB1 WHICH IS EARLY

1372
00:51:39,457 --> 00:51:41,860
IN TRANSFORMATION PROCESS, WE

1373
00:51:41,860 --> 00:51:43,595
TART TO OBSERVE UPREGULATION OF

1374
00:51:43,595 --> 00:51:45,163
EXPORTING 1 AND UPON TREATMENT

1375
00:51:45,163 --> 00:51:47,199
WITH [INDISCERNIBLE] THERAPY WE

1376
00:51:47,199 --> 00:51:50,135
GIVE UPREGULATION OF PROTEIN 1

1377
00:51:50,135 --> 00:51:52,204
TOGETHER WITH SOX 2 WHICH IS

1378
00:51:52,204 --> 00:51:53,371
ESSENTIAL FOR TRANSFORMATION AND

1379
00:51:53,371 --> 00:51:55,140
THAT WHY WE GET TRANSFORMATION,

1380
00:51:55,140 --> 00:51:57,142
HOWEVER WITH TARGETED THERAPY WE

1381
00:51:57,142 --> 00:51:59,211
HAVE THE INHIBITOR AND WE SEE

1382
00:51:59,211 --> 00:52:03,415
THE SOX EXPRESSION DECREASED AND

1383
00:52:03,415 --> 00:52:06,818
THAT PREVENTS TRANSFORMATION

1384
00:52:06,818 --> 00:52:07,185
[INDISCERNIBLE].

1385
00:52:07,185 --> 00:52:08,653
AND THE LAST PART OF THE TALK

1386
00:52:08,653 --> 00:52:10,655
WILL BE ABOUT A DIFFERENT

1387
00:52:10,655 --> 00:52:11,890
THERAPEUTIC TARGET THAT'S EVEN

1388
00:52:11,890 --> 00:52:14,459
MORE POTENT.

1389
00:52:14,459 --> 00:52:18,630
THIS IS C67 AND WE IDENTIFY IT

1390
00:52:18,630 --> 00:52:20,131
IN CRISPR SCREEN, AND IT IS A

1391
00:52:20,131 --> 00:52:22,467
PROTEIN THAT IS RESPONSIBLE TO

1392
00:52:22,467 --> 00:52:25,403
INITIATE DNA REPLICATION AND

1393
00:52:25,403 --> 00:52:26,571
USELESS BEEN INVOLVED IN

1394
00:52:26,571 --> 00:52:27,572
[INDISCERNIBLE] COHESION AND

1395
00:52:27,572 --> 00:52:28,940
ALSO [INDISCERNIBLE].

1396
00:52:28,940 --> 00:52:30,475
AND IT'S AN INTERESTING TARGET

1397
00:52:30,475 --> 00:52:32,310
BECAUSE THERE'S ALREADY

1398
00:52:32,310 --> 00:52:35,247
INHIBITORS THAT ARE

1399
00:52:35,247 --> 00:52:40,418
[INDISCERNIBLE] TESTING AND HAVE

1400
00:52:40,418 --> 00:52:41,486
ALREADY SHOWN PROMISING RESULTS

1401
00:52:41,486 --> 00:52:47,592
IN TERMS OF EFFICACY.

1402
00:52:47,592 --> 00:52:50,262
WE EXPRESS THE EXPRESSION OF 67

1403
00:52:50,262 --> 00:52:53,131
IN OUR CLINICAL SPECIMENS

1404
00:52:53,131 --> 00:52:53,932
UNDERGOING TRANSFORATION BOTH IN

1405
00:52:53,932 --> 00:52:57,302
THE LUNG AND PROSTATE AND AND AS

1406
00:52:57,302 --> 00:53:06,244
YOU CANY HERE--AS YOU CAN SEE

1407
00:53:06,244 --> 00:53:07,579
HERE, WE HAVE THIS COMPARED TO

1408
00:53:07,579 --> 00:53:11,049
LUNG AND PROOF THE EAT TUMORS,

1409
00:53:11,049 --> 00:53:12,951
AND WE WERE TRANSFORMING

1410
00:53:12,951 --> 00:53:14,786
CARCINOMAS SUGGIESTING AGAIN

1411
00:53:14,786 --> 00:53:16,187
THAL UPREGULATION

1412
00:53:16,187 --> 00:53:17,355
[INDISCERNIBLE] IN THE

1413
00:53:17,355 --> 00:53:18,657
TRANSFORMATION PROCESS AND

1414
00:53:18,657 --> 00:53:20,058
SIMILARLY TO WHAT WE OBSERVE FOR

1415
00:53:20,058 --> 00:53:22,260
EXPORTING 1 WHEN WE HAVE A LUCK

1416
00:53:22,260 --> 00:53:24,029
AT THIS PUBLICLY AVAILABLE

1417
00:53:24,029 --> 00:53:26,631
COHORTS, AGAIN, 2 IN LUNG AND 1

1418
00:53:26,631 --> 00:53:28,933
IN THE PROSTATE, BUT THOSE WITH

1419
00:53:28,933 --> 00:53:32,304
THE MUTATION SHOWING INCREASED

1420
00:53:32,304 --> 00:53:33,004
EXPRESSION OF CA-C7.

1421
00:53:33,004 --> 00:53:37,108
AND AGAIN, THE CELL LINES WHERE

1422
00:53:37,108 --> 00:53:38,610
WE WOULD ENACTIVATE, WERE

1423
00:53:38,610 --> 00:53:39,711
SHOWING INCREED IN SENSITIVITY

1424
00:53:39,711 --> 00:53:43,648
TO [INDISCERNIBLE] WHICH IS THE

1425
00:53:43,648 --> 00:53:45,183
C67 INHIBITORS AGAIN, SUGGESTING

1426
00:53:45,183 --> 00:53:46,351
THAT [INDISCERNIBLE] 1

1427
00:53:46,351 --> 00:53:47,986
ACTIVATION DON'T ONLY LEAD TO

1428
00:53:47,986 --> 00:53:50,121
INCREASED EXPRESSION OF IT BAH

1429
00:53:50,121 --> 00:53:51,056
ALSO INCREASED DEPENNENCY,

1430
00:53:51,056 --> 00:53:53,925
AGAIN, THIS PROVIDED A RATIONAL

1431
00:53:53,925 --> 00:53:56,728
TO INHIBIT C67, ALSO TO INHIBIT

1432
00:53:56,728 --> 00:53:58,363
TRANSFORMATION, AND IN THIS

1433
00:53:58,363 --> 00:53:59,964
CASE, THE RESULTS WERE EVEN MORE

1434
00:53:59,964 --> 00:54:00,231
STRIKING.

1435
00:54:00,231 --> 00:54:01,866
WE WERE LIKE ALL TUMORS

1436
00:54:01,866 --> 00:54:02,600
DISAPPEAR NOTHING 1 OF THE

1437
00:54:02,600 --> 00:54:04,836
MODELS WHERE WE TREATED WITH THE

1438
00:54:04,836 --> 00:54:07,105
COMBINATION, AND YOU CAN SEE

1439
00:54:07,105 --> 00:54:08,640
AGAIN, THAT EVEN IN THIS CASE,

1440
00:54:08,640 --> 00:54:13,178
LIKE THE TUMOR AND THE

1441
00:54:13,178 --> 00:54:14,612
DEVELOPMENT RESISTANCE, THAT

1442
00:54:14,612 --> 00:54:17,148
RESPONSE TO TARGETED THERAPY WAS

1443
00:54:17,148 --> 00:54:18,183
VERY DRAMATICALLY EXTENDED OVER

1444
00:54:18,183 --> 00:54:18,383
TIME.

