GOOD AFTERNOON, I'M ALLAN
WEISSMAN,
AND BEFORE INTRODUCING OUR
SPEAKER I WOULD REMIND EVERYBODY
TO SIGNIFY LEPS THEIR PHONES AND
SO THAT ANYONE WATCHING REMOTELY
CAN HEAR.
IT'S A PLEASURE TO INTRODUCE
DR. ZEEV ROIN AI, HE EARNED HIS
Ph.D. IN 1980 AND AFTER
JOINING THE FACULTY AT MOUNT
SINAI WHERE HE IS NOW THE
DIRECTOR OF THE DESIGNATED
CANCER CENTER--I'M SORRY ABOUT
THAT, BEFORE THAT HE WAS AT
MOUNT SINAI AND MOVED TO
LA JUDGE, CORRELATED YA TO JOIN
THE MEDICAL DISCOVERY INSTITUTE
WHERE HE'S NOW THE DIRECT
OVERLAPPING THE NCI DESIGNATE
THE CANCER CENTER.
HE IS THE PROFESSOR OF CANCER
METABOLISM AND MICROBIOME
PROGRAM, OVER A NUMBER OF YOAN
MONCADAERS HE HELD A NUMBER OF
OTHER POSITIONS AND PLAYED A
MAJOR ROLE IN THE LEADERSHIP
COMMUNITY INCLUDING ESTABLISHING
LARGE GRANT INITIATIVES AND
CHIEF AND MELANOMA RESEARCH, FOR
SEVERAL YEARS HE ALSO DIVIDED
HIS TIME BETWEEN LA JOYA AND
THEY APPLIED HIS VISION OF
INTEGRATED ADVANCED PRINCIPLES
AND COMPUTATIONAL BIOLOGICAL
SCIENCE CAN APPLIED THIS TO HIS
PASSION FOR UNMET NEEDS IN
CANCER RESEARCH.
HIS OVER 300 PUBLICATIONS HAVE
INBEEN CITED OVER 3000 TIMES, HE
IS THE NUMEROUS RECIPIENT OF
AWARDS, HE'S BEEN INVITED TO
SEVERAL FORUMS AND SEVERAL
CONFERENCES AND BEING AWARDED
THE MELANOMA'S LIFETIME
ACHIEVEMENT AWARD IN 2016.
THE OVERALL EMPHASIS OF HIS
RESEARCH IS ON EPIGENETIC
MODIFICATIONS, UNDERLYING ISSUES
OF TUMOR DEVELOPMENT, PROGRESS
AND RESISTANCE AS WELL AS OTHER
POST TRANSLATIONAL
MODIFICATIONS, I COULD GO ON ADD
INFINITE UM ABOUT HIS ACHIEVE
AMS SO I WILL MENTION A FEW
THINGS, ZEEV HAS MADE
CONTRIBUTIONS IN IMMEDIATE
STRESS RESPONSES PARTICULARLY
HIS EARLY WORK ON GENE KINASE
AND ALTERATIONS IN SIGNALING
THROUGH KINASES AND CANCER IN
GENERAL EMPLOY HE'S MADE MANY
PARADAME SHIFTING IN THE ROLES
OF LIGASES AND FUNDAMENTAL
CELLULAR PROCESSES INCLUDING
PROCESSES AND CANCER RESISTANCE
AND THERAPY AS WELL AS
AUTOIMMUNITY.
HIS RECENT WORK DEMONSTRATING
THAT LOW LEVELS MAP KINASE
INHIBITORS IN MELANOMA HAS LED
TO CLINICAL TRIALS THAT ARE
ONGOING ON THE UNIVERSITY OF
OREGON USING COMPARITTORS OF
GENE UP TAKE INTO THE CELL.
HIS WORK ON METHYLTRANSFERASE 5,
HAVE ALREADY PROVED TO BE
EFFECTIVE WITH TUMOR IRMUNITY.
WITHOUT FURTHER ADO I WILL TURN
IT OVER TO ZEEV FOR HIS TALK.
[ APPLAUSE ]
>> THANK YOU FOR THE
INTRODUCTION AND JUST KNOW IT BE
DOWN HILL FROM HERE.
[LAUGHTER]
[ APPLAUSE ]
ONE OF THE SLIDES I WILL SHARE
DURING MY PRESENTATION WAS
COVERED IN LENGTH MAYBE 10 YEARS
AGO AND YOU WILL FIGURE OUT
WHERE IT COMES FROM.
YOU ARE GOING TO HEAR ABOUT WHAT
I THINK ABOUT CERTAIN ASPECTS,
BELIEFS AND THEY'RE ONLY MINE.
SO TAKE IT WITH A GRAIN OF SALT
OF COURSE.
TO TOPICS I WOULD LIKE TO
DISCUSS WITH YOU TODAY OTHERS
BOTH ARE BASICALLY REFLECTING
WITH RESEARCH AND I WILL START
WITH PUBLISHED AND END UP WITH
UNPUBLISHED IN BOTH CASES.
THE FIRST WILL BE THE MICROBI
OTA PATH IN THE UNEXPECTED WAY
AND THE SECOND UBIQUITIN LIGASE,
BOTH OF THEM STEM FROM THE
STORY, SECOND IS MORE UBIQUITIN
LIKE BASED STORY.
ASK I'M GOING TO DWELL A LITTLE
BIT ABOUT THE FIELD OF UBIQUITIN
LIGASE,RY MIND ME A LITTLE BIT
OF THE FIELD OF PROTEIN
PHOSPHATASES CHA IS HOW TO
MAINTAIN BECAUSE I DON'T SEE
CTGAs AND THE LIKE BUT I WILL
SPEAK ABOUT THIS A LITTLE LATER.
SO THE CROSS TALK BETWEEN THE
TUMOR AND THE MICROENVIRONMENT
AND THIS IS A SIMPLE
PRESENTATION OF THE DIFFERENT
COMPLEMENTS THAT ARE PRESENT IN
THE MICROENVIRONMENT THAT THEY
PLAY A ROLE IN TUMOR EVOLUTION,
SO IT'S NOT ONLY THE TUMOR
BEHAVIOR BUT IT'S INTERACTION OF
THE MICROENVIRONMENT THAT
DETERMINE WHAT AND HOW IT WILL
EVOLVE, AND WE USED TO THINK
ABOUT--LET'S SEE HOW THAT WORKS,
WE USED TO THINK ABOUT THE CAPS
AND THEIR INTERACTION WITH THE
TUMOR CELLS, WE PAY A LOT OF
ATTENTION TO IMMUNE CELLS,
IMMUNE CELL COMPETENT AND THEN I
BELIEVE TO INFILTRATE THE TUMOR
CELLS AND FIGHT THE TUMOR CELLS,
I THINK THE STORY IS WAY MORE
COMPLICATED, I THINK THE STORY
HAS TO DO WITH IMMUNE CELLS
INTERACTION WITH THIS TRAUMA
BEFORE IT IS EDUCATED TO DO
SOMETHING WITHIN OR INTO THE
TUMOR, AND THAT'S A PART OF A
PROJECT WE ARE CURRENTLY PAYING
ATTENTION AT THE LAB TO.
WHEN WE ARE SPEAKING ABOUT
EPIIMENETTIC AND THE WHOLE TALK
WILL DISCUSS EPIGENETIC
REGULATION RATHER THAN GENETICS,
WE USED TO THINK ABOUT
METHYLATION, HISTONES
ACETYLATION AND LESS WE THINK
ABOUT PROTEIN METHYLATION,
PROTEIN MODIFICATION, THIS IS A
MASS SPEC WE HAVE BEEN DWELLING
ON AND PAYING A LOT OF ATTENTION
IN RECENT YEARS.
I WILL SPEAK ABOUT UBIQUITIN
LIGASE AS A MEDIATOR OF OTHER
SIGNALING PATHWAY AND HOW THOSE
ARE ABLE TO EFFECT BOTH THE
TUMOR AND THE MICROENVIRONMENT
AND NOT NECESSARILY IN THE SAME
WAY.
AND SO THAT'S 1 THING THAT 1 OF
THE TAKE HOME MESSAGES--I'M
GOING TO TRY TO MAKE THE STORY
TELLERS A LITTLE BIT MORE SIMPLE
AND THE STORY BEGAN FROM A
UBIQUITIN LIGASE THAT WE WORKED
ON FOR QUITE A FAW YEARS IN THE
LABORATORY PROTEIN NUMBER 5, RNA
5, GENERATED THE MICE MAYBE 20
YEARS AGO THAT LIKE THE GENE AND
THEY DIDN'T HAVE PHENOTYPE AND
THEY DESIGNATED THE MICE AS THE
BORING MICE, NOTHING
INTERESTING, AND THAT IS UNTIL
[INDISCERNIBLE] DECIDED TO PUT
MELANOMA CELLS INTO THESE MICE
AND GUESS WHAT, MELANOMA DIDN'T
GROW.
