I AM WIN ARIAS, SENIOR SCIENTIST
EMERITUS AT THE NATIONAL
INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
AND WITH MY COLLEAGUE, DAN
KASTNER, OF THE HUMAN GENOME
RESEARCH INSTITUTE.
WE WELCOME YOU TO THE 16TH
SESSION OF THE 23RD YEAR OF A
COURSE CALLED DEMYSTIFYING
MEDICINE.
THE PURPOSE OF THIS COURSE,
WHICH IS REALLY A COURSE IN
BRIDGE BUILDING, AND IT'S REALLY
TO BRIDGE THE EXCITING
DEVELOPMENTS GOING ON IN BIOLOGY
AND ENGINEERING SCIENCES WITH
MEDICINE.
THE LOGO, SHOWN HERE, IS THE
WORLD FAMOUS BROOKLYN BRIDGE.
AND THE ONLY THING WRONG WITH
THIS PHOTOGRAPH IS THAT FOR
TODAY, THERE SHOULD BE THREE
PEOPLE ON THE CATWALK.
ONE IS A PATIENT, WHO WILL
BRIEFLY DISCUSS HIS ILLNESS.
THE SECOND IS AN ACCOMPLISHED
TRANSLATIONAL ONCOLOGICAL
SURGEON, AND THE THIRD IS A
BASIC SCIENTIST, AND THEY'RE ALL
CONCERNED WITH A MAJOR
BIOLOGICAL AND MEDICAL PROBLEM,
NAMELY, THE METASTASIS OF
MALIGNANCIES.
NOW, CANCER METASTASIS IS IN
SOME RESPECTS A TERRIFYING
SITUATION.
IT IS TRULY A LETHAL CHALLENGE
IN THE SENSE THAT MOST PATIENTS
WHO HAVE CANCER DIE FROM THE
METASTASES, AND NOT FROM THEIR
PRIMARY TUMOR.
FURTHERMORE, DISTRESSINGLY, IF A
METASTASIS IS CLINICALLY
EVIDENT, THE CHANCES OF SURVIVAL
OR CURE ARE EXTREMELY SLIM.
SO WE'VE LEARNED MUCH ABOUT
METASTASIS TEU DUE TO THE
DEVELOPMENT OF NEW TECHNOLOGIES
IN MANY AREAS, AND THE CONSENSUS
IS THAT IT'S A COMPLEX EVOLVING
SYSTEM.
IT'S SORT OF A DISEASE UNTO
ITSELF, AND IT REQUIRES THE
SUCCESSION OF TRAITS OR
CHARACTERISTICS IN ORDER TO
DISSEMINATE, TO ENTER AND LEAVE
THE STATE OF DORMANCY, WHICH LE
WILL HLE -- WHICH WE WILL HEAR ,
AND THEN TO COLONIZE DISTANT
SITES.
MANY FACTORS ARE INVOLVED IN
EACH OF THESE STEPS AND IN THE
CONSORTIUM OF THEM ALL TOGETHER.
INCLUDING THE BLOOD SUPPLY,
ANGIOGENESIS AND PERHAPS EVEN
ANTIANGIOGENESIS.
SO ALL OF THESE EVENTS ARE
DRIVEN BY COMPLEX SELECTION AND
A KIND OF DYNAMIC TRANSITION TO
ONE STATE TO THE NEXT.
AND ULTIMATELY THE ABILITY TO
COOPT SYSTEMS OF THE HOST,
PARTICULARLY THE IMMUNE SYSTEM.
EACH OF THESE ARE HIGHLY COMPLEX
AND CHALLENGING, BOTH AT THE
BEDSIDE AND IN THE RESEARCH
LABORATORY.
I CALL YOUR ATTENTION TO AN
EXCELLENT REVIEW IN THE
APRIL 13'S EDITION OF CELL BY
GERSTBERGER AND COLLEAGUES, A
WONDERFUL REVIEW OF THE ENTIRE
FIELD OF CANCER METASTASES.
SO TODAY WE HAVE TWO INDIVIDUALS
WHO ARE HIGHLY ACCOMPLISHED AND
EXPERT AND HAVE DEVOTED ENORMOUS
ENERGY TOWARD THIS BIG PROBLEM
OF TRYING TO UNDERSTAND
METASTASES AND WHAT TO DO WITH
THEM.