1445
00:54:18,383 --> 00:54:20,318
AND WHEN WE ANALYZED THE TUMORS

1446
00:54:20,318 --> 00:54:24,122
OF THE EARLY MODEL FOR WHICH THE

1447
00:54:24,122 --> 00:54:24,856
COMBINATION TUMORS SURVIVE, AND

1448
00:54:24,856 --> 00:54:27,158
WE HAD A LOOK AT THE EXPRESSION

1449
00:54:27,158 --> 00:54:30,128
OF THE MARKERS, YOU OBSERVED

1450
00:54:30,128 --> 00:54:31,996
THAT A SUSPECTED [INDISCERNIBLE]

1451
00:54:31,996 --> 00:54:33,498
TARGETED THERAPY WOULD INDUCE

1452
00:54:33,498 --> 00:54:36,568
THE EXPRESSION OF AN THE MARKERS

1453
00:54:36,568 --> 00:54:42,240
BUT THIS PHENOTYPE WAS CHANGED

1454
00:54:42,240 --> 00:54:48,079
IN THE [INDISCERNIBLE].

1455
00:54:48,079 --> 00:54:51,816
AND RESULT WAS COMPARED TO THE

1456
00:54:51,816 --> 00:54:57,856
CONTROL IT WAS SUPPRESSED WITH

1457
00:54:57,856 --> 00:55:00,458
THE ENZALUTAMID, AND WE WHEN WE

1458
00:55:00,458 --> 00:55:03,561
OBSERVE WITH AN INHIBITOR, WE

1459
00:55:03,561 --> 00:55:04,562
SEE THIS PHENOTYPE IS COMPARED

1460
00:55:04,562 --> 00:55:06,331
TO AND LED US TO THE CONTROL

1461
00:55:06,331 --> 00:55:06,598
CONDITION.

1462
00:55:06,598 --> 00:55:07,866
SO SUGJOAOF THE THANKSGIVING

1463
00:55:07,866 --> 00:55:12,103
COMBINATION MAY BE ABLE TO

1464
00:55:12,103 --> 00:55:13,271
REALLY SUPPRESS [INDISCERNIBLE]

1465
00:55:13,271 --> 00:55:13,638
TRANSFORMATION.

1466
00:55:13,638 --> 00:55:14,973
IN ORDER TO LOOK FOR THE

1467
00:55:14,973 --> 00:55:21,513
MECHANISM FOR THIS, WE OBSERVED

1468
00:55:21,513 --> 00:55:24,883
THAT ENZALUTAHAD MID WOULD

1469
00:55:24,883 --> 00:55:25,917
INHIBIT MYC, AND ALSO

1470
00:55:25,917 --> 00:55:27,218
[INDISCERNIBLE] AS WE MENTIONED

1471
00:55:27,218 --> 00:55:30,622
AND WE OBSERVED THAT SIMILARLY

1472
00:55:30,622 --> 00:55:33,792
IS A INHIBITOR WOULD ABROGATE

1473
00:55:33,792 --> 00:55:36,428
THE EXPRESSION OF MYC IN BOTH

1474
00:55:36,428 --> 00:55:37,962
MODELS OF TRANSFORMATION THAT WE

1475
00:55:37,962 --> 00:55:38,196
TESTED.

1476
00:55:38,196 --> 00:55:40,698
AND AFTER HAVING A LOOK AT THE

1477
00:55:40,698 --> 00:55:43,268
EXPRESSION LEVELS OF THE MRNA OF

1478
00:55:43,268 --> 00:55:44,736
MYC, WE SAID THERE WERE REALLY

1479
00:55:44,736 --> 00:55:45,770
NO DIFFERENCES SUGGIESTING THAT

1480
00:55:45,770 --> 00:55:49,741
THE DOWN REGULATION OF MYC WAS

1481
00:55:49,741 --> 00:55:53,178
NOT DUE TO TRANSCRIPTIONAL

1482
00:55:53,178 --> 00:55:54,913
CHANGES BUT RATHER POST

1483
00:55:54,913 --> 00:55:56,614
TRANSLATIONAL MODIFICATIONS SO

1484
00:55:56,614 --> 00:55:58,817
WE KNEW THAT MYC WAS MOSTLY

1485
00:55:58,817 --> 00:55:59,884
[INDISCERNIBLE] IN THE

1486
00:55:59,884 --> 00:56:00,952
PROTEOSOME, SO WE DECIDE TO

1487
00:56:00,952 --> 00:56:02,787
STUDY THE ACTIVATION OF THE

1488
00:56:02,787 --> 00:56:06,591
PROTEOSOME IN CELL LINES WHERE

1489
00:56:06,591 --> 00:56:07,826
C-CELL WAS INHIBITED.

1490
00:56:07,826 --> 00:56:09,961
SO WHAT WE OBSERVE IS THAT IN 2

1491
00:56:09,961 --> 00:56:10,929
DIFFERENT CELL LINES, 1 FROM THE

1492
00:56:10,929 --> 00:56:13,531
LUNG AND 1 FROM THE PROOF

1493
00:56:13,531 --> 00:56:16,234
THEASTY, WHEN YOU INHIBIT C67

1494
00:56:16,234 --> 00:56:19,671
EITHER BY USING CANNED WHAT OR

1495
00:56:19,671 --> 00:56:21,439
BY KNOCKING OUT C67 BY

1496
00:56:21,439 --> 00:56:23,107
IDENTIFICATION, WE OBSERVED IT

1497
00:56:23,107 --> 00:56:24,676
WAS INCREASED ACTIVATION OF THE

1498
00:56:24,676 --> 00:56:25,743
PROTEIN COMPLEXIOSOME.

1499
00:56:25,743 --> 00:56:28,146
SO WE SUGGIEST THAD THIS

1500
00:56:28,146 --> 00:56:38,323
ACTIVATION OF THE  PROTEIN

1501
00:56:38,323 --> 00:56:40,358
COMPLEXIOSOME, AND WE OBSERVED

1502
00:56:40,358 --> 00:56:42,560
THAT IN THE CONTROL THERE WAS NO

1503
00:56:42,560 --> 00:56:44,329
SIGNIFICANT EXPRESSION OF

1504
00:56:44,329 --> 00:56:45,363
NEURONAL MARKERS, TARGETED

1505
00:56:45,363 --> 00:56:46,097
THERAPY WOULD INDUCE THE

1506
00:56:46,097 --> 00:56:51,636
EXPRESSION OF THESE MARKERS,

1507
00:56:51,636 --> 00:56:52,770
TREATMENT WITH THIS PHENOTYPE

1508
00:56:52,770 --> 00:56:56,741
BUT THEN WHEN WE WOULD

1509
00:56:56,741 --> 00:56:57,675
OVEREXPRESS AN [INDISCERNIBLE]

1510
00:56:57,675 --> 00:57:04,816
MYC THAT IS RESISTANT TO THE

1511
00:57:04,816 --> 00:57:06,184
[INDISCERNIBLE] PROTEOSOME, AND

1512
00:57:06,184 --> 00:57:10,421
THIS IS THE MECHANISM BY WHICH

1513
00:57:10,421 --> 00:57:17,462
C87 IS PREVENTING 

1514
00:57:17,462 --> 00:57:21,866
TRANSFORMATION, SO BASICALLY, IT

1515
00:57:21,866 --> 00:57:23,735
INCREASES THE GENE, AND

1516
00:57:23,735 --> 00:57:25,103
ULTIMATELY LEADING TO

1517
00:57:25,103 --> 00:57:26,204
TRANSFORMATION BUT WHEN WE

1518
00:57:26,204 --> 00:57:29,874
COMBINE TARGETED THERAPY WITH A

1519
00:57:29,874 --> 00:57:32,644
INHIBITORS WE OVERACTIVATE THE

1520
00:57:32,644 --> 00:57:34,979
PROTEOSOME, AND WE INTEGRATE MYC

1521
00:57:34,979 --> 00:57:37,782
AND THE CELLS TRANSFORM AND THEY

1522
00:57:37,782 --> 00:57:40,251
BASICALLY ARE ABLE TO RESPOND TO

1523
00:57:40,251 --> 00:57:42,787
TARGETED THERAPY FOR A LONGER

1524
00:57:42,787 --> 00:57:46,090
TIME AND POTENTIALLY UNDER GO

1525
00:57:46,090 --> 00:57:47,091
[INDISCERNIBLE] RESISTANCE THAT

1526
00:57:47,091 --> 00:57:48,426
WAS PROBABLY LESS AGGRESSIVE

1527
00:57:48,426 --> 00:57:52,196
THAN SMALL CELL TRANSFORMATION.