SO THAT WAS THE BEGINNING OF A
VERY EXCITING PROJECT, WHERE
USING DIFFERENT MELANOMA TYPES
WE WERE ABLE TO DEMONSTRATE THAT
THE MICE ARE COMPLETELY
RESISTANT TO TUMOR DEVELOPMENT
AND WAS NOT ONLY MELANOMA, WE
WERE ABLE TO SHOW IT FOR COLON
CANCER AS WELL.
SOON AFTER, WE DEMONSTRATED THAT
THE REASON MELANOMA DIDN'T GROW
IN THESE ANIMALS IS BECAUSE
THERE IS EXTENSIVE INFILTRATION
OF IMMUNE CELLS INTO THE TUMOR,
WHICH FOUGHT THE TUMOR.
SO IN THIS CASE, YOU CAN SEE THE
CD4, CD8 POSITIVE
T-CELLS--ESTABLISH THIS
INFILTRATION OF THESE T-CELLS
THAT CAUSE THE REJECTION
PHENOTYPE THAT WE HAVE SEEN.
AND NEUTRALIZING ANTIBODY
AGAINST CD8 IS SHOWN THIS SLIDE
WAS SUFFICIENT TO BLOCK THE
INHIBITION OF TUMOR GROWTH, WE
LOST IT WHEN WE NEUTRALIZE CD8
ANTIBODIES.
SO, UBIQUITIN LIGASE CAUSE
ANTITUMOR MOBILITY, LIMITED
GROWTH, HOW DOES IT WORK?
SO YOU WANT TO DEMONSTRATE THIS
IS IMMUNE INHERIT MECHANISM IS
TO DO BONE MARROW TRANSFER, TAKE
THE BONE MARROW FOR 1 MICE, FOR
ANOTHER MICE, IF THE IT HAS TO
DO WITH THE IMMUNE SYSTEM, IT
WILL TRANSFER TO THE RECIPIENT
MICE AND HERE WE GO, IT'S IMMUNE
RELATED BUT IN THIS PARTICULAR
CASE, IT DID NOT.
SO THAT FOR US WAS THE FIRST
INDICATION THAT SOMETHING ELSE
IS GOING ON HERE WHICH IS
INDEPENDENT OF THE INHERIT
IMMUNE SYSTEM.
SO WHAT CAN THIS BE.
ASK THIS WAS THE TIME NOW, WE'RE
TALKING 2017, 18, WHERE THE
MICROBIOME WAS A VERY ATTRACTIVE
AREA, STUDIES FROM LEFT AND
RIGHT CAME ABOUT AND YOU SEE
JUST A SMALL COLLECTION HERE
DEMONSTRATING THAT A SPECIFIC
BACTERIA STRAINS ARE SUFFICIENT
TO CAUSE ENHANCED AUTOIMMUNITY
BY INCREASING CTLA-4.
IT WENT TO THE GREE THAT EVEN
THE SINGLE BACTERIAL STRAIN WAS
TO MAKE THIS WORK, UNFORT MATILY
THINGS DIDN'T WORK OUT LATER IN
CLINICAL TRIALS BUT THE MESSAGE
WAS LOUD AND CLEAR, BACTERIA IT
HAVE AN EFFECT ON THE DEGREE OF
ANTITUMOR FIGHT BY
[INDISCERNIBLE].
SO WE CHECKED WHETHER IT COULD
BE IF IT'S NOT IMMUNE RELATED
WHICH WAS THE BONE MICROBIOME
HERE, IT COULD BE THE MICROBIOME
AT PLAY HERE SO WHEN WE TARTED
TO MAP THE COMPOSITION OF THE
MICROBI OTA IN THE KNOCKOUT MICE
VERSUS THE WILD-TYPE, WE
IMMEDIATELY SAW THE 2 DIFFERENT
DISTRIBUTION 2 DIFFERENT
CONCENTRATION OF BUGS
SUGGIESTING THAT THERE IS
SOMETHING DIFFERENT IN THE
COMPOSITION OF MICROBI OTA IN
THE KNOCKOUT MICE COMPARED TO
THE WILD-TYPE.
THAT LED US TO DO 2 VERY SIMPLE
EXPERIMENTS AND SIMPLE,
SOMETIMES IS GOOD, SOMETIMES IS
BETTER AND THE FIRST SIMPLE
EXPERIMENT IS TO TAKE THE MICE,
TREAT THEM WITH A COCKTAIL OF
ANTIBIOTICS THAT IS KNOWN TO
ELIMINATE MOST OF THE STRAINS,
SO IF I TAKE MICE ELIMINATE THE
BACTERIA POPULATION BY A
COCKTAIL OF ASPECT BIOTICS, I
CAN WHETHER THESE THE MICROBI
OTA WAS RESPONSIBLE FOR THE
PHENOTYPE AND THIS THE
EXPERIMENT SHOWN HERE, WE SEE
THE EJECTION PHENOTYPE IN THE
KNOCKOUT MICE AND WE LOST IT
LARGELY UPON TREATING WITH
ANTIBIOTIC MIX TOUR.
SO THAT FIRST, NOT DIRECT BUT
THE FIRST INDICATION THAT INDEED
BUGS OR MICROBI OTA CAN BE
INVOLVED THE SECOND EXPERIMENT
WAS EVEN BETTER THAN THE FIRST
EXPERIMENT THE SECOND WAS MIXING
THE MICE FROM THE KNOCK OUT WITH
THE WILD-TYPE MICE ASKING
WHETHER THE CO HOUSING WHEN
SHARING IT FOR A COUPLE WEEKS
WILL BE SUFFICIENT TO ELIMINATE
THE TUMOR TYPE OF INHIBITION.
AND AS CAN YOU SEE THE TUMOR
INHIBIT THAT WAS ALONE WAS LOST
UPON THE CO HOUSING EXPERIMENT.
THAT SUGGEST THAD BUGS ARE
INDEED INVOLVED.
AGAIN INDIRECTLY.
SO WE MOVE ON ALONG THE SAME
LINE THE PHENOTYPE I'VE SHOWN
YOU BEFORE WAS ALSO LOST UPON
THIS CO HOUSING.
IN OTHER WORDS INFILTRATION OF
CD4 OR CD8 T-CELLS ARE NO LONGER
SEEN UPON THIS CO HOUSING
EXPERIMENT WHICH IS SHOWN HERE.
AND THAT'S OKAY, WELL, YOU HAVE
THE MICROBI OTA THAT DICTATES
ANTITUMOR IMMUNITY AND IF YOU
ARE MESSING UP WITH THAT
COMPOSITION, YOU ARE GOING TO
ELIMINATE OR ABOLISH THE SECOND
PHENOTYPE.
SO WE WENT 1 STEP FORWARD AND WE
SAID LET'S SEE IF WE CAN TAKE
THE FECAL SAMPLES FROM THE
KNOCKOUT MICE, GIVE THEM TO THE
WILD-TYPE MICE, WOULD WE BE ABLE
TO KEEP THE PHENOTYPE OF TUMOR
INHIBITION.
AND THIS SAMPLE YOU ARE LOOKING
AT HERE WAS SUFFICIENT TO GROW
TUMOR INHIBITION WHILE
INFILTRATING INHIBITION OF THE
IMMUNE CELLS.
SO TRANSFERRING THE FECAL FROM
THE WILD-TYPE TO THE KNOCK OUT
WAS SUFFICIENT TO MAINTAIN THE
MELANOMA IN THE RECIPIENT MICE.
OKAY, SO THAT'S 1 STEP FORWARD
BUT TILL NOT GOOD ENOUGH BECAUSE
WHO WOULD ASK WHAT ARE THE
BACTERIAL RESPONSE FOR THIS
CHANGE?
AND THAT EXPERIMENT TOOK US
ABOUT A YEAR TO SORT OUT WHAT IS
INDEED INVOLVES AND WE USED
MAYBE 4 OR 5 EXTREMELY COMPUTER
SCIENCE FOLKS TO HELP US OUT,
[INDISCERNIBLE] WAS 1 OF THEM.
AND THE RESULT OF THAT WAS
MAPPING THE DIFFERENT SEQUENCES
WE HAVE MET 16A SEQUENCING AT
THE TIME AND THIS PICTURE YOU'RE
LOOKING AT HERE TOOK US ABOUT A
YEAR TO GENERATE AND I'M SERIOUS
ISSUES I CAN GIVE A WHOLE
LECTURE ON HOW WE GENERATE AND
CAME TO THIS COP CLIEWGZ.
AND WHAT HAS ALLOWED US TO
SIMPLY MAP THE STRAINS OF THE
DIFFERENT IN THE KNOCK OUT
VERSUS THE WILD-TYPE MICE.
AND WITH THAT, WE WERE NOW
EQUIPPED WITH THE KNOWLEDGE OF
THE SPECIFIC BUT STRAINS WE CAN
ADMINISTER TO THE MICE, YOU KNOW
TO SEE WHETHER THEY BY
THEMSELVES WOULD BE SUFFICIENT
TO INHIBIT TUMOR.
THAT'S EXACTLY WHAT WE HAVE
DONE.
WE HAVE SELECTED 11 BACTERIAL
STRAINS, NOW FROM THE CANNED
WHAT WE HAVE IN OUR BODY, LISTEN
IS A ERROR REDUCTIONIST
APPROACH.