SO OUR FIRST SPEAKER IS GOING TO
BE JONATHAN HERNANDEZ, WHO
RECEIVED HIS MEDICAL DEGREE FROM
THE UNIVERSITY OF FLORIDA, HIS
SURGICAL RESIDENCY AT THE
UNIVERSITY OF SOUTH FLORIDA,
WHERE HE ALSO SPENT TIME IN THE
MOFFIT CANCER CENTER AT THE
UNIVERSITY OF CALIFORNIA
SAN FRANCISCO STUDYING THE
MOLECULAR DIAGNOSIS,
PARTICULARLY OF LIVER
METASTASES.
AND THAT WAS FOLLOWED BY A
FELLOWSHIP AT THE MEMORIAL SLOAN
KETTERING CANCER CENTER IN
NEW YORK IN SURGICAL ONCOLOGY
AND PARTICULARLY HE HEPATOBILIAY
SURGERY, SURGERY OF LIVER AND
BILIARY TRACT.
DURING THIS TIME, HE WAS PART OF
THE ESTEEMED CELL BIOLOGY
PROGRAM, WHICH DEALS WITH
RESEARCH ON METASTATIC
COLONIZATION.
HE CAME TO THE NIH IN 2016, AND
IN THE NATIONAL CANCER
INSTITUTE, IS THE HEAD OF THE
METASTASIS BIOLOGY SECTION, AND
CHIEF OF THE SURGICAL ONCOLOGY
BRANCH.
HIS RESEARCH IS FOCUSED ON A
NOVEL EX VIVO CULTURE STUDYING
HUMAN CANCER AND METASTASES, AND
ALSO RESEARCH ON THE POSSIBLE
ROLE OF EXOSOMES.
NOW, OUR SECOND SPEAKER IS
KANDICE TANNER, WHO RECEIVED A
PH.D. IN PHYSICS FROM THE
UNIVERSITY OF ILLINOIS AT
CHAMPAGNE URBANA, DID A
POSTDOCTORAL FELLOWSHIP AT THE
UNIVERSITY OF CALIFORNIA AT
IRVINE, STUDYING THE DYNAMIC
IMAGING OF THICK SECTIONS OF
TUMORS, OF TISSUE, AND THEN
ANOTHER POSTDOCTORAL FELLOW --
FELLOWSHIP AT THE UNIVERSITY OF
CALIFORNIA, BERKELEY, THE
LAWRENCE NATIONAL LAB OF DR.
DR. BISSELL, WHO HAS DEVELOPED
EXTENSIVELY RESEARCH INTO
EXTRACELLULAR MATRIX.
IN 2012, SHE CAME TO NIH AS AN
NCI STADTMAN TENURE TRACK
INVESTIGATOR, AND IN 2020, SHE
BECAME TENURED AND IS NOW AN NIH
SENIOR INVESTIGATOR IN THE
NATIONAL CANCER INSTITUTES.
SO KANDICE'S RESEARCH HAS BEEN
ON BRIDGING MOLECULAR BIOPHYSICS
WITH CELL BIOLOGY, IN ORDER TO
LEARN HOW CELLS AND TISSUES
SENSE AND RESPOND TO THEIR
PHYSICAL ENVIRONMENT.
HER RESEARCH HAS RESULTED IN
SEVERAL AWARDS, INCLUDING THE
ARTHUR FLEMING AWARD AND THE
NATIONAL CANCER INSTITUTE
DIRECTOR'S AWARD.
SHE'S A FELLOW OF THE AMERICAN
PHYSICAL SOCIETY, WHERE SHE
SERVED ON THE COUNCIL, AND THE
AMERICAN SOCIETY OF CELL
BIOLOGY, AND HAS ALSO BEEN ON
THE COUNCIL OF THE BIOPHYSICAL
SOCIETY.
SO WE WILL BEGIN, JONATHAN,
WOULD YOU PLEASE CARRY ON.
DR. ARIAS, THANK YOU FOR THAT
KIND INTRODUCTION.