1528
00:57:52,196 --> 00:57:57,702
AND AS A TAKE HOME MESSAGE,

1529
00:57:57,702 --> 00:57:59,837
[INDISCERNIBLE] BUT IT IS WHAT

1530
00:57:59,837 --> 00:58:00,438
IT IS.

1531
00:58:00,438 --> 00:58:03,575
SO WE OBSERVED THAT POTENTIALLY,

1532
00:58:03,575 --> 00:58:06,644
ADEN O CARCINOMA MAY UNDERGO

1533
00:58:06,644 --> 00:58:08,947
INTERMEDIARY STATE THAT IS MORE

1534
00:58:08,947 --> 00:58:10,248
PLASTIC AND TARGETED THERAPY MAY

1535
00:58:10,248 --> 00:58:11,883
BE ABLE TO INTIEWS THIS STATE

1536
00:58:11,883 --> 00:58:15,186
TOGETHER WITH THE OCCURRENCE OF

1537
00:58:15,186 --> 00:58:17,555
DIFFERENT MOLECULAR ALTERATIONS,

1538
00:58:17,555 --> 00:58:19,958
THISITATE IS CHARACTERIZED BY

1539
00:58:19,958 --> 00:58:21,993
SUPPRESSIONAL IMMUNE RESPONSE

1540
00:58:21,993 --> 00:58:24,729
AND UPREGULATION PATHWAYS LIKE

1541
00:58:24,729 --> 00:58:28,733
AKT AND MYC AND THEN

1542
00:58:28,733 --> 00:58:29,467
ADDITIONALLY OTHER ALTERATIONS

1543
00:58:29,467 --> 00:58:30,368
MAY LEAD TO DIFFERENT FATE.

1544
00:58:30,368 --> 00:58:33,571
BUT AGAIN THIS IS NOT USUALLY AS

1545
00:58:33,571 --> 00:58:40,111
EASY AS IT SEEMS. 

1546
00:58:40,111 --> 00:58:41,412
ADEN O CARCINOMA LOOK

1547
00:58:41,412 --> 00:58:42,146
[INDISCERNIBLE] CARCINOMA AND

1548
00:58:42,146 --> 00:58:49,087
YOU SEE SOME DEGREE OF THE

1549
00:58:49,087 --> 00:58:51,556
UNITY; THESE INCREASE

1550
00:58:51,556 --> 00:58:52,156
TRANSCRIPTOMIC HETEROGENEITY,

1551
00:58:52,156 --> 00:58:55,727
EVEN THOUGH THEY LOOK LIKE

1552
00:58:55,727 --> 00:58:57,495
SQUAMOUS CELL CARCINOMA OR

1553
00:58:57,495 --> 00:59:00,999
[INDISCERNIBLE], AND WE SEE THE

1554
00:59:00,999 --> 00:59:01,799
INCREASED [INDISCERNIBLE] IN THE

1555
00:59:01,799 --> 00:59:05,103
PROFILES AND MAYBE THESE

1556
00:59:05,103 --> 00:59:05,603
ADDITIONAL MOLECULAR

1557
00:59:05,603 --> 00:59:06,404
[INDISCERNIBLE] PUSH TOWARDS SO

1558
00:59:06,404 --> 00:59:11,242
IT MAY MAKE THAT THE CELLS WE

1559
00:59:11,242 --> 00:59:13,878
THINK ALL THAT MAY MAKE BRIEF

1560
00:59:13,878 --> 00:59:15,413
SPECIFIC PHENOTYPE IN THIS CASE,

1561
00:59:15,413 --> 00:59:16,614
IN THIS CASE, SQUAMOUS SORE

1562
00:59:16,614 --> 00:59:17,982
SMALL CELL, IN THE CASE OF

1563
00:59:17,982 --> 00:59:19,384
SQUAMOUS SARS INFECTION NOAMA,

1564
00:59:19,384 --> 00:59:22,520
IT SEEMS THAT AKT INHIBITION OR

1565
00:59:22,520 --> 00:59:25,156
MYC MAY BE ABLE TOW PREVEBT

1566
00:59:25,156 --> 00:59:26,324
TRANSORMATION TO SQUAMOUS AND IN

1567
00:59:26,324 --> 00:59:30,495
THE CASE OF SMALL CELL,

1568
00:59:30,495 --> 00:59:31,663
[INDISCERNIBLE] MIGHT BE

1569
00:59:31,663 --> 00:59:32,864
INTERESTING THERAPEUTIC TARGETS

1570
00:59:32,864 --> 00:59:33,965
FOR THIS.

1571
00:59:33,965 --> 00:59:36,834
AND VERY IMPORTANT, SINCE THAT

1572
00:59:36,834 --> 00:59:40,371
MUTATION IS AKT AND AB

1573
00:59:40,371 --> 00:59:42,006
PATHWAY,--RB PATHWAY MAY BE ABLE

1574
00:59:42,006 --> 00:59:44,575
TO PREDICT THOSE PATIENTS THAT

1575
00:59:44,575 --> 00:59:45,943
ARE HIGH RISK TO SQUAMOUS.

1576
00:59:45,943 --> 00:59:47,545
SO WITH THAT I WOULD LIKE TO

1577
00:59:47,545 --> 00:59:50,314
ACKNOWLEDGE ALL MY AMAZING LAB

1578
00:59:50,314 --> 00:59:52,050
MEMBERS AND COLLABORATORS FROM

1579
00:59:52,050 --> 00:59:54,018
MSK AND THE BROAD.

1580
00:59:54,018 --> 00:59:58,656
AND ALSO PATIENTS AND FAMILIES

1581
00:59:58,656 --> 01:00:00,491
FOR THEIR CONSENTING TO SHARE

1582
01:00:00,491 --> 01:00:01,993
THEIR CLINICAL SPECIMENS FOR US

1583
01:00:01,993 --> 01:00:03,995
TO DO TUMOR ANALYSIS AND TO MY

1584
01:00:03,995 --> 01:00:07,298
FRIENDS FAMILY AND MENTORS

1585
01:00:07,298 --> 01:00:07,932
INCLUDING [INDISCERNIBLE] THAT

1586
01:00:07,932 --> 01:00:09,701
CAME HERE FOR SUPPORT AND OF

1587
01:00:09,701 --> 01:00:13,271
COURSE ALL THE FUNDING SOURCES.

1588
01:00:13,271 --> 01:00:15,006
SO HAPPY TO TAKE ANY QUESTIONS,

1589
01:00:15,006 --> 01:00:16,307
THANK YOU SO MUCH FOR YOUR

1590
01:00:16,307 --> 01:00:23,147
ATTENTION. .