ELEVEN BACTERIAL STRAINS
ADMINISTERED TO MICE AND
MELANOMA INOCULATED IN THESE
MICE AND THE MELANOMA WAS NICELY
INHIBITED, TOGETHER WITH
INFILTRATION OF THE IMMUNE
SYSTEM AND ANTITUMOR IMMUNITY.
SO, FROM EVERYTHING THAT WE HAVE
DONE, WE ARE NOW AT A STAGE
WHERE WE FORGOT ABOUT UBIQUITIN
LIGASE, WE ARE DOWN TO THE
BACTERIAL STRAINS THAT ARE
UNIQUE, VERY UNIQUE UPON THE
LOSS OF LIGASE AND THOSE 11
STRAINS WERE BY THEMSELVES
ENOUGH TO INHIBIT TUMOR GROWTH
AND EMPHASIZE IN MICE, IN MICE
THAT IS GERM-FREE.
AND SO, THIS IS A VERY IMPORTANT
POINT TO MAKE BECAUSE IN THIS
ANIMAL, THE ONLY 11 BACTERIAL
STRAIN TOGETHER WITH THE BASAL
MIX OF 8 FOR THESE MICE TO,A LOW
THEM TO EVEN SURVIVE.
SO SUPRISING HERE, AND I WILL
NOT EMPHASIZE IT BUT WE HAVE
REACHED THE TAIJ WHERE A SELECT
SET OF BACTERIAL STRAINS
TAKEN--THEY BY THEMSELVES
INHIBIT TUMOR GROWTH.
WHAT DO WE DO WITH THAT?
THAT TAKES ME TO THE UNPUBLISHED
PORTION OF THE WORK WE'VE BEEN
CONDUCTING SO WE ASK A SIMPLE
EXPERIMENT AND WE ASK A SIMPLE
QUESTION AND THE QUESTION WAS,
INDEED WE INOCULATED 11 BUGS
INTO THE MICE, AND INDEED WE
HAVE SEEN INHIBITION OF TUMOR
GROWTH 20 DAYS LATER, BUT WE DID
NOT ASSESS HOW MANY OF THOSE 11
BUGS WERE PROMINENT AFTER 20
DAYS.
IN OTHER WORDS, IS IT POSSIBLE
THAT NOT ONLY 11 PROPAGATED THE
SAME EFFICIENCY, AND THE END OF
THE EXPERIMENT WE DIDN'T HAVE 11
BUT WE HAD FEWER STRAINS THAT WE
MAY WANT TO PAY ATTENTION TO.
AND THAT'S WHAT WE ARE DONE,
PAID ATTENTION TO THE
CONCENTRATION OF BACTERIAL
STRAINS AND PREVALENCE OF THEM
AT THE END OF THE EXPERIMENT AND
NOT THE BEGINNING AND THAT LED
US TO 3 BACTERIAL STRAINS, SO
ONLY 3 OUT OF 11 WERE FROMINENT
AT THE END OF THE EXPERIMENT, SO
THE NEXT OBVIOUS QUESTION IS,
CAN YOU DO THE SAME EXPERIMENT
RETREAT AND WOULD YOU BE ABLE TO
GET INHIBITION OF MELANOMA WITH
3, 2, OR 1 STRAINS?
AND AS CAN YOU SEE HERE, TO MACK
A LONG STORY SHORT BECAUSE THIS
PROJECT HAS BEEN GOING ON FOR
THE LAST COUPLE OF YEARS, 1
BACTERIA WILL STRAIN, NOT 3 IS
ENOUGH TO GET INHIBITION OF THE
MICE, AND THE DEGREE IS PRETTY
NOTABLE.
NOW I HAVE TO SAY THESE
EXPERIMENTS ARE BEING DONE IN
NEBRASKA BECAUSE IN OUR FACILITY
AND OUR PLACE, WE DON'T HAVE A
[INDISCERNIBLE] MOUSE FACILITY,
YOU NEED A SPECIAL FACILITY TO
ACCOMMODATE THESE ANIMALS AND
THESE EXPERIMENTS ARE DONE
MULTIPLE TIMES AND NOW WE'RE
ASKING HOW IT'S POSSIBLE THAT
THE 1 BUG CAN HAVE AN EFFECT ON
TUMOR GROWTH INHIBITION, AGAIN
IN AUTOBIOTIC ENVIRONMENT.
SO WE'VE DONE 2 TYPE OF ANALYSIS
WHICH I WILL SHOW IN THE NEXT
COUPLE OF MINUTES, THE FIRST ASK
WHAT HAPPENS TO THE TUMORS, SO
IF WE TAKE THE TUMORS THAT WERE
AFFECTED, GREW LOWER, SOME OF
THEM DIDN'T APPEAR AT ALL, CAN
WE IDENTIFY ANY SIGNALING
PATHWAY THAT STAND OUT IN THESE
TUMORS AND THE SECOND
EXPERIMENT, TAKE THE FECAL
SAMPLES OF THESE ANIMAL ANDS DO
A WHOLE METRICS TAB O LOAMIC
ANALYSIS AND SEE IF WE CAN FIND
ENRICHMENT OR DECREASE OF
METABOLITES THAT MAY HAVE BEEN
AFFECTED BY THIS BACTERIA WHICH
COULD ALSO EXPLAIN HOW IT'S
POSSIBLE.
SO WHEN WE HAVE DONE THE
ANALYSIS GEAP, THIS IS A PCA AND
THIS IS AN INITIAL--OH WOW THIS
IS MOVING WITHOUT ME EVEN
TOUCHING SO THIS IS COOL.
SO LOOKING AT THE RNASEQ
ANALYSIS, THE PRIMARY CHANGES
THAT YOU CAN ADENTIFY HERE ARE
CHANGES IN THE IMMUNE SYSTEM.
WELL, NOT SO SURPRISING BECAUSE
WE ALREADY KNEW FROM THE
PREVIOUS EXPERIMENTS THAT WHEN
YOU HAVE ACTIVATION OF THE
IMMUNE SYSTEM, YOU WILL BE ABLE
TO DO SIEWMOR GROWTH AND SIZE,
AND THIS IS WHAT WE SEE IN THESE
TUMORS THAT RESPOND TO 1 BUG, SO
SORT OF VALIDATION I WOULD SAY
SO.
THIS WAS A METABOLIC ANALYSIS,
AND THE METABOLISM WAS DONE IN
COLLABORATION WITH DAN KELLIE
AND CHRIS [INDISCERNIBLE] AT
UPEN, ANALYSIS OF EXTENSIVE LINE
OF METABOLITES AND THE 1S THAT
STAND OUT HERE IS DECREASE IN
TRYPTOPHAN AND DECREASE IN
TYROSEEN IN THE ANIMALS THAT
RECEIVED THOSE SINGLE BUGS, SO
WHEN YOU LOOK AT THAT TO SAY,
WELL, OKAY, WHAT DOES IT MEAN?
RIGHT?
BUT APPARENTLY BOTH TRYPTOPHAN
AND TYROSEEN HAVE BEEN TODAYED
IN THE CONTEXT OF THE IMMUNE
ACTIVATING SYSTEM AND THIS IS 1
EXAMPLE OF PAPER THAT WAS
PUBLISHED JUST A YEAR AGO OR
LESS THAN THAT THAT DEMON TRAITS
HOW TRYPTOPHAN NEGATIVELY
REGULATE THE'MUNE SYSTEM,
ANTITUMOR IMMUNITY.
SO IF TRYPTOPHAN, AND THERE ARE
MORE THAN THIS SINGLE PAPER.
IF TRYPTOPHAN SERVED TO BLOCK
THE IMMUNE SYSTEM, REDUCE LEVEL
OF TRYPTOPHAN AND ENABLE THE
IMMUNE SYSTEM AND THIS IS THE
PHENOTYPE WE OBSERVE.
NOW YOU CAN ASK, WHY THERE IS A
DECREASE IN TRYPTOPHAN IN THE
FIRST PLACE, AND I WILL--AND
ANSWER AND SAY THAT
[INDISCERNIBLE], WAS IDENTIFIED
AND SUFFICIENT TO CAUSE THE
CHANGE IS KNOWN TO CONSUME
TRYPTOPHAN, TO RELY ON
[INDISCERNIBLE] TRYPTOPHAN, SO
IT CONSUMES IT BECAUSE OF THAT,
THERE IS LESS INHIBITION OF THE
UMPIRESUNE SYSTEM, AND THE
RESULT IS THE ANTITUMOR
IMMUNITY.
YES?
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> IT REMINDS ME OF A PAPER BY
[INDISCERNIBLE] IN NATURE, LAST
YEAR ARE I THINK IT WAS THAT
DEMON TRAITED THE LACK OF
[INDISCERNIBLE] IMMUNE SYSTEM
AND IN PART BY AFFECTING
RIBOSOME BIOSYNTH TIS PATHWAYS
AND I'M FAMILIAR WITH THAT AND
AS I SAID, THIS IS ONLY 1.
SO WE HAVE TO PROVE THAT IN OUR
SYSTEM, THE HYPOTHESIS I JUST
LAID OUT IS CORRECT, THE
EVIDENCE SUPPORT THAT EXISTS.