WHAT I THOUGHT I'D DO WITH MY
TIME IS SHARE A CLINICIAN'S VIEW
ABOUT HOW WE LOOK AT METASTASIS
BIOLOGY, AND THEN I HAVE A
PATIENT OF MINE WITH ME BEHIND
ME WHO WILL SHARE THE EXPERIENCE
OF A PATIENT AND WHAT THIS LOOKS
LIKE, AND I'LL END WITH SOME
THINGS WE'VE BEEN WORKING ON TO
SORT OF BETTER UNDERSTAND
METASTASIS BIOLOGY FROM A
TRANSLATIONAL PERSPECTIVE.
IF YOU ASKED ME, I WOULD SAY THE
BIOLOGY OF METASTASES, AT LEAST
AS IT RELATES TO SOLID TUMORS,
IS CANCER BIOLOGY.
AS YOU MENTIONED, DR. ARIAS,
PREVIOUSLY, YOU KNOW, THIS IS
WHY PEOPLE DIE FROM CANCER.
MOST PATIENTS WITH A PRIMARY
TUMOR, SOMEBODY LIKE ME CAN
SIMPLY CUT THEM OUT.
THE ISSUE BECOMES, WE CANNOT CUT
OUT WHAT WE CANNOT SEE, AND
THERE ARE DISSEMINATION OF
CELLS, AND SOME OF THESE
EVENTUALLY OUTGROW IN A VERY
COMPLICATED PROCESS CALLED THE
METASTATIC CASCADE.
I'VE HIGHLIGHTED THAT PROCESS
HERE AND I'LL SORT OF WALK YOU
THROUGH IT.
A GIVEN PATIENT WILL HAVE A
PRIMARY TUMOR THAT'S BEEN
IDENTIFIED BECAUSE OF EITHER A
SYMPTOM OR SCREENING, BUT THAT
CAN BE A POTENTIALLY LATE EVENT,
THAT IDENTIFICATION OF THIS.
BUT THIS TUMOR, BEFORE WE EVER
IDENTIFY IT, CAN RELEASE CELLS
INTO THE CIRCULATORY SYSTEM.
THERE ARE A LOT OF STRESSORS ON
THESE CELLS DURING THIS PROCESS,
AND THIS THANKFULLY -- THIS
PROCESS IS INCREDIBLY
INEFFICIENT, BUT FOR SOME
PEOPLE, THIS PROCESS DOES
COMPLETE, AND WHEN THAT HAPPENS,
A PATIENT DEVELOPS STAGE IV
DISEASE, WHICH WE HAD PREVIOUSLY
OUTLINED IS AN EVENT USUALLY
ASSOCIATED WITH ABBREVIATED
SURVIVAL.
NOT ALWAYS, BUT USUALLY
ASSOCIATED WITH AN ABBREVIATED
SURVIVAL.
IN ANY EVENT, THAT PRIMARY TUMOR
WILL RELEASE CELLS INTO THE
CIRCULATORY SYSTEM, WHICH CAN
EXTRAVASATE, THEY WILL LAND
SOMEWHERE IN A FOREIGN
ENVIRONMENT, A NEW ORGAN, A
PLACE THEY ARE NOT SUPPOSED TO
BE.
AND THEY CAN EITHER DIE AT THAT
POINT, KILLED BY THE IMMUNE
SYSTEM, THEY CAN ENTER INTO A
STATE OF KIE ESSENCE OR DORMANCY
WHERE THEY REALLY DON'T MOVE A
WHOLE LOT AND THERE'S THIS BACK
AND FORTH OF STARTING TO GROW
AGAIN OR NOT, AND THIS WOULD BE
TERMED MICROMETASTASIS.
THAT CAN EVENTUALLY OUTGROW
AGAIN, AS I'VE SAID, LEADING TO
WHAT WOULD OSTENSIBLY BE
MOVEMENT OF THIS TUMOR TO A NEW
PLACE, BUT THIS PROCESS IS
INCREDIBLY COMPLICATED AND BEEN
ONGOING FOR SOME TIME.
WE JUST SIMPLY DON'T RECOGNIZE
IT, WE DON'T HAVE A WAY TO TRACK
IT IN ACTUAL PATIENTS, BUT BASED
ON ALL OF OUR MODELING, THIS IS
WHAT THIS PROCESS LOOKS LIKE.