1591
01:00:23,147 --> 01:00:33,357
[ APPLAUSE ]

1592
01:00:35,893 --> 01:00:37,795
>> THANKS A LOT THAT WAS
QUITE A

1593
01:00:37,795 --> 01:00:39,997
TOUR DEFORCE, AND I HAD A COUPLE

1594
01:00:39,997 --> 01:00:41,599
QUESTIONS ABOUT THE LAST PART.

1595
01:00:41,599 --> 01:00:47,271
YOU KNOW I HAVE AN INTEREST IN

1596
01:00:47,271 --> 01:00:47,872
NEUROENDOCRINE TRANSFORMATION,

1597
01:00:47,872 --> 01:00:50,174
YOU, IN THE MODELS WHERE YOU

1598
01:00:50,174 --> 01:00:51,943
ACTUALLY TREATED THE TUMORS,

1599
01:00:51,943 --> 01:00:53,878
SOME OF THE COMBINATIONS

1600
01:00:53,878 --> 01:00:56,547
ACTUALLY SHOWED VERY GOOD

1601
01:00:56,547 --> 01:00:57,782
ESPECIALLY EXPORT INHIBITOR FOR

1602
01:00:57,782 --> 01:00:59,450
LIKE 77 DAYS BUT THEN YOU HAD

1603
01:00:59,450 --> 01:01:02,754
RELAPSE, AND YOU IMPLICATED THAT

1604
01:01:02,754 --> 01:01:03,955
THE RELAPSE THROUGH MODELING

1605
01:01:03,955 --> 01:01:07,291
WITH SOX 2, DID YOU SEE SOX 2

1606
01:01:07,291 --> 01:01:09,927
REEXPRESSION IN THE RELAPSED

1607
01:01:09,927 --> 01:01:11,295
TUMORS FROM THAT--THOSE

1608
01:01:11,295 --> 01:01:11,662
EXPERIMENTS?

1609
01:01:11,662 --> 01:01:12,830
>> WE DIDN'T SPECIFICALLY
HAVE A

1610
01:01:12,830 --> 01:01:17,235
LOOK AT THAT BUT WE HAVE STUDIED

1611
01:01:17,235 --> 01:01:18,402
THAT THOSE TUMORS BECAUSE WHEN

1612
01:01:18,402 --> 01:01:21,305
WE ANALYZE THE TUMORS FOR

1613
01:01:21,305 --> 01:01:22,440
ENDOCRINE MARKERS THOSE WERE AT

1614
01:01:22,440 --> 01:01:23,641
END POINT SO THEY WOULD REGROW

1615
01:01:23,641 --> 01:01:27,111
AND THEY WERE NOT REALLY SHOWING

1616
01:01:27,111 --> 01:01:28,479
ENDOCRINE PHENOTYPE SO I WOULD

1617
01:01:28,479 --> 01:01:30,014
ASSUME THAT SOX MIGHT NOT HAVE

1618
01:01:30,014 --> 01:01:30,982
BEEN ON OVEREXPRESSED BUT WE

1619
01:01:30,982 --> 01:01:33,084
DIDN'T REALLY HAVE A LOOK AT IT.

1620
01:01:33,084 --> 01:01:34,786
>> OKAY, BECAUSE I JUST
THINK

1621
01:01:34,786 --> 01:01:37,188
THAT IF THE MODEL IS PREDICTING

1622
01:01:37,188 --> 01:01:40,291
WHAT WOULD GO ON IN THE PATIENT

1623
01:01:40,291 --> 01:01:41,926
YOU KNOW YOU MAY BE ABLE TO SEE

1624
01:01:41,926 --> 01:01:44,028
IT JUST BY THE TREATMENTS YOU

1625
01:01:44,028 --> 01:01:44,228
GIVE.

1626
01:01:44,228 --> 01:01:46,430
THE RESISTANCE WOULD GIVE YOU

1627
01:01:46,430 --> 01:01:48,733
CLUES AS TO WHAT WOULD RELAPSE.

1628
01:01:48,733 --> 01:01:49,100
>> EXACTLY.

1629
01:01:49,100 --> 01:01:50,468
IT WOULD BE INTERESTING TO LOOK

1630
01:01:50,468 --> 01:01:52,804
AT THOSE TUMORS AND SEE HOW THEY

1631
01:01:52,804 --> 01:01:53,371
BECAME A RESISTANT.

1632
01:01:53,371 --> 01:01:54,438
>> AND I HAVE A GENERAL
QUESTION

1633
01:01:54,438 --> 01:01:55,840
THAT YOU CAN ANSWER AT THE END

1634
01:01:55,840 --> 01:01:57,708
OF THE SCIENTIFIC QUESTIONS,

1635
01:01:57,708 --> 01:02:01,112
YOU'VE HAD AN EXTREMELY

1636
01:02:01,112 --> 01:02:11,589
SUCCESSFUL YOU KNOW TRAINING

1637
01:02:13,124 --> 01:02:14,192
EXPERIENCE AND WHAT DID YOU

1638
01:02:14,192 --> 01:02:16,861
KNOWLEDGE WAS THE KEY TO YOUR

1639
01:02:16,861 --> 01:02:17,328
SUCCESS?

1640
01:02:17,328 --> 01:02:19,597
>> SO I THINK I WAS
LACKING NOT

1641
01:02:19,597 --> 01:02:21,666
TO LIKE LAND IN A LAB WHERE

1642
01:02:21,666 --> 01:02:23,634
THERE WERE A LOT OF RESOURCES.

1643
01:02:23,634 --> 01:02:26,070
WE WERE VERY SPOILED, WE

1644
01:02:26,070 --> 01:02:28,573
WOULDN'T DO OUR IN VIVO SPRMS

1645
01:02:28,573 --> 01:02:30,408
OURSELVES, FOR EXAMPLE, LIKE

1646
01:02:30,408 --> 01:02:31,375
[INDISCERNIBLE], SO THAT WAS

1647
01:02:31,375 --> 01:02:34,846
[INDISCERNIBLE] SOMETHING ELSE

1648
01:02:34,846 --> 01:02:39,116
AND THAT'S HOW MANY IN OUR LAB

1649
01:02:39,116 --> 01:02:41,986
LOOKED TO BE MORE PRODUCTIVE.

1650
01:02:41,986 --> 01:02:43,621
THERE'S NO REAL SECRET, I AM

1651
01:02:43,621 --> 01:02:45,022
ABLE TO TAKE SEVERAL APPROACH AT

1652
01:02:45,022 --> 01:02:46,991
THE SAME TIME IF YOU CAN DO THAT

1653
01:02:46,991 --> 01:02:48,259
THAT'S ALWAYS A GOOD IDEA

1654
01:02:48,259 --> 01:02:50,528
BECAUSE IF YOU PUT YOUR EGGS

1655
01:02:50,528 --> 01:02:52,630
ONLY IN 1 BASK, IF THAT DOESN'T

1656
01:02:52,630 --> 01:02:53,698
WORK THEN YOU'RE SCREWED BUT YOU

1657
01:02:53,698 --> 01:02:57,568
HAVE A FEW THEN, PARTICULARLY

1658
01:02:57,568 --> 01:03:00,171
SOME PLAN B, SOMETHING THAT'S

1659
01:03:00,171 --> 01:03:02,907
GOING TO BE PUBLICKED NO MATTER

1660
01:03:02,907 --> 01:03:04,909
WHAT, SO MAYBE LESS RISK, LOWER

1661
01:03:04,909 --> 01:03:06,677
REWARD BUT GETS YOU A PAPER,

1662
01:03:06,677 --> 01:03:08,312
THAT'S NIGHT TO HAVE THAT AS A

1663
01:03:08,312 --> 01:03:13,784
BACK UP PLAN.