BUT WE NEED TO DEMONSTRATE THAT
IN OUR CASE WE INCREASE
TRYPTOPHAN AND EFFECTIVE ILY
ELIMINATE THE [INDISCERNIBLE]
WILL BE 1 SIMPLE EXPERIMENT YOU
CAN STOP IT.
YES?
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> SO WHAT GLEN REFERS TO IN
RUEING TRYPTOPHAN, 1 MAY USE IT
TO GET THE EFFECT HERE, I AM
TOTALLY WITH YOU, THE ONLY
COMMENT I WOULD MAKE IS THAT
EVIDENCE OF TRYPTOPHAN IS
CONFIRMATION OF THE ABILITY OF
DIVERSE SYSTEMS USING DIFFERENT
MOUSE MODELS, SO, I WOULD ASSUME
THAT THE RELATIVE AMOUNT SHOULD
NOT BE TOO HIGH, TO OBSERVE THE
DIFFERENCE ISSUES THE LEVEL WE
LOOK AT HERE IS PICO MOLAR SO I
THINK THAT IT IS FEASIBLE DO I
RECOMMEND TO ELIMINATE
TRYPTOPHAN FROM THE FOOD, NOT
YET.
I WILL GET TO THAT IN ANOTHER
STUDY FOR THE NEXT FEW MINUES
BUT IT DOES GIVE US AN
INTERESTING HYPOTHESIS TO FOLLOW
UP, AS PER HOW TO EXPLAIN THE
OBSERVATION WE JUST MADE HERE.
A ALL RIGHT, SO I JUST RELATED
TO THAT AND I DISCUSSED IT AND
THE KEY QUESTION WE'RE ASKING
OURSELVES CAN USE A
PHARMAICOLOGICAL APPROACH TO
MIMIC OR PHENOCOPY THE
OBSERVATION MADE BECAUSE 1
BACTERIAL STRAIN TO ADMINISTER
TO A MICE, EVEN THAT HAS A
COMPLETE MICROBI OTA AND MOST
LIKELY TO HAVE THE IMPACT, SO WE
NEED TO COME AT THIS FROM A
DIFFERENT DIRECTION.
THAT TAKES ME TO THE BIGGER
QUESTION.
CAN THE SINGLE BACTERIAL STRAIN
MAKE A DIFFERENCE?
I PERSONALLY DON'T THINK SO, BUT
IT CAN TEACH US A LOT ABOUT AN
UNDERLYING MECHANISM THAT WE CAN
LEARN FROM AND ENHANCE AND
AMPLIFY, I. E. THE TRYPTOPHAN I
JUST SHARED WITH YOU.
ARE THERE ALTERNATIVES,
PREBIOTICS, PRO BIOTICS NO DOUBT
HAVE SHOWN IF YOU ADMINISTER
PROBIOTIC, YOU ARE CHANGING THE
EQUILL LIBRARY
EQUILL LIBRARY FOUNDATIONIUM.
WE'RE TALKING ABOUT FIBERS AND
FIBROLIKE AND I WILL SHOW YOU 1
EXAMPLE THAT YOU CAN IMAGINE
ADDING TO A SERIAL IN THE
MORNING TO HAVE A CHANGE IN YOUR
MICROWIMBERLY OTA POSITION TO
IMPART ANTITUMOR IMMUNITY.
AND FASCINATING BY A GROWING
NUMBER OF TODAYS THAT SHOWS THE
COP NEKS BETWEEN OUR BRAIN AND
THE GUT MICROBIOME AND THE
IMMUNE SYSTEM BY WAY OF
INNOVATION AND HOW THOSE AFFECT
MICROBI OTA COMPOSITION,
SOMETHING WE NEED TO TAKE INTO
CONSIDERATION WHEN LOOKINGA THE
THIS GOING FORWARD.
SO BASED ON THE STUDIES I'VE
JUST SHOWED WITH YOU, KNOCKOUT
MICE AND MET ALL THE MICROBI OTA
FOR THESE MICE, WE ASK WHETHER
THERE COULD BE A PREBIOTIC THAT
COULD PHENOCOPY EACH IN PART,
PARTLY, CHANGES WE HAVE SEEN IN
THE KNOCKOUT MICE, AND WHETHER
THIS PREBIOTIC WOULD HAVE THE
EFFECT THAT WE'VE SEEN IN THE
KNOCKOUT MICE AND I'M JUST
SHOWING YOU A COUPLE OF SLIDES,
NOT MORE THAN THAT DEMONSTRATING
THAT INDEED, 2 PREBIOTIC
[INDISCERNIBLE] WERE FOUND TO
HAVE EFFECT IN TUMOR GROWTH
INHIBITION, IN THE MELANOMA MICE
MODEL AND WHILE INHIBITING THEY
WERE ACTIVATING THE ANTITUMOR
IMMUNITY.
IT WAS TO THE DEGREE THAT BEING
NOT BE SUBSTANTIATED BY PDL431,
SO THAT LED US TO CONCLUDE
TAKEN--THEY WE ARE MORE OR LESS
ON THE SAME PATHWAY AS PDL1
WOULD HAVE OTHERWISE DONE.
NOT ONLY THAT WE'RE ABLE TO
INHIBIT MELANOMA GROWING BUT
ALSO ABLE TO OVERCOME RESISTANCE
TO THERAPY AND IN THIS
PARTICULAR CASE, WE LOOKED AT
[INDISCERNIBLE] RESISTANCE
MANAGE WE HAVE AS AN UNMET NEED
TODAY IN THE CLIPPIC SO THIS
PREBIOTIC CAN PLAY A ROLE IN
MEDIATING THOSE CHANGES EMPLOY
SO THIS IS 3 YEARS OLD, SO WE
CONSIDER IT OLD.
WHAT HAVE WE DONE SINCE THEN IN
1 THING, SO THIS IS THE
COMBINATION OF PD1 THAT I JUST
MEPGZED TO YOU.
IT DOES NOT DO BETTER
SUGGIESTING THAT WHATEVER THE
IMUT MICROBIOME CHANGES, THEY
HAVE MADE, AFFECTED MORE OR LESS
SIMILAR TO PD1 BECAUSE OTHERWISE
I WOULD HAVE EXPECTED TO SEE
CHANGES.
SO 1 APPROACH THAT WE UNDERTAKE
AND I STILL DON'T KNOW THE
RESULT OF THIS ONGOING STUDY IN
THE LAB IS TO TRY TO TAKE
INIULYN WHICH WAS THE BETTER
BETWEEN THE 2 I JUST SHARE WIDE
YOU AND SEE IF WE CAN USE THE
SIMPLER VERSION OF INULIN FOR
THE SAME EFFECT?
IT'S COMING FROM A
[INDISCERNIBLE] PLANT AND HAS A
COMPLEX COMCISION OF ABOUT 60
POLARIZED UNITS THAT ARE ON EACH
OTHER.
AND THE VARIETY OF INULIN
DEPENDS, VARIESOT SOLUTIONS YOU
GET.
MOST OF THEM ARE ABOUT 50, 60
ISSUES UNITS THAT ARE COUPLED TO
EACH OTHER, SO WE ASK IS IT
POSSIBLE TO DO THIS WITH A
VERSION OF ONLY 10, 10 IS THE
MEANING AND THIS EXPERIMENT
GOING NOW AND I CAN TELL YOU
THAT THE FIRST GLANCE IT TOOKS
LIKE YOU CAN GET THE SAME EFFECT
WITH SMALLER OR SIMPLER VERSION
OF INULIN BUT THIS IS JUST THE
BEGINNING OF AN EXPERIMENT.
AND THE BIGGER QUESTION IS CAN
YOU DO IT EVEN SIMPLER AND I
DON'T KNOW HOW MANY OF YOU ARE
FAMILIAR WITH [INDISCERNIBLE], A
FRENCH SCIENTIST IN THE
[INDISCERNIBLE] IN PARIS WHO
HAVE DONE A VERY SIMPLE
EXPERIMENT WHERE HE DEMON
TRAITED THAT YOU CAN EFFECT THE
MEMORY OF MICE BY TRANSPLANTING
FECAL SAMPLES FROM OLD MICE TO
YOUNG MICE AND YOUNG MICE WILL
LOSE THE MEMORY.
SO IF YOU CAN DO SOMETHING LIKE
THAT AND THIS IS PUBLISHED, IT'S
GOOD STUFF.
IF THIS IS PUBLISHED, CAN WE
THINK ABOUT SYSTEMS IN CANCER
WHERE WE CAN COMPARE THE YOUNG
AND THE OLD AND SEE WHETHER WE
CAN AFFECT 1 OR ANOTHER VICE
VERSA AND IN THIS LINE OF
EXPERIMENT THAT'S GOING ON IN
THE LAB AT THE MOMENT.
SO JUST THE KEY PLAYERS,
[INDISCERNIBLE] DID MOST OF THE
WORK.
[INDISCERNIBLE] DID THE
PREBIOTIC EXPERIMENTS.