THE QUESTION ALWAYS COMES UP,
WELL, WHEN DOES THIS?
FOR A LONG TIME, THIS WAS THE
MODEL WE THOUGHT WAS HAPPENING.
YOU WOULD GET -- A PATIENT WOULD
HAVE A PRIMARY TUMOR, THAT
PRIMARY TUMOR WOULD GROW AND GET
BIGGER AND EVOLVE, AND IT SHOULD
BE STRESSED THAT THESE PRIMARY
TUMORS AS THEY RELATE TO SOLID
TUMORS ARE NOT ONE BALL OF
CELLS, THEY'RE A COMPLICATED MIX
OF MULTIPLE DIFFERENT CELL TYP
TYPES.
IT WAS THOUGHT THIS WOULD OCCUR
SORT OF LATE IN THE PROCESS.
AND THEN IT BECAME SORT OF THIS
THINKING, ONLY IF WE COULD CUT
THESE THINGS OUT EARLY ENOUGH,
WE COULD SORT OF HELP MORE
PATIENTS.
ON SOME LEVEL, THAT IS TRUE.
THIS IS AN EXAMPLE OF COLON
CANCER.
I'VE SELECTED THIS AS SIMPLY AN
EXAMPLE TO THAT
EARLIER STAGE TUMORS, PATIENTS
DO MUCH BETTER.
AND ON THE Y AXIS HERE, WE HAVE
SURVIVAL, AND HERE IS TIME, AND
OVER TIME WHAT WE REALIZE IS
EVEN PATIENTS WITH EARLY STAGE
COLON CANCER, SOME OF THEM WILL
SUCCUMB TO DISEASE BUT A
MINORITY OF THEM.
MORE AND MORE PATIENTS WILL
ULTIMATELY SUCCUMB TO THIS
DISEASE.
THE REASON, OF COURSE, IS NOT
THAT YOU COULDN'T CUT OUT THE
PRIMARY TUMOR IN THEIR COLON.
AS IT TURNS OUT, YOU DON'T NEED
MUCH OR ANY OF YOUR COLON, WE
COULD CERTAINLY DO THAT.
THE PROBLEM, OF COURSE, IS THAT
THOSE CELLS HAVE DISSEMINATED
AND THOSE PATIENTS HAVE HAD
RECURRENCE OF THAT TUMOR.
THEY'VE HAD COMPLETION OF THE
METASTATIC CASCADE.
THAT EVEN HAPPENS TO PATIENTS
WITH EARLY STAGE DISEASE BUT
IT'S MORE COMMON IN PATIENTS
WITH LATER STAGE DISEASE.
SO BECAUSE IT HAPPENS WITH EARLY
STAGE DISEASE, PROBABLY THE
PARALLEL PROGRESSION MODEL MAY
BE MORE APPLICABLE HERE.
THIS WOULD STATE THAT A PRIMARY
TUMOR DOESN'T NEED TO BE HUGE OR
EVOLVING OVER VERY LONG PERIODS
OF TIME BUT PROBABLY BEGINS TO
SEND OFF THOSE CELLS INTO THE
BLOODSTREAM, INTO THE
CIRCULATORY SYSTEM, PRETTY EARLY
ON.
AND THIS PROCESS AND THE
METASTASES CAN EVOLVE AND THE
PRIMARY TUMORS CAN EVOLVE, AND
THIS CAN ALL BE HAPPENING IN
PARALLEL.
I WOULD SAY SOME OF THE MORE
STRONGER EVIDENCE FOR THINGS
LIKE THIS IS EVEN WHEN A PATIENT
HAS A PRECANCEROUS LESION, AND
I'M SHOWING YOU DATA HERE FROM
THREE CANCEROUS PANCREAS
LESIONS, SOME OF THOSE CELLS ARE
MEASURABLE IN THE BLOODSTREAM.
SO EVEN PATIENTS WITH
PRECANCEROUS LESIONS, SOME OF
THOSE CELLS ESCAPE.