1664
01:03:13,784 --> 01:03:14,151
>> THANK YOU.

1665
01:03:14,151 --> 01:03:16,053
NTHANK YOU VERY MUCH FOR YOUR

1666
01:03:16,053 --> 01:03:16,888
TALK.

1667
01:03:16,888 --> 01:03:18,723
I'M ELAINE JAFFE, I WORK ON

1668
01:03:18,723 --> 01:03:20,157
LYMPHOMA NOT LUNG CANCER BUT

1669
01:03:20,157 --> 01:03:22,894
I'VE ALSO BEEN INTERESTED IN

1670
01:03:22,894 --> 01:03:25,963
TRANSDIFFERENTIATION AND LINEAGE

1671
01:03:25,963 --> 01:03:30,401
PLASTICITY AND MAINLY B-CELL

1672
01:03:30,401 --> 01:03:32,370
LYMPHOMAS WHICH CAN UNDERGO

1673
01:03:32,370 --> 01:03:33,537
TRANSFORMATIONS FOR ACIDIC TUMOR

1674
01:03:33,537 --> 01:03:36,240
ONS AND IN THE LYMPHOMAS WE'VE

1675
01:03:36,240 --> 01:03:40,044
STUDIED, YOU CAN--WE CAN SEE

1676
01:03:40,044 --> 01:03:40,978
TRANSDIFFERENTIATION EVEN BEFORE

1677
01:03:40,978 --> 01:03:42,513
ANY THERAPY SO IT'S NOT

1678
01:03:42,513 --> 01:03:44,482
NECESSARILY DRIIVE BY THERAPY,

1679
01:03:44,482 --> 01:03:48,085
SUGGESTING THAT THE CELLS THAT

1680
01:03:48,085 --> 01:03:50,354
PROMOTE THAT ARE LAWYER THERE,

1681
01:03:50,354 --> 01:03:51,889
AND ACTUALLY IN SOME STUDIES YOU

1682
01:03:51,889 --> 01:03:53,658
CAN SHOW THAT PARTICULARLY IN

1683
01:03:53,658 --> 01:03:55,059
FOLLICULAR LYMPHOMA, THE

1684
01:03:55,059 --> 01:03:58,829
IMENETTIC PROFILE OF THE

1685
01:03:58,829 --> 01:04:00,564
TRANSDIFFERENTIATED CELL, IS

1686
01:04:00,564 --> 01:04:02,500
ACTUALLY CLOSELY RELATED TO A

1687
01:04:02,500 --> 01:04:06,771
BONE MARROW STEM CELL, SO IT WAS

1688
01:04:06,771 --> 01:04:08,839
PROBABLY THERE VERY EARLY IN

1689
01:04:08,839 --> 01:04:10,474
TUMOR INITIATION AND I WONDER IF

1690
01:04:10,474 --> 01:04:13,878
YOU'VE SEEN ANYTHING LIKE THAT,

1691
01:04:13,878 --> 01:04:16,080
MODEL IN THE LUNG TUMORS?

1692
01:04:16,080 --> 01:04:19,283
>> SO WE DO SEE MANY CASES
WITH

1693
01:04:19,283 --> 01:04:21,352
TRANSFORMATION, OF COURSE

1694
01:04:21,352 --> 01:04:23,487
SPONTANEOUSLY WITHOUT TREATMENT,

1695
01:04:23,487 --> 01:04:26,123
AND THOSE CASES ARE ADEN O

1696
01:04:26,123 --> 01:04:27,992
SQUAMOUS TUMORS AND A SQUAMOUS

1697
01:04:27,992 --> 01:04:29,293
COMPONENT BUT ALSO COMBINE ADEN

1698
01:04:29,293 --> 01:04:32,530
O SMALL CELL TUMORS, SO IT'S

1699
01:04:32,530 --> 01:04:33,431
DEFINITELY OCCURRED AND WE'VE

1700
01:04:33,431 --> 01:04:35,333
ALSO LIST THOSE TUMORS FOR OUR

1701
01:04:35,333 --> 01:04:36,600
ANALYSIS BECAUSE IT'S HARD TO

1702
01:04:36,600 --> 01:04:38,669
GET THIS PREAND POST

1703
01:04:38,669 --> 01:04:39,837
TRANSFORMATION SAMPLES AND IN

1704
01:04:39,837 --> 01:04:43,808
THE END, I THINK THAT WHAT

1705
01:04:43,808 --> 01:04:46,177
TRANSFORMATION IS THE SERIOUS OF

1706
01:04:46,177 --> 01:04:47,878
MOLECULAR EVENTS AND THOSE MAY

1707
01:04:47,878 --> 01:04:50,181
OCCUR IN THE [INDISCERNIBLE]

1708
01:04:50,181 --> 01:04:50,448
TREATMENT.

1709
01:04:50,448 --> 01:04:52,383
IT IS TRUE THAT AS FAR AS WE

1710
01:04:52,383 --> 01:04:55,319
HAVE SEEN OUR MODELS, THE

1711
01:04:55,319 --> 01:04:57,755
TARGETED THERAPY, BASICALLY

1712
01:04:57,755 --> 01:04:59,357
POTENTIATING OR ACCELERATES

1713
01:04:59,357 --> 01:05:03,060
TRANSFORMATION BASICALLY BY

1714
01:05:03,060 --> 01:05:05,062
INHIBITING THE MOLECULAR

1715
01:05:05,062 --> 01:05:06,430
PATHWAYINGS THAT DETERMINE THE

1716
01:05:06,430 --> 01:05:07,598
ADEN O CARCINOMA STATE, BUT THAT

1717
01:05:07,598 --> 01:05:10,534
DOESN'T MEAN THAT THERE'S OTHER

1718
01:05:10,534 --> 01:05:11,869
MEANS BY WHICH THOSE PATHWAYS

1719
01:05:11,869 --> 01:05:16,140
MIGHT BE DOWN REGULATED SO

1720
01:05:16,140 --> 01:05:19,910
BASICALLY, I THINK THAT X,

1721
01:05:19,910 --> 01:05:21,712
Y,-POTENTIAL WILL GIVE YOU A

1722
01:05:21,712 --> 01:05:23,481
DIFFERENT TUMOR IF THEY DMR

1723
01:05:23,481 --> 01:05:24,849
WHATEVER CONTEXT, NO MATTER

1724
01:05:24,849 --> 01:05:30,588
WHETHER IT'S A STEM SOLE OR

1725
01:05:30,588 --> 01:05:30,855
CARCINOMA.

1726
01:05:30,855 --> 01:05:33,057
>> THANK YOU.

1727
01:05:33,057 --> 01:05:39,730
>> HI, TELENT 
TELE--EXCELLENT I

1728
01:05:39,730 --> 01:05:41,399
HAVE 2 QUESTIONS FOR YOU, THE

1729
01:05:41,399 --> 01:05:42,833
FIRST QUESTION IS WHAT DO YOU

1730
01:05:42,833 --> 01:05:43,868
SEE PLASTICITY IN THE SENSE,

1731
01:05:43,868 --> 01:05:46,303
WHAT DETBREE, I SHOULD SAY DO

1732
01:05:46,303 --> 01:05:48,372
YOU SEE HETEROGENEITY IN THE

1733
01:05:48,372 --> 01:05:49,573
PLASTICITY THAT YOU SEE WHERE,

1734
01:05:49,573 --> 01:05:52,676
YOU KNOW YOU'RE SHOWING US LIKE

1735
01:05:52,676 --> 01:05:54,512
DEFINITELY KIND OF A LINEAR

1736
01:05:54,512 --> 01:05:55,780
TRANSFORMATION, IT'S PROBABLY

1737
01:05:55,780 --> 01:05:58,215
NOT LINEAR, IT'S CIRCULAR, BUT

1738
01:05:58,215 --> 01:05:59,617
ANYWAY, HAPPENING, CIRCULAR

1739
01:05:59,617 --> 01:06:01,152
LITTLE BALL HAPPENING OVER TIME,

1740
01:06:01,152 --> 01:06:03,354
BUT TO WHAT EXTENT ARE THERE

1741
01:06:03,354 --> 01:06:06,390
DIFFERENCES WITHIN THE CELL

1742
01:06:06,390 --> 01:06:07,458
POPULATIONS THAT YOU'VE EXAMINED

1743
01:06:07,458 --> 01:06:08,859
IN THAT WAY, AND THEN I WILL GET

1744
01:06:08,859 --> 01:06:10,194
TO MY SECOND QUESTION.