AND AT THE MOMENT THE PERSON WHO
RUNS THIS LINE OF EXPERIMENT IS
[INDISCERNIBLE].
WE'VE BEEN ASH CYSTED BY A LONG
LIST OF COLLABORATORS, I WILL
JUST OUTLINE THE CANNED WHAT
FROM THE UNIVERSITY OF NEBRASKA
AND CANNED CANNED--[INDISCERNI]
BIOINFORMATIC ANALYSIS THAT
HELPS US LOOK AT THINGS LEFT TO
RIGHT.
MOVING TO THE SECOND PART OF MY
TALK, I STILL HAVE TIME SO
THAT'S GOOD.
UBIQUITIN LIGASES BECAME A
PAINFUL TOPIC ISSUES YES A NOBEL
PRIZE WAS GIVEN TO 2 SCIENTISTS,
A FEW YEARS AGO BECAUSE THEY
DISCOVERED UBIQUITIN.
IT IS BELIEVED TO PLAY AN
IMPORTANT ROLE IN BIOLOGY NOT
ONLY BECAUSE IT MARKED PROTEIN
DEGRADATION
GRATES--GRATUEIGATION BUT ALSO
BECAUSE IT SIGNALED COMPLEX
ACTIVITY AND COLONIZEITION AND I
CAN KEEP ON GOING BUT THERE IS A
PROBLEM, YOU DON'T DETECT IT.
SO IF YOU ARE TRYING TO SEE WHAT
HAPPENS TO UBIQUITIN LINES OF
YOUR CHOOSING, YOU WILL NOT FIND
ANYTHING BECAUSE IT'S BORE,
THEY'RE ALL THE SAME.
AND THE PROTEIN ITSELF IS HARD
TO DETECT, BECAUSE THEY ARE
BUILT IN A WAY THAT IS DESIGNED
TO SELF-DESTRUCK, THEY'RE SO
IMPORTANT THAT ANY RELATIVE
AMOUNT OF THE PROTEIN IS
CRITICALLY IMPORTANT FOR THEIR
ACTIVITY AND THEREFORE IF YOU
LIMIT THAT, THAT'S THE WAY
BIOLOGY WORKS.
SO YOU DON'T DETECT THE RNA, YOU
DON'T--YOU BARELY PROTECT THE
PROTEIN, YOU HAVE TO REALLY DO
TRICKS TO SEE THE PROTEIN, AND
BECAUSE OF THAT, IT'S VERY HARD
TO HAVING THEM APPRECIATE IT, SO
THE COMMON--COMMON THAT YOU GET
ON PAPERS OR ON GRANTS, IF YOU
DON'T SEE THEM, THEY'RE NOT
IMPORTANT.
BUT WHEN I'M GOING TO SHOW YOU
IN THE NEXT FEW MINUES UE--MINUS
IS 1 CASE OF UBIQUITIN LIGASE
WHICH IS CRITICAL IMPORTANT FOR
CANCER AND WHY WE BELIEVE IN
THAT.
I WILL SPEAK ABOUT 1 BUT THIS IS
PART OF A REVIEW WE PUBLISHED A
FEW YEARS AGO AND IF YOU CAN
SEE, CAN YOU SEE A NUMBER OF
UBIQUITIN LIGASES UNDER
DIFFERENT SECTIONS, AREAS IN
TERMS OF FUNCTIONAL SIGNIFICANCE
AND ALL OF THOSE THAT ARE LISTED
THERE, ARE SOMEHOW SCREWED UP,
DEREGULATED IN CANCER.
SO THE EVIDENCE FOR THE
IMPORTANCE OF THIS UBIQUITIN
LIGASE COMES FROM A VARIETY OF
STUDIES CONDUCKED OVER THE LAST
2 DECADES.
WE KNOW THEY ARE CRITICALLY
IMPORTANT BUT TODAY WHEN
EVERYBODY LOOKS AT THOSE TCGA
ONCO9, WHAT NOT, IT'S HOW TO
MAKE A CASE.
SO I'M GOING TO SPEAK ABOUT
UBIQUITIN LIGASE, 2 MEMBERS OF
THE FAMILY, THE COMPOSITION OF
THIS AS SHOWN HERE IS VERY
SIMPLE CLASSIC COMBINATION OF
600 QUING FINGER PROTEINS IN THE
CELL, THE RING REALLY
INTERESTING GENE, THAT'S WHAT
RING STAND FOR.
THEY CONTAIN ACTIVE PORTION OF
PROTEIN THAT IS ENABLING THE
UBIQUITIN CONJUGATION
CAPABILITIES, THE STRUCTURAL
LIGASE WAS MET OVER 10 YEARS AGO
BY DAVID PATTLE AND COLLEAGUES
SHOWING TO BE A DIMER, SO THAT
IS INTERESTING FOR THE NOTION
THAT IF YOU DON'T ALLOW TO FORM
A DIMER, MOST LIKELY YOU'RE NOT
ABLE TO GET ACTIVITY.
AND OVER THE YEARS WE HAVE DEMON
TRAITED THAT THE LIGASE CAN
RECOGNIZE A NUMBER OF DIFFERENT
SUBSTRATES AND I WILL SPEND OUR
FOCUS ON 2 BECAUSE OF THEIR
IMPORTANCE.
THE FIRST IS A WORK OF
[INDISCERNIBLE] AND NOW WE'RE
TALKING ABOUT 20 YEARS AGO WHO
SHOWED THAT THE LIGASE IS
IMPORTANT IN THE CONTROL OF
HYPOXIA, AND THERE THE REASON
FOR THE HYPOXIA IS BECAUSE IT'S
HYDROX LACE 1 AND 3 AND IN DOING
THAT IT'S DETERMINES HOW MUCH
WHICH NEED TO BE MODIFIED BY
POLYHYDROXALATION BEFORE IT CAN
BE TARGETED FOR DEGRADATION BY
VHL, THAT WILL DETERMINE HOW
MUCH WILL BE AVAILABLE IN THE
CELL.
SO, THIS IS--WAS THE BEGINNING
OF OUR JOURNEY AND WE WERE VERY
EXCITED ABOUT THIS PLAYING A
ROLE IN HYPOXIA CONTROL, UNTIL
WE REALIZE THAT HYPOXIA IS ONLY
SMALL PORTION OF A BIGGER
PICTURE AND THE BIGGER PICTURE
WAS THE UPL, SO SIAH, NOT ONLY
CONTROL LEAF BUT ATF IS ALSO
REGULATABILITY.
THIS CONTROLS STRESS AND HYPOXIA
AND THESE ARE 2 KEY FUNDAMENTAL
PROCESSES THAT ARE ESSENTIAL FOR
MUCH OF WHAT HAPPENED IN THE
CELL, ESPECIALLY IN THE CANCER
CELL.
AND OVER THE YEARS AND I'M GOING
TO JUST BROWSE THROUGH THIS VERY
QUICKLY, WE HAVE DEMON TRAITED
HOW THE LIGASE IS CRITICAL FOR
MELANOMA, FOR PROSTATE CANCER,
NEXT COUPLE OF SLIDES AND OTHER
SCIENTIST VS SHOWN HOW IMPORTANT
THIS CONTEXT OF DIFFERENT CANCER
TYPES.
AND IN THE CASE OF MELANOMA, WE
WERE ABLE TO DISTINGUISH BETWEEN
HYPOXIA DEPENDENT CONTROL WHICH
AFFECT METASTASIS TO PRIMARY
TUMOR CONTROL WHICH EFFECT THE
PRIMARY TUMOR FORMATION, THERE
WERE SOME SECURITIZATION. NIICAL
TRICK WE HAVE USED AT THE TIME
THAT ENABLED US TO DISTINGUISH
BETWEEN THE 2 PATHWAY AND THE 2
KEY SIGNALING EVENTS.
LATER ON A MORE COMPLEX STUDY
SHOWNING IN PROSTATE CANCER IF
YOU HAVE A CR, YOU GET LIVER
METASTASIS, VERY ABUNDANTLY BUT
IF YOU DON'T HAVE THIS UBIQUITIN
LIGASE, YOU DON'T SEE THE
METASTASIS AND WE
MECHANISTICALLY EXPLAINED HOW
THAT WORK ANDS HOW IT IS
IMPORTANT IN THE CONTROL OF
THESE PROCESSES AND THIS IS WHAT
I BELIEVE I SPOKE ABOUT 10 YEARS
AGO IN WHEN I WAS HERE.
AND SEBS QUENT FROM THAT WE WENT
THROUGH THE CAPSER RESISTANT
WHICH ARE THE MORE AGGRESSIVE
FORMS OF CANCER AND DEMONSTRATED
HOW THE LIGASE IS IMPORTANT IN
THOSE FORMS OF CANCER THROUGH A
TOTALLY DIFFERENT MECHANISM THAT
HAS TO DO WITH CONTROL OF
ANDROGEN RECEPTOR SIGNALING.