YOU MAY THINK THAT'S INCONGRUOUS
WITH WHAT I'VE SAID SO FAR, BUT
REMEMBER, THE EVENT THAT'S
ASSOCIATED WITH A BAD OUTCOME IS
NOT THE CELLS LEAVING THE TUMOR.
IT'S NOT THE CELLS LANDING IN A
NEW ENVIRONMENT.
IT'S THAT THEY'RE STILL GROWING
IN THAT NEW ENVIRONMENT.
WHAT WE KNOW FROM PRECANCEROUS
LESIONS IS THAT THEY DON'T EVER
DO THAT, THEY'RE NEVER ABLE TO
COMPLETE THE METASTATIC CASCADE,
EVEN THOUGH THIS SHEDDING EVENT
IS HAPPENING CONSTANTLY.
I LIKE TO THINK OF THE PARALLEL
PROGRESSION SORT OF LIKE THIS,
SUCH THAT AS THAT TUMOR GROWS,
IT BEGINS SHEDDING OFF MORE AND
MORE DISSEMINATING CELLS, AND
THESE CELLS, I WOULD SAY, ARE
PROBABLY MOST FIT OR BEST SUITED
TO COLONIZE THAT DISTANT FOREIGN
ORGAN.
SO I LIKE TO THINK OF THE
PROCESS LIKE THIS.
I LIKE THIS VIDEO.
I HAD THIS MADE BECAUSE IT HELPS
CONCEPTUALIZE HOW I SEE THIS.
AND SO THIS IS A PRIMARY TUMOR
IN THE PA PANCREAS OR THE END OF
THE BILE DUCT, AND AS THAT TUMOR
BEGINS TO GROW, IT SHEDS CELLS
ALL OVER THE PLACE.
LIVER, LUNG, THE PERITONEAL
CAVITY, AND THEN AT SOME POINT
IN TIME, THAT PATIENT WILL
DEVELOP METASTASES.
I PIVOTED.
WE LEFT COLON CANCER AND WE WENT
TO MORE AGGRESSIVE TUMORS LIKE
PANCREAS AND BILE DUCT CANCER,
OTHERWISE KNOWN -- THE CHANCES S
METASTATIC CASCADE COMING TO
COMPLETION ARE SIGNIFICANTLY
HIGHER THAN PATIENTS WITH COLON
CANCER.
SO THIS IS A SCAN TO SORT OF
DEMONSTRATE THIS.
BY ALL SORT OF METRICS, A GIVEN
PATIENT WILL HAVE A PRIMARY
TUMOR ONLY.
OUR LIMITS OF DETECTION, WE CAN
NEVER SEE SINGLE CELLS OR EVEN
SMALL CLUSTERS OF CELLS,
CLINICALLY WE CAN NEVER SEE
THIS.
THAT WE'RE LIMITED BY WHAT WE
CAN DO TO LIVING PATIENTS, WE
CAN'T DO ANYTHING SUPER
INVASIVE.
SO BASED ON A PET SCAN OR A CT
SCAN, ALL METRICS WOULD TELL US
THIS PATIENT HAS LOCALIZED
DISEASE BUT THAT METASTATIC
PROCESS HAS BEGUN HAPPENING
ALREADY.
AND THE SCAN I'M GOING TO SHOW
YOU NOW IS THE SCAN OF THE
PATIENT THAT I HAVE BEHIND ME, A
PATIENT OF MINE FROM SEVERAL
YEARS AGO.
THIS IS EXACTLY WHAT HAPPENED TO
KATE.
SHE CAME TO ME AND THIS IS HER
SCAN.
SHE HAD A PRIMARY TUMOR IN THE
END OF HER BILE DUCT,
CHOLANGIOCARCINOMA.
I'LL DRAW YOUR ATTENTION TO IT
IN THIS AREA HERE.
THESE ARE, AGAIN, BAD ACTORS.
KATE WAS SICK.
THE CHANCES OF THIS COMING BACK
FOR KATE WERE QUITE HIGH.
WE HAD DISCUSSIONS ABOUT ALL OF
THESE THINGS, WHAT THIS MEANS,
WHAT SURGERY CAN AND CANNOT DO,
SO THIS IS SORT OF WHAT HAPPENS.