1745
01:06:10,194 --> 01:06:12,596
>> SO WE HAVEN'T HAD A
LOOK AT

1746
01:06:12,596 --> 01:06:13,798
THE [INDISCERNIBLE] YET, WE ARE

1747
01:06:13,798 --> 01:06:19,603
DOING THAT NOW, I THINK  OUR

1748
01:06:19,603 --> 01:06:21,405
SPECIMEN IS IN TRANSFORM EGG, SO

1749
01:06:21,405 --> 01:06:23,240
THESE ARE THE IMMUNO DEFICIENT

1750
01:06:23,240 --> 01:06:24,975
MODELS BUT WE HAVE SOME VERY

1751
01:06:24,975 --> 01:06:26,277
INTERESTING IMAGES WHERE WE SEE

1752
01:06:26,277 --> 01:06:29,380
FOR EXAMPLE, A COMBINED ADEN O

1753
01:06:29,380 --> 01:06:32,116
SMALL CELL TUMORS, YOU SEE THAT

1754
01:06:32,116 --> 01:06:33,651
THE CARCINOMA PORTION IS FILL

1755
01:06:33,651 --> 01:06:37,788
WIDE IMMUNE CELLS AND THEN THE

1756
01:06:37,788 --> 01:06:39,890
LITTLE SPACE THAT IS SMALL IS

1757
01:06:39,890 --> 01:06:41,659
COMPLETELY EMPTY, SO I BEING I

1758
01:06:41,659 --> 01:06:45,930
WAS DISCUSSING THAT PREVIOUSLY

1759
01:06:45,930 --> 01:06:46,864
LIKE, THIS TRANSFORMATION MAY

1760
01:06:46,864 --> 01:06:48,365
GIVE US HINTS ABOUT HOW SMALL

1761
01:06:48,365 --> 01:06:53,671
CELL FOR EXAMPLE IS ABLE TO LIKE

1762
01:06:53,671 --> 01:06:54,839
REPRESS THE [INDISCERNIBLE] OF

1763
01:06:54,839 --> 01:06:56,740
IMMUNE CELLS OR THE IMMUNO

1764
01:06:56,740 --> 01:06:58,175
PHENOTYPE BECAUSE DURING THIS

1765
01:06:58,175 --> 01:06:58,976
PROCESS OF TRANSFORMATION, YOU

1766
01:06:58,976 --> 01:07:02,046
SEE THAT THERE'S A LOT OF

1767
01:07:02,046 --> 01:07:03,914
PATHWAYS THAT ARE DRIVEN TO

1768
01:07:03,914 --> 01:07:05,416
IMMUNE PATHWAYS TO SUPPRESS BUT

1769
01:07:05,416 --> 01:07:07,852
WE DONT KNOW YET HOW THAT

1770
01:07:07,852 --> 01:07:09,753
HAPPENS.

1771
01:07:09,753 --> 01:07:10,054
>> RIGHT.

1772
01:07:10,054 --> 01:07:11,055
SO MY SECOND QUESTION IS RELATED

1773
01:07:11,055 --> 01:07:12,790
TO THAT SO NORMALLY WE SPEND A

1774
01:07:12,790 --> 01:07:14,225
LOT OF TIME IN MY LAB AND WE

1775
01:07:14,225 --> 01:07:15,726
THINK ABOUT TUMOR AND

1776
01:07:15,726 --> 01:07:16,660
MICROENVIRONMENT CROSS TALK AND

1777
01:07:16,660 --> 01:07:19,196
HOW THEY'RE SHAPING BUT THE

1778
01:07:19,196 --> 01:07:20,364
OTHER MICROENVIRONMENT IS THE

1779
01:07:20,364 --> 01:07:21,799
MICROENVIRONMENT OF THE TUMOR

1780
01:07:21,799 --> 01:07:22,666
CELL POPULATION, SO I'M TALKING

1781
01:07:22,666 --> 01:07:24,735
ABOUT IF WE WERE THE TUMOR AND

1782
01:07:24,735 --> 01:07:26,637
WE WERE ALL TUMOR CELLS IN HERE,

1783
01:07:26,637 --> 01:07:27,771
I AM VERY DIFFERENT THAN PICK

1784
01:07:27,771 --> 01:07:29,240
ANYBODY ELSE BECAUSE I'M VERY

1785
01:07:29,240 --> 01:07:30,441
DIFFERENT THAN ANYBODY ELSE

1786
01:07:30,441 --> 01:07:31,809
HERE, EVERYBODY'S DIFFERENT THAB

1787
01:07:31,809 --> 01:07:33,444
EVERYBODY ELSE, THAT'S ITS OWN

1788
01:07:33,444 --> 01:07:34,478
LITTLE MICROENVIRONMENT, AND

1789
01:07:34,478 --> 01:07:37,148
EVERYBODY THINKS OF IT AS VERY

1790
01:07:37,148 --> 01:07:40,117
ANTAGONISTIC I WOULD SAY LIKE

1791
01:07:40,117 --> 01:07:41,051
SURVIVAL OF THE FITTEST, LIKE I

1792
01:07:41,051 --> 01:07:42,586
WILL GET A GRANT THEREFORE THIS

1793
01:07:42,586 --> 01:07:46,690
PERSON'S NOT GOING TO--THAT'S A

1794
01:07:46,690 --> 01:07:49,326
JOKE BECAUSE OBVIOUS 3 THAT'S

1795
01:07:49,326 --> 01:07:50,194
NOT HAPPENING.

1796
01:07:50,194 --> 01:07:50,461
[LAUGHTER]

1797
01:07:50,461 --> 01:07:51,529
BUT ANYWAY, SOMEBODY EVERY THERE

1798
01:07:51,529 --> 01:07:53,264
MAY NOT GET A GRANT BUT MAYBE

1799
01:07:53,264 --> 01:07:55,599
IT'S WHEN I GET THE GRANT, HE

1800
01:07:55,599 --> 01:07:57,101
LOOKS REAL GOOD AND THEN HE WILL

1801
01:07:57,101 --> 01:07:59,537
GET THE NEXT GRANT, SO THERE'S

1802
01:07:59,537 --> 01:08:00,337
COOPERATIVITY WITH THE

1803
01:08:00,337 --> 01:08:02,039
MICROENVIRONMENT THAT COULD

1804
01:08:02,039 --> 01:08:04,341
HAPPEN EVEN AMONG THE TUMOR, AND

1805
01:08:04,341 --> 01:08:05,743
PEOPLE DON'T THINK OF THE

1806
01:08:05,743 --> 01:08:09,914
MICROENVIRONMENT THIS WAY BUT

1807
01:08:09,914 --> 01:08:11,448
IT'S THE SAME BIOLOGY.