SO THROUGH A NUMBER OF SYSTEMS,
A NUMBER OF PATHWAYS WE'VE SHOWN
OW THIS UBIQUITIN PATHWAY IS
TUMOR FORMATION BUT COMMON TO
ALL OF THEM IS THE INTRINSIC
TUMOR EFFECT, SO IN ALL CASES,
THIS UBIQUITIN LIGASE CONTROLLED
TUMOR FORMATION BECAUSE OF
CHANGES IN THE TUMOR ITSELF, WE
HAVE NOT TOUCHED UNTIL NOW THE
MICROENVIRONMENT.
SO NOW WE STARTED TO ASK WHAT
HAPPENED IN THE
MICROENVIRONMENT, WHAT--IS THIS
UBIQUITIN LIGASE, AS IMPORTANT
IN THE MICROENVIRONMENT.
AND THIS IS WORK THAT IN THE LAB
OVER THE LAST FEW YEARS, AND AS
YOU CAN SEE, TUMORS THAT ARE
GROWN IN ANIMALS THAT LACK THE
UBIQUITIN LIGASE, SIAH, 2, AND
YOU HAVE ON DO A KNOCK OUT OF
SI,A H 2 TO GET AS FAR AS CAN
YOU GET FOCUSED ON GET THE TOTAL
KNOCK OUT APPROACH.
AND THAT WAS SUFFICIENT TO SEE
INHIBITION OF TUMOR GROWTH.
THAT WAS SUFFICIENT TO IDENTIFY
UPREGULATION OF ANTITUMOR
IMMUNITY.
THAT WAS THE PHENOTYPE.
WELL THE TUMOR ITSELF IS
SIAH UNTOACHED BUT THE
MICROENVIRONMENT DOESN'T HAVE
SIAH[INDISCERNIBLE].
I EMPHASIZE THIS BECAUSE I WILL
PLAY THE OPPOSITE ROLE IN ABOUT
5 MINUTES SO I EMPHASIZE WE NEED
TO ELIMINATE FROM THE OLD
MICROENVIRONMENT, FROM THE
SYSTEMIC ELIMINATION OF SIAH,
TUMORS ARE STILL INHIBITED AND
THEY ARE IPT GREATER HIB
THORSITTED BECAUSE THERE IS AN
INCREASE IN THE
INFILTRATION--I'M SORRY,
DECREASED IN THE INFILTRATION OF
TREGS, REGULATORY CELLS WHICH
ARE NEGATIVELY REGULATE THE
IMMUNE SYSTEM.
THIS IS A SIMPLE MAP FROM SINGLE
CELL RNASEQ ANALYSIS, AND
FURTHER DEMONSTRATED HERE BY WAY
OF FAX ANALYSIS WHERE WE
DEMONSTRATE THERE IS REDUCTION
IN T-CELL AND ESPECIALLY TREGS.
THERE IS ENHANCED CYTOTOXIC
INFILTRATION WHILE THERE IS
REDUCTION OF TREGULATORY CELL
INFILTRATION AND THAT ALLOW TO
ENHANCE ANTITUMOR IMMUNITY, THE
MECHANISM UNDERLYING THE CHANGES
I'VE JUST DESCRIBED HAS TO DO
WITH A KNOWN SUBSTRATE FOR THE
UBIQUITIN LIGASE, LEVEL OF P27,
UPREGULATED IN THE ABSENCE OF
THE SIA AND WHEN WE PUT BACK
SIA, P27, WHEN WE INHIBIT P27 IN
THIS 1 TEXT WE'RE ABLE TO
RESCUE, GET TUMOR NO LONGER
INHIBITED, THEY GROW BETTER IN
THE ABSENCE OF P27, SUBSTANTIATE
THE ROLE OF THE SUBSTRATE
MEDIATING THE PHENOTYPE THAT WE
HAVE DISCUSSED HERE.
ONE COOL THING ABOUT THIS
FINDING WITH THE SIAH KNOCKOUT
MICE IS THE PHENOTYPE WOE HAVE
NOTED IN THESE MICE RESEMBLE
VERY MUCH PHENOTYPES THAT ARE
SEEN IN ANIMALS THAT WERE
TREATED IN CDK46 INHIBITION AND
USED IN THE CLINIC AND THE CA2
KNOCKOUT MICE BY EXPRESSION OF
PROFILE AND BEHAVIOR HAD VERY
SIMILAR CHARACTERISTIC TO THE
CDK46 INHIBITION AND INDEED,
WITH THE PD1, ALSO KNOCK OUT 2
MICE, CR2 KNOCKOUT MICE IN THIS
PARTICULAR CASE WAS VERY NICELY
RESPONSIVE ENHANCE AUTOIMMUNITY
WHEN SUBJECTED TO COMBINATION
PD1.
SO TO SUMMARIZE THIS PORTION OF
MY SIAH PRESENTATION, I
EMPHASIZED IMPORTANCE IN
HYPOXIA, I SPOKE A LITTLE BIT
ABOUT ITS ROLE IN AT4 AND UPL, I
DID MENTION THE FINDING THAT
IT'S IMPORTANT IN THE
MITOCHONDRIA FISSION, LACK OF
TIME, IMPORTANT PROSTATE CANCER,
MELANOMA AND THE ROLE OF TUMOR
INTRINSIC AND EXTRINSIC SO
EVERYTHING I TOLD YOU SO FAR IS
THAT SIAH IS SERVING AS AN ORCHG
O GENE IN THE TUMOR AND IN THE
MICRO ENVIRONMENT AND THE
INHIBITION OF SI,A H WOULD
INHIBIT TUMORS REGARDLESS OF
INHIBITION IN THE TUMOR ITSELF
OR THE MICROENVIRONMENT, SO NOW
I WILL TELL YOU THIS IS NOT SO
SIMPLE.
AND TECHNOLOGY ALLOWED US TO GO
FROM TOTAL KNOCK OUT TO
CONDITIONAL KNOCK OUT.
ASK WHEN HAVE YOU CONDITIONAL
KNOCKOUT MICE, WE CAN ASK WHAT
CAN HAPPEN TO ELIM NATION OF
THIS UBIQUITIN LIGASE ONLY IN
SPECIFIC TISSUE TYPE AND WE
START WITH MACROPHAGES.
GIVEN THE EFFECT WE HAVE SEEN SO
FAR, WE FOCUSED ON THE
MACROPHAGES AND WE KNOCKED OUT
SIAH 1 AND 2 IN MACROPHAGES OR
SIAH 1 INDEED TUMOR MACROPHAGES
WITH THIS CONDITION AND ASK WHAT
HAPPENED TO TUMOR GROWTH.
AND TO OUR SURPRISE, WE FOUND
THAT IN BOTH CASES, LUNG CANCER
AND MELANOMA GREW BETTER IF SIAH
1, 2, IN THE CASE OF LUNG OR
WOOR 1 BY ITSELF IN THE CASE OF
MELANOMA WERE
CERTAINLY--CERTAINLY
EMILYINATEED ONLY IN
MACROPHAGES.
SO OPPOSITE TO WHAT I'VE JUST
SHOWED YOU, A FEW MINUTES AGO,
ELIMINATION ONLY IN MACROPHAGES
WILL HAVE AN OPPOSITE EFFECT.
AND THIS IS A VERY IMPORTANT
LESSON FOR ALL OF US TO KNOW
BECAUSE THE MORE YOU DIG, THE
BETTER YOU FIND THE RELATIVE
PORTION AND ACTIVITY OF A
PROTEIN THAT YOU STUDY.
AND THAT'S A LESSON THAT WE
LEARNED IN OUR APPLICATIONS.
IN THE LUNG CANCER FORMATION WE
PENTINE REGIMEN TO LUNG CANCER
IMMUNITY BECAUSE A MAJ OR
PHENOTYPE WE'VE SEEN IS INCREASE
IN OR DECREASE IN AVERMEN
INFECTED OULAR MACROPHAGE
PRODUCTION ASK WHEN YOU SLEEP
APNEA AND OBESITYY DECREASE IN
THE LEVEL OF ALVEOLAR
MACROPHAGES SHOWN HERE, WE LOOK
INTO LUNG AND LUNG CARCINOGEN
WAS SUFFICIENT TO HAVE A
PHENOTYPE AND THERE WERE MORE
TUMORS, MORE LUNG TUMORS THAT
WERE FORMED IN THE ABSENCE OF
SIAH 1, 2, IN THE MACROPHAGES
ONLY.
AND FOLLOW DEMONSTRATING THROUGH
SINGLE CELL RNA SEQ AND WHAT
NOT, THEY--THE EXHAUSTIAN OF
T-CELL POPULATION THAT WAS
IDENTIFIED IN THOSE ANIMALS THAT
[INDISCERNIBLE] ONLY
MACROPHAGES.
AND THE MORE RECENT STUDY, WE
FOCUSED ON 1 LIGASE, AND
ELIMINATION OF ONLY 1 IN
MACROPHAGES WAS ENOUGH TO
INCREASE MELANOMA CAN THAT YOU
SLEEP APNEA AND OBESITYY THE
INCREASE PRETTY STRONGLY.
SO, OVER THE LAST 20 YEARS
PERHAPS, THERE ARE DOZENS OF
STUDIES ON THIS UBIQUITIN
LIGASES.