AND THIS IS WHAT HAPPENED TO
KATE.
I REMOVED THE HEAD OF HER
PANCREAS IN AN OPERATION CALLED
A WHIPPLE, A FAIRLY EXTENSIVE
OPERATION.
MOST OF THE TIME AFTER THIS,
PATIENTS ARE GIVEN SOME SORT OF
THERAPY, AND THAT THERAPY, THE
INTENT OF THAT THERAPY IS TO
KILL WHAT WE CANNOT SEE, TO STOP
WHAT WE CANNOT SEE, AND WE
REALLY DON'T UNDERSTAND THIS
PROCESS VERY WELL.
IN PATIENTS ARE THESE CELLS AND
CLUSTERS OF CELLS, ARE THEY
GROWING AND DYING, WHAT DO THEY
LOOK LIKE IN PATIENTS?
THIS IS, AGAIN, REALLY HARD TO
KNOW IN PATIENTS.
IT'S HARD TO KNOW IN MOUSE
MODELS, BUT IT'S REALLY HARD TO
KNOW IN PATIENTS.
BUT MY ANGLES ARE MOSTLY
TRANSLATIONAL, SO I ALWAYS ASK
THE QUESTION, WHAT CAN WE DO
ABOUT THIS?
WELL, YOU WOULD INTUITIVELY
THINK THAT ONCE THAT
QUINTESSENTIAL PRIMARY TUMOR IS
REMOVED, ALL THAT IS LEFT IN
THAT PATIENT, AS FAR AS DISEASE
IS CONCERNED, IS THE STUFF WE
CANNOT SEE.
THE SOURCE IS REMOVED, SO THE
DISSEMINATED CELLS HAVE
DISSEMINATED, THEY ARE EITHER IN
TARGET ORGANS OR THEY'RE NOT.
IF THEY'RE NOT, THE PATIENT IS
NOT GOING TO HAVE RECURRENCE OF
THAT PROBLEM.
BUT FOR MOST PATIENTS,
ESPECIALLY WITH CERTAIN KINDS OF
TUMORS, THE LIKELIHOOD OF THAT
PROBLEM IS REALLY HIGH.
THE LIKELIHOOD OF HAVING
DISSEMINATED TUMOR CELLS IN
VARIOUS PARTS OF THEIR BODY IS
REALLY HIGH, AND SO WE COULD
THINK OF THIS AS, WELL, IT'S NOT
A HUGE TUMOR, THERE'S NOT A HUGE
MICROENVIRONMENT, THERE ISN'T --
MAYBE THIS IS A TIME WHERE THOSE
CELLS WOULD BE MOST SUSCEPTIBLE
TO CHEMOTHERAPY, AND THAT'S WHAT
WE THOUGHT FOR A LONG TIME.
AND SO WHAT I'M SHOWING YOU HERE
IS, I'M USING COLON CANCER AS AN
EXAMPLE AGAIN, COLON CANCER
WOULD PROBABLY BE THE G.I.
CANCER THAT HAS THE MOST
CHEMOTHERAPY OPTIONS AVAILABLE
TO PATIENTS WITH THIS DISEASE.
BUT WHAT YOU SEE HERE ON THE
LEFT IS THE RECURRENCE-FREE
SURVIVAL, ON THE RIGHT IS THE
OVERALL SURVIVAL, AND WHAT WE'VE
BEEN ABLE TO DO -- AND THIS IS
DATA I WANT TO CALL YOUR
ATTENTION FROM 1990, WITH THE
DRUG CA, WE'VE BEEN ABLE TO
DECREASE THE CHANCES OF THESE
MICRO ME TAS MICRO M METASTASIZE
CERTAINLY HAVEN'T FICKED ALL THE
PROBLEM, WE'VE BEEN ABLE TO HELP
SOME PEOPLE BUT THERE'S A LOT OF
PROBLEMS WITH THIS.
I'LL DRAW YOUR ATTENTION TO THE
BOTTOM HERE.
MOST PATIENTS ARE NOT GOING TO
HAVE THIS EVENT, SO WE ARE
POTENTIALLY SUBJECTING A LOT OF
PATIENTS TO THERAPY THEY MAY NOT
EVEN NEED.