1808
01:08:11,448 --> 01:08:13,184
>> I SHOWED HERE OUR

1809
01:08:13,184 --> 01:08:15,853
[INDISCERNIBLE] STUDIES COMBINED

1810
01:08:15,853 --> 01:08:19,657
SMALL CELL AND AND AS YOU CAN

1811
01:08:19,657 --> 01:08:20,157
SEE, THE NONSMALL CELL

1812
01:08:20,157 --> 01:08:20,658
COMOPPOSITE BEHAVIORIAL

1813
01:08:20,658 --> 01:08:21,759
PHENOTYPE SENT MINIMAL, IT'S

1814
01:08:21,759 --> 01:08:23,961
LIKE AROUND 5% AND YOU HAVE THAT

1815
01:08:23,961 --> 01:08:28,933
PDX THAT IS PASSAGE OVER MANY

1816
01:08:28,933 --> 01:08:30,734
MICE, AND THAT NONNEURONAL

1817
01:08:30,734 --> 01:08:32,203
COMPONENT STAYS THERE, SO THAT

1818
01:08:32,203 --> 01:08:34,205
SUGGESTS THERE MY BE INTERACTION

1819
01:08:34,205 --> 01:08:35,839
BETWEEN THE CARCINOMA AND SMALL

1820
01:08:35,839 --> 01:08:38,442
CELL COMPONENTS AND THIS IS

1821
01:08:38,442 --> 01:08:40,611
ACTUALLY OTHER DATA IN SMALL

1822
01:08:40,611 --> 01:08:41,912
CELL TUMORS WHERE 2 DIFFERENT

1823
01:08:41,912 --> 01:08:43,080
POPULATIONS HAVE BEEN LIKE

1824
01:08:43,080 --> 01:08:45,049
IDENTIFIED AND 1 OF THEM THAT

1825
01:08:45,049 --> 01:08:46,550
YOU GO INVITRO AND IT LIKE

1826
01:08:46,550 --> 01:08:48,052
STICKS TO THE PLATE AND THE

1827
01:08:48,052 --> 01:08:49,687
OTHER 1 IS LIKE FLEETING AND THE

1828
01:08:49,687 --> 01:08:52,089
FLOATING 1 IS MORE NEUROI HAD

1829
01:08:52,089 --> 01:08:54,959
BEEN O KRIEN AND THE OTHER IS

1830
01:08:54,959 --> 01:08:57,294
MORE NEUROINDCOKRIEN AND ENT AND

1831
01:08:57,294 --> 01:08:58,996
THEY HAVE IDENTIFIED FOR

1832
01:08:58,996 --> 01:09:02,900
EXAMPLE, WHEN YOU LIKE--AND GRAB

1833
01:09:02,900 --> 01:09:05,202
THEM SEPARATELY, THE METABOLIC

1834
01:09:05,202 --> 01:09:06,170
POTENTIAL AND INDUCED, BUT WHEN

1835
01:09:06,170 --> 01:09:07,538
YOU GRAB THEM TOGETHER, THE

1836
01:09:07,538 --> 01:09:09,240
MOUSE IS FULL WITH METASTASIS.

1837
01:09:09,240 --> 01:09:11,942
AND THEY HAVE SEEN THAT 1 OF

1838
01:09:11,942 --> 01:09:12,810
THESE POPULATIONS,

1839
01:09:12,810 --> 01:09:15,512
[INDISCERNIBLE] IS ENRICHED FOR

1840
01:09:15,512 --> 01:09:16,413
RECEPTORS OF [INDISCERNIBLE],

1841
01:09:16,413 --> 01:09:17,848
WHILE THE OTHER EXPRESSES THE

1842
01:09:17,848 --> 01:09:19,583
LIGANDS SO THERE MUST BE A

1843
01:09:19,583 --> 01:09:21,318
RELATIONSHIP BETWEEN THEM BUT WE

1844
01:09:21,318 --> 01:09:24,788
DON'T KNOW, WE EXPLORE THAD IN

1845
01:09:24,788 --> 01:09:25,022
DETAIL.

1846
01:09:25,022 --> 01:09:26,090
>> WELL I CAN'T WAIT TO

1847
01:09:26,090 --> 01:09:26,390
COLLABORATE.

1848
01:09:26,390 --> 01:09:27,791
THANK YOU VERY MUCH.

1849
01:09:27,791 --> 01:09:28,626
>> THANK YOU VERY MUCH FOR
THE

1850
01:09:28,626 --> 01:09:29,026
TALK.

1851
01:09:29,026 --> 01:09:31,629
IT WAS A GREAT TAILBACK SO I'M

1852
01:09:31,629 --> 01:09:33,464
WAY BIOINFORMATICIAN, SO I HAVE

1853
01:09:33,464 --> 01:09:35,132
ALREADY, I MAY ALREADY HAVE MANY

1854
01:09:35,132 --> 01:09:36,867
QUESTIONS FOR YOU, SO MY FIRST

1855
01:09:36,867 --> 01:09:39,737
QUESTION IS THAT AS YOU HAVE

1856
01:09:39,737 --> 01:09:48,612
SAID THAT THE [INDISCERNIBLE]

1857
01:09:48,612 --> 01:09:49,680
TRANS DIFFERENTIATED

1858
01:09:49,680 --> 01:09:52,883
[INDISCERNIBLE] OR IS IT

1859
01:09:52,883 --> 01:09:54,351
UNIDIRECTIONAL OR URT, LUSC

1860
01:09:54,351 --> 01:09:56,053
TRANSFORM OR ALSO INTO YOUR

1861
01:09:56,053 --> 01:09:57,788
[INDISCERNIBLE] THAT WAS MY

1862
01:09:57,788 --> 01:09:58,922
FIRST QUESTION FOR YOU.

1863
01:09:58,922 --> 01:10:00,157
AND THE SECOND QUESTION IS THAT

1864
01:10:00,157 --> 01:10:02,960
AS YOU SAID, THERE'S GENOME IRK

1865
01:10:02,960 --> 01:10:05,496
ALTERATION IN THE RB PATHWAY AKT

1866
01:10:05,496 --> 01:10:06,597
WOULD HELP TO TRANSFORMATION

1867
01:10:06,597 --> 01:10:09,233
CANNED WHAT SO AS A

1868
01:10:09,233 --> 01:10:10,100
BIOINFORMATICIAN APPROACH, WHAT

1869
01:10:10,100 --> 01:10:11,635
KIND OF FEATURES OR DESSCRIPTORS

1870
01:10:11,635 --> 01:10:13,704
I'M LOOKING FOR SO I CAN PREDICT

1871
01:10:13,704 --> 01:10:15,673
OR DEVELOP A METHOD WHICH CAN

1872
01:10:15,673 --> 01:10:16,840
COULD TELL YOU THAT IS THE

1873
01:10:16,840 --> 01:10:21,745
PROBABILITY OF THE A CELL TO GET

1874
01:10:21,745 --> 01:10:22,179
[INDISCERNIBLE] AS

1875
01:10:22,179 --> 01:10:22,546
[INDISCERNIBLE]?

1876
01:10:22,546 --> 01:10:28,285
THOSE ARE 2 QUESTIONS.

1877
01:10:28,285 --> 01:10:28,986
[INDISCERNIBLE]

1878
01:10:28,986 --> 01:10:30,954
>> SO CAN YOU REPEAT YOUR
FIRST

1879
01:10:30,954 --> 01:10:33,424
QUESTION, I'MORRY.