IN MOST CASES PEOPLE LOOKED AT
THE BIOCHEMISTRY IN TERMS OF HOW
THIS DO WHATEVER THEY DO IN
CULTURE, OR IN VITRO, AND THERE
WERE NO DIFFERENCES THAT PEOPLE
COULD POINT OUT BETWEEN 1 ANY 2,
WE AND OTHERS CONSIDER THEM MORE
OR DOING THE SAME.
COUPLE OF STUDIES AND I MEAN
COUPLE, 1-2-MAYBE 3, OVER THE
LAST 10 YEARS SUGGIESTED THAT S
IH1 MAY SERVE BUT NO BEDDING AS
TO WHY IT WOULD HAPPEN.
THIS STUDY HERE MAY PROVIDE THE
FIRST BLUEPRINT TO UNDERSTAND
HOW UBIQUITIN LIGASE UNDER IN A
SPECIFIC TISSUE ENVIRONMENT CAN
BEHAVE AS A TUMOR SUPPRESSOR.
SO WHAT WE NOTICED IN THIS
PARTICULAR CASE, THEY'RE
INCREASING THE NTSCs, DECREASE
IN THE IMPORTANT CELLS THAT WILL
OTHERWISE MEDIATE ANTITUMOR
IMMUNITY, CD4, CD8 AND NK AND
THE PATHWAY AND I DON'T SHOW
YOU, THE RESULT BECAUSE OF TIME,
SUGGIESTS THAT CO1 A CONTROL THE
P300 COMPLEX PROTEINS, CONTROL
HISTONE ACETYLATION AND
CONSEQUENTLY THE CHANGES WERE
NOTED IN THE PPLGAMMA AND
INFLAMMATORY GENES IS AN
MECHANISM THAT UNDERLIE TUMOR
SUPPRESSOR ACTIVITY.
AGAIN, TUMOR SUPPRESSOR IN
MACROPHAGES.
SO THE QUESTION IS: WHICH 1
WINS?
IF YOU GO AND DEVELOP A DRUG
AGAINST UBIQUITIN LIGASE WITH AN
APPROACH FOR A TOTAL KNOCK OUT
THAT WOULD BE INSUFFICIENT FOR
TUMORS OR RABLGHTER GO AFTER 1
OF THESE LIGASE ONLY SIAH 2 IS
AN ONCA GENE AND AVOID TOUCHING
SIAH1A AND THEY'RE VERY, VERY
SIMILAR TO EACH OTHER AND IF YOU
DO SO, MAYBE YOU WILL HAVE A
MOLD, DRUG OF INTEREST THAT CAN
BE FURTHER ARK ASSESSESSED AND
DEVELOPED.
--ASSESSED AND DEVELOPED.
SO, I JUST COVERED THAT AND I'LL
FINISH BY GOING BACK TO A SLIDE
THAT I STARTED WITH, WHERE I'VE
OUTLINES THE DIFFERENT STROMA
COMPETENT THAT ARE SURROUNDING
THE TUMOR AND ARE REQUIRED FOR
TUMOR REVOLUTION AND IT'S NO
LONGER GOING TO BE A ONE-ON-ONE
INTERACTION BUT RATHER A CROSS
TALK BETWEEN STROMAL CONFIDENCE
THEMSELVES BEFORE THEY CAN DO
ANYTHING ON THE TUMOR ITSELF, SO
FOR 1, THE POSSIBILITY OF THE
TIER CELLS NEED TO BE EDUCATED
OR GET PERMISSION QUOTE-UNQUOTE
FROM STROMA BEFORE THEY INFILL
STRAIGHT IS AN APPEALING
HYPOTHESIS THAT WE HAVE SOME
REASON TO BELIEVE IS WORKING AND
WE ARE TESTING IT OUT.
THE CR-GROUP STARTED WITH
[INDISCERNIBLE] DISCOVERED
POLYHYDROX LACE, [INDISCERNIBLE]
DID ALL THE WORK IN PROSTATE
CANCER AND [INDISCERNIBLE]
DIFFUSION AND ALL THE TUMOR
EXTRENSIC MECHANISMS, TUMOR
MICROENVIRONMENT WORK BY MARZIA.
SO TO SUMMARIZE, I TOLD YOU 2
STORIES TODAY, 1 HAD TO DO WITH
THE MICROBI OTA, AND THE SECOND
WITH THE TUMOR EXTRINSIC
FUNCTION.
NOT SO SIMPLE AS 1 CAN THINK,
ARE WE ABLE TO LEARN FROM THE
ABILITY OF SINGLE BACTERIA TO
ELIMINATE OR INHIBIT TUMOR
GROWTH, CAN WE TAKE IT FARTHER
AND WHAT DOES IT MEAN, 1 OF THE
TAKE HOME MESSAGES AND THE
SECOND IS, IS IT POSSIBLE TO
TARGET UBIQUITIN LIGATION TO
INTERFERE WITH CANCER, SOMETHING
I WILL LEAVE WITH YOU TO THINK
OF AS WE ARE DWELLING IN THIS
OURSELVES.
CURRENT LAB MEMBERS INCLUDE
FOLKS THAT ARE INVOLVED IN EACH
OF THE STUDIES I DISCUSSED WITH
YOU AND SOME OF THOSE THAT I
HAVE NOT, AND WE HAVE BEEN
COLLABORATIVE, COLLABORATING
EXTENSIVELY WITH MEMBERS OF OUR
DRUG DISCOVERY, CENTER AND
MELANOMA THAT WE'RE GETTING FROM
ALL OVER THE WORLD,
BIO-INFORMATICS FROM ALL OVER
THE WORLD AND LOCAL AND
MICROBIOME STUFF THAT WE ARE
BEING HELPED BY EXPERT AS WELL.
I WILL BE GLAD TO ANSWER ANY
QUESTIONS; THANK YOU.
COMPREHEND.
>> ANOTHER TOUR DEFORCE.
THAIRNGS --THANKS, THAT WAS GRE.
I HAVE A QUESTION FOR EACH PART,
WHEN YOU KNOCK OUT SIAH, AND THE
TARGET IT TO MACROPHAGES, MAYBE
I MISSED THIS DID YOU TARGET IT
TO A SPECIFIC MACROPHAGE AND
EITHER WAY DID YOU KNOW IF IT
CHANGED THE MACROPHAGE IN THE
KNOCK OUT SO IT CHANGED THE
FUNCTION OF THE MACROFAJ?
>> SO IN THE CASE OF THE LUNG
CANCER STUDY WE'VE DONE 2 KNOCK
OUT BY 2 DIFFERENT CREES, CD11 C
AND LYS2 AND WHICH STARTED A
DIFFERENT POPULATION OF
MACROPHAGES AND IN DOING SO WE
COVERED DIFFERENT ASPECTS.
THE MAJOR CHANGE WE'VE SEEN WAS
DIFFERENTIATION, DEVELOPMENTAL
IN THE [INDISCERNIBLE] 1S,
SOMETHING THAT DOES NOT HAVE
[INDISCERNIBLE] IN THE MELANOMA
STORY.
WE DID CHANGE, WE DID SEE BY
PERFORMING YEEN EXPRESSION
PROFILES WITHIN THE MACROPHAGE
THEMSELVES, SO JUST THE LACK OF
CI IS SUFFICIENT TO CAUSE THOSE
CHANGES.
WE BELIEVE THAT PART OF THEM HAS
TO DO WITH THE ASPECT OF
CIRCULATION AND WE'RE
CO-WORKERSING ON THAT NDO YOU
THINK THOSE CHANGES, START A
CASCADE THAT STARTS WITH THE
MACROPHAGE AND TRIGGERS THESE
OTHER THINGS THAT YOU SEE?
>> YES, CORRECT.
>> OKAY.
>> AND THEN THE MACROPHAGES WILL
DETERMINE ACTIVITY AND
MACROPHAGE FUNCTION SHIFT TO
COMPACT [INDISCERNIBLE] VICE
VERSA AND SO ON AND SO FORTH.
NAND DO YOU THINK THAT CAN
HAPPEN WITHOUT GENETIC
ENGINEERING IN THE PATIENT BY
SOME OTHER MECHANISM?
>> I DO THINK SO, AND AGAIN,
THIS--THIS ANSWER DOES NOT RELY
ON WHAT WE'VE DONE IN
MACROPHAGES PER SE, BUT WHAT
WE'VE LEARNED IS CI BEHAVIOR,
AND CI IS A CLASSIC STRESS
RESPONSIVE UBIQUITIN LIGASE.
SO TO ACTIVATE CI IN CELLS YOU
NEED STRESS, BY SAYING STRESS, I
MEAN YOU NEED TO ACCOUNTAIVATE
UPR, THIS IS CONTROLLED BY
[INDISCERNIBLE] SPLICE X-BP1.
SO UNLESS YOU HAVE ACTIVATION OF
UPL SIGNALING STRESSED TO A
CERTAIN DEGREE, YOU DON'T SEE CR
GETTING INTO THE ACTION AND I
THINK IN THE MACROPHAGE, IT
WOULD BE SOMEWHAT SIMILAR AND WE
KNOW THAT THAT THE HARSH
ENVIRONMENT WILL CAUSE
EPIGENETIC CHANGES THAT COME IN
THE FORM OF UPL SIGNALING THAT
ARE UPREGULATED SO I THINK THIS
WILL BE THE MECHANISM FOR CR
RESPONSE, YOU DON'T NEED TO DO
GENETIC, IT WOULD BE EPIGENETIC
NETWORK MAKES SENSE, AND THEN
THE OTHER QUESTION ON THE FIRST
PART OF THE TALK IS A BIT MORE
PHILOSOPHICAL.
YOU KNOW YOU HAVE A BEAUTIFUL
TRYPTOPHAN MODEL WHICH I THINK
THERE'S ALSO EVIDENT FOR BUT I
WOULD BET THAT IF, YOU KNOW 12
PEOPLE OR 24 PEOPLE DID STUDIES,
THEY WILL FIND ANOTHER BACTERIUM
THAT DID SOMETHING ELSE AND I
WAS WONDERING IF YOU THINK WE
WILL GET TO THE POINT WHERE
MAYBE WE WILL IDENTIFY A HANDFUL
OF BACTERIA THAT HAVE GREATER
THAN THE SUM OF THE PARTS WHICH
IS WHY I ASK YOU ABOUT THE
TRYPTOPHAN LOGISTICS AND I
WONDER IF AT THAT POINT, YOU BE
USE SORT OF BROAD SPECTRUM
ANTIBIOTICS IN PATIENTS, AND
THEN RECONSITUTE THEIR SYSTEM
WITH A COCKTAIL OF BACTERIA THAT
MIGHT BE ANTITUMOR GENIC?
>> IT'S A GOOD QUESTION AND IT
REFLECTS ON THE AGONY THAT WE
THE COMMUNITY HAVE WHEN WE LOOK
AT WHAT HAPPENED TO THE
MICROBIOME FIELD OVER THE LAST
5, 6 YEARS.
BECAUSE THERE WERE A NUMBER OF
STUDIES THAT CLAIM FOR ACTIVITY
OF THIS BUG OR THAT BUG DEPENDS
ON WHERE IT CAME FROM AND NONE
OF THEM CAME TO FRUITION,
CLINICAL TRIALS WERE HELD,
COMPANIES WERE ESTABLISHED, NONE
OF THEM WENT ANY FARTHER FELT
THIS IS THE BOTTOM LINE, IN ALL
OUR STUDIES THAT TRAY TO EXPLAIN
WHY NOT?
IN 1 OF THE EXPLANATION IS THAT
THE BUGS IN PARIS ARE DIFFERENT
THAN THE BUGS IN CHICAGO AND THE
BUGS IN WASHINGTON OR IN TEXAS.
I DON'T THINK THIS IS THE CASE,
BUT I DON'T THINK THIS WILL BE
THE SOLUTION, SO I THINK THE
SOLUTION TO THE PROBLEM WILL NOT
BE BUG A, BUG B, BUG C TO BE
COMBINED BUT RATHER WHAT IS IT
THAT THEY PRODUCE THAT WE CAN
PUT TOGETHER.
SO IF WE CAN IDENTIFY WHAT ARE
THE METABOLITES THAT ARE
ELICITING THE PHENOTYPE, WE WILL
BE MUCH STRONGER POSITION TO
REPRODUCE DATA REGARDLESS WHERE
IT CAME FROM.
NOW WE ALL KNOW THAT DIFFERENT
BACTERIAL STRAINS CAN PREVIOUSLY
PRACTICES METABOLITE BUT QUITE
FEW THAT PRODUCE THE SAME
METABOLITES, AND IT'S NOT ONLY
PRODUCK, IT'S ALSO DEPENDENCE ON
SO IT'S A LITTLE MORE COMPLEX
RELATIONSHIP THAT HAPPENS HERE.
THE BOTTOM LINE IS, I THINK WE
NEED TO MAKE METABOLITES AND
ONCE WE HAVE MET THEM,
ADMINISTER THEM AND DEMON TRAIT
THAT THEY'RE ABLE TO TO ELICIT A
PHENOTYPE.
WHEN WE ARE ON THOSE GROUNDS IT
WILL BE MUCH SAFER EXTERIOR US
TO PROCEED, WE ARE NOT THERE, WE
ARE HEADING THERE YOU ABOUTY WE
ARE NOT THERE?
>> [INDISCERNIBLE]
>> I WISH.
GLEN INDICATED COMBINATION IS A
POSSIBILITY, I HOPE SO.
ALAN?
>> SO GETTING BACK TO THE RNF5
AND THE CD8S, ANY CLUES ABOUT
DIRECT SUBSTRATES OR WHAT'S
BEING AFFECTED?
>> [INDISCERNIBLE]
>> YEAH, YEAH, YEAH.
>> SO THE QUESTION IS HOW IT
AFFECT THE MICROBI OTA?
HOW THIS HAPPENED IN THE FIRST
PLACE?
SO WHAT I HAVE NOT AND I
APOGGIZE FOR THIS, IS JUMPING
OVER A LARGE BODY OF EVIDENCE
THAT WE GENERATED AT THE TIME
DEMON
DEMONSTRATING THAT L-STRESS
HAPPENS AND IT HAPPENS IN THE
INTESTINAL EPITHELIAL CELLS AND
THAT IS BY ITSELF SUFFICIENT TO
CAUSE CHANGE IN THE MICROBI OTA
COMPOSITION.
AND WE DEMONSTRATED THE SIMILAR
CHANGES IN THE SIGNALING PATIENT
THAT ARE BETTER AND NOT
RESPONSIVE TO IMMUNE CHECK POINT
THERAPIES, SO IT HAS TO DO WITH
UPLSHAIZ CHANGE IN THE
INTESTINAL EPITHELIAL CELLS.
>> SO IN REGARDS, YOU KNOW
IDENTIFIED METABOLITES THAT FROM
THE BACTERIA IN THE GUT, SO THE
STUDY REFER TO TRYPTOPHAN AND
TRYPTOPHAN THAT IS THE PRECURSOR
OF SEROTONIN.
SO IT'S PROBABLY THAT ALL OF US
[INDISCERNIBLE] STUDY BUT COULD
IT BE POSSIBLE AS ACTUALLY THE
REAR TARGET IS A METABOLITE THEN
TO AFFECT THE NEUROSYSTEM, TO
THEN COME BACK TO AFFECT TO
REGULATE THE IMMUNE RESPONSE.
>> I CANNOT EXCLUDE THAT
POSSIBILITY.
ABSOLUTELY POSSIBLE.
IT'S POSSIBLE A METABOLITE
AFFECT INDIRECT IMMUNE
DYSFUNCTIONUNE CELLS, AND
THEY--THE WAY BY WHICH I CAN
POINT TO ARROWS THAT CAUSE THIS
INDIRECT IS ENDLESS ALMOST BUT
WE DO NEED TO REMEMBER THAT
THESE BUGS EAT TO SURVIVE,
CONSUME TO SURVIVE, AND WHAT
THEY CONSUME IS ACTUALLY
DEPLETED.
SO THE CHANGE IN THIS
EQUILIBRIUM WHERE WE HAVE
CERTAIN DECREASE IN METABOLITE
ANDS OTHERS IS THE BALANCE THAT
KEEPS IN MIND PHENOTYPE AND THAT
COULD BE THE TRYPTOPHAN LOSS
BECAUSE THIS SPECIFIC BUG LIKE
INDEPENDENT ON THIS, MAY BE THE
MECHANISM TO EXPLORE FURTHER BUT
I CANNOT ROLL OUT THAT THERE IS
INDIRECT EFFECT THAT IS MEDIATED
BY MORE ENTICING MECHANISM,
ABSOLUTELY.
>> JUST HAD A THOUGHT
EXPERIMENT, I DON'T KNOW IF
YOU'VE EVER DONE YOUR RNF5 CROSS
WITH A PML MODEL OR WHETHER YOU
THINK THAT WOULD ELIMINATE ITS
ABILITY TO CONTROL A B16 TUMOR
MODEL GIVEN ITS EFFECTS ON CD8.
>> NO, WE HAVE NOT DONE THAT
EXPERIMENT.
WE HAVE DONE AN EXPERIMENT WHICH
AGAIN I DID NOT MENTION WHERE WE
HAVE CROSSED IT WITH TLR 4 KNOCK
OUT OR SOMETHING ALONG THOSE
LINES AND WE LOST THE PHENOTYPE
AS WELL.
SO, VERY, VERY CLEVERLY, A LOSS
OF 5 TRIGGER ANTITUMOR IMMUNITY
AND PLAYING WITH THE KEY
COMPETENCE WHETHER IT'S A MYD88
WAS THE KNOCK OUT WE USE THE AT
TIME WAS SUFFICIENT TO ELIMINATE
THE PHENOTYPE BUT IT BASICALLY
COMES FROM INTESTINAL EPITHELIAL
CELLS TO START WITH CAN WHEN YOU
TRY TO MESS UP WITH ICs IT'S
WAY MORE COMPLICATED.
I CAN TELL YOU THAT.
ALL RIGHT, THANK YOU VERY MUCH.
[ APPLAUSE ]