1880
01:10:33,424 --> 01:10:35,492
>> SO THE FIRST QUESTION
IS ONCE

1881
01:10:35,492 --> 01:10:39,029
THE CELL GETS TRANSFORMED FROM

1882
01:10:39,029 --> 01:10:40,064
[INDISCERNIBLE], AND INTO

1883
01:10:40,064 --> 01:10:42,766
[INDISCERNIBLE], IT LOSES ITS

1884
01:10:42,766 --> 01:10:49,106
ABILITY TO BE TRANSFORMED FROM

1885
01:10:49,106 --> 01:10:50,574
[INDISCERNIBLE] TO SCLC, SO

1886
01:10:50,574 --> 01:10:53,744
THERE'S LIKE VERY RECENT DATA ON

1887
01:10:53,744 --> 01:10:57,514
THE PROCESS SETTING WHERE THEY

1888
01:10:57,514 --> 01:10:58,649
HAVE ANSWERED ANALYSIS TO WHAT I

1889
01:10:58,649 --> 01:11:00,551
HAVE SHOWN HERE AND THE ANALYSIS

1890
01:11:00,551 --> 01:11:03,887
FROM THE CARCINOMA TO THE SMALL

1891
01:11:03,887 --> 01:11:04,588
CELL, LIKE PHENOTYPES, THEY

1892
01:11:04,588 --> 01:11:09,159
OBSERVE THAT IN THE MIDDLE

1893
01:11:09,159 --> 01:11:10,627
THERE'S AN INCREASED PHENOTYPE

1894
01:11:10,627 --> 01:11:13,897
THAT MUST BE ASSOCIATED TO

1895
01:11:13,897 --> 01:11:16,166
[INDISCERNIBLE] CELL OR SQUAMOUS

1896
01:11:16,166 --> 01:11:17,468
TRANSCRIPTOMIC PROFILE.

1897
01:11:17,468 --> 01:11:19,036
SUGGEST NOTHING THIS MODEL I'M

1898
01:11:19,036 --> 01:11:21,872
SHOWING HERE THAT MIGHT BE AN

1899
01:11:21,872 --> 01:11:23,173
INTERMEDIATE, THAT MIGHT BE

1900
01:11:23,173 --> 01:11:27,878
SQUAMOUS CARCINOMA SO I DON'T

1901
01:11:27,878 --> 01:11:29,446
THINK IT'S LIKE A LINEAR

1902
01:11:29,446 --> 01:11:32,983
PROCESS, IT MIGHT BE IF LIKE AT

1903
01:11:32,983 --> 01:11:34,351
SOME POINT, CELLS REACH 1

1904
01:11:34,351 --> 01:11:37,755
CERTAIN STATE, THEY MIGHT GET

1905
01:11:37,755 --> 01:11:39,356
[INDISCERNIBLE] BUT FOR EXAMPLE,

1906
01:11:39,356 --> 01:11:41,225
LET'S SAY, TO BECOME SMALL CELL,

1907
01:11:41,225 --> 01:11:45,996
WE NEED MUTATIONS IN WHY, X OR

1908
01:11:45,996 --> 01:11:48,065
YX PATHWAYS AND IF THOSE ARE

1909
01:11:48,065 --> 01:11:50,134
[INDISCERNIBLE] MUTATION THAT IS

1910
01:11:50,134 --> 01:11:53,103
NOT REVERSIBLE THEN THEY MIGHT

1911
01:11:53,103 --> 01:11:53,871
GET [INDISCERNIBLE].

1912
01:11:53,871 --> 01:11:58,175
BUT THERE'S ALSO A POSSIBILITY

1913
01:11:58,175 --> 01:12:00,010
THERE MIGHT BE REALLY

1914
01:12:00,010 --> 01:12:01,278
DIFFERENTIATION TO PRESERVE THAT

1915
01:12:01,278 --> 01:12:03,347
AND WE HAD 1 INTERESTING PATIENT

1916
01:12:03,347 --> 01:12:07,017
IN MSK WHERE WE WOULD GET LIKE

1917
01:12:07,017 --> 01:12:08,519
LONGITUDINAL SAMPLES FROM THE

1918
01:12:08,519 --> 01:12:11,455
[INDISCERNIBLE], THIS WAS A

1919
01:12:11,455 --> 01:12:12,089
TRANSFORMATION CASE AND

1920
01:12:12,089 --> 01:12:13,223
EVERYTHING WE WOULD GET A NEW

1921
01:12:13,223 --> 01:12:14,958
SAMPLE FROM HER IN A DIFFERENT

1922
01:12:14,958 --> 01:12:18,762
TIME POINT IT WOULD LOOK LIKE A

1923
01:12:18,762 --> 01:12:19,229
[INDISCERNIBLE].

1924
01:12:19,229 --> 01:12:23,834
SO FIRST IT WOULD LOOK LIKE A

1925
01:12:23,834 --> 01:12:25,102
[INDISCERNIBLE] AND THEN WE

1926
01:12:25,102 --> 01:12:26,670
WOULD DO THE TEST AND THEN IT

1927
01:12:26,670 --> 01:12:32,543
WOULD BE ADEN O CARCINOMA AGAIN 

1928
01:12:32,543 --> 01:12:34,878
SO I THINK THAT IT'S NOT LIKE A

1929
01:12:34,878 --> 01:12:37,714
LINEAR PROCESS, BUT IT MIGHT BE

1930
01:12:37,714 --> 01:12:39,783
IF ONCE THERE'S LIKE A GIVEN

1931
01:12:39,783 --> 01:12:41,819
STATE BY MUTATION IS NOT

1932
01:12:41,819 --> 01:12:42,119
REVERSIBLE.

1933
01:12:42,119 --> 01:12:51,261
>> THANK YOU VERY MUCH.

1934
01:12:51,261 --> 01:12:52,930
>> THANK YOU ALVARO FOR AN

1935
01:12:52,930 --> 01:12:55,899
AMAZING TALK AND CONGRATULATIONS

1936
01:12:55,899 --> 01:12:59,036
AGAIN ON WINNING THE SERIES

1937
01:12:59,036 --> 01:12:59,636
WACHTEL PRIZE.

1938
01:12:59,636 --> 01:13:01,438
A BIG THANK YOU TO THE AUDIENCE

1939
01:13:01,438 --> 01:13:03,073
BOTH IN PERSON AND VIRTUAL AND

1940
01:13:03,073 --> 01:13:08,679
PLEASE DO SPREAD THE WORD ABOUT

1941
01:13:08,679 --> 01:13:11,882
THIS AWARD THE 13th ANNUAL

1942
01:13:11,882 --> 01:13:13,050
WACHTEL PRIZE APPLICATION WILL

1943
01:13:13,050 --> 01:13:15,252
OPEN MIDSEPTEMBER OF THIS YEAR,

1944
01:13:15,252 --> 01:13:17,087
SO NEXT MONTH.

1945
01:13:17,087 --> 01:13:18,222
FOR IN-PERSON ATTENDEES I HOPE

1946
01:13:18,222 --> 01:13:20,224
YOU WILL STAY FOR LUNCH WHICH IS

1947
01:13:20,224 --> 01:13:22,292
READY FOR YOU IN THE FAES

1948
01:13:22,292 --> 01:13:24,528
TERRACE AND WE HAVE COPIES OF

1949
01:13:24,528 --> 01:13:26,830
HIS AWARD WINNING ESSAY WHICH

1950
01:13:26,830 --> 01:13:28,565
WAS JUST PUBLISHED ON SEM ON

1951
01:13:28,565 --> 01:13:30,200
WEDNESDAY AND YOU CAN FIND IT AS

1952
01:13:30,200 --> 01:13:32,069
YOU EXIT THE AUDITORIUM.

1953
01:13:32,069 --> 01:13:34,037
SO THANK YOU ALL.

1954
01:13:34,037 --> 01:13:44,248
[ APPLAUSE ]