WE JUST DON'T HAVE A WAY TO
DECIPHER WHO IS WHO.
MOREOVER, THERE'S A SMALL
IMPROVEMENT BUT IT'S NOT A LOT.
THIS IS 1990.
CLEARLY 2023 WOULD BE DIFFERENT.
LET ME SHOW YOU.
SO LET'S GO -- LET'S FAST
FORWARD.
THIS IS 2004.
FOR 14 YEARS, ALL WE HAD YAS
ADJUNCT 5FU.
WE CAN ADD NEWER DRUGS,
OXALIPLATIN.
WE SEE A SMALL IMPROVEMENT IN
RECURRENCE-FREE SURVIVAL AND WE
SEE A SMALL IMPROVEMENT IN
OVERALL SURVIVAL, BUT AGAIN, AND
THIS IS THE HIGHEST RISK GROUP,
THESE PATIENTS, MOSTLY DIDN'T
NEED THIS, AND THERE'S STILL A
SUBSTANTIAL PORTION OF PATIENTS
DYING OF THEIR DISEASE.
AGAIN, THIS IS 2004.
LET'S FAST FORWARD TO 2023.
WE DON'T HAVE ANYTHING MORE, BUT
THOSE SIMPLE DRUG COMBINATIONS
OF 5FU AND OXOLIPLATIN, HOW CAN
THAT BE?
IT BECOMES REALLY COMPLICATED TO
SORT OF TARGET SOMETHING YOU
CAN'T REALLY SEE, YOU DON'T
REALLY KNOW ABOUT, AND THE ONLY
WAY TO KNOW IS TO GIVE TO PEOPLE
AND YOU CAN'T EVEN MEASURE
ANYTHING.
AS LEAST WE COULDN'T FOR A VERY
LONG PERIOD OF TIME.
SO HERE WE ARE AS CANCER
SURGEONS, WE'RE REMOVING TUMORS,
SOME OF THESE ARE POTENTIALLY
HUGE OPERATIONS.
BUT ONLY TO HAVE SOME OF THE
PATIENTS COME BACK WITH
RECURRENCES, AGAIN, THIS WOULD
BE STAGE IV, THEY HAVE COMPLETED
THEIR METASTATIC CASCADE, SOME
OF THOSE CELLS HAVE COMPLETED
THE METASTATIC CASCADE AND WE
DON'T REALLY HAVE A VERY GOOD
WAY OF INTERRUPTING THEM.
THIS KEEPS ME UP AT NIGHT.
THIS IS A HUGE PROBLEM IN SOLID
TUMOR ONCOLOGY.
AND SO I LIKE THIS SLIDE, IT'S
OLD, IT'S FROM A MOUSE MODEL,
BUT I THINK IT HIGHLIGHTS THE
POINT.
AND THIS IS FROM DR. WEINBERG A
NUMBER OF YEARS AGO.
AND WHAT HE BASICALLY SHOWED IN
THIS MOUSE MODEL IS WHEN THESE
CELLS ARE DISSEMINATED AND
THEY'RE KIE HE SENT OR DORMANT,
THEY WERE GIVING THESE MICE
CHEMOTHERAPY TO KILL THE TUMORS
THEY COULD SEE WHICH WAS DOING A
GOOD JOB BUT IT DID NOT DO
ANYTHING TO THESE DORMANT CELLS.
THIS SORT OF HOLDS TRUE.
WHEN YOU LOOK AT WHAT 5FU AND
OXALIPLATIN DOES TO TUMORS THAT
WE CAN SEE, THE RESPONSE RATES
ARE REALLY GREAT.
BUT WHEN YOU TRY AND GET RID OF
STUFF YOU CANNOT SEE, IT'S A
LITTLE BIT BETTER, IT IS BETTER,
BUT YOU DON'T GET A LOT OF BANG
FOR YOUR BUCK, SO TO SPEAK.
AND I THINK THIS HIGHLIGHTS THE
FACT THAT WE HAVE FUNDAMENTAL
LACK OF UNDERSTANDING ABOUT WHAT
THESE DISSEMINATED TUMOR CELLS
AND MICRO METASTASES ARE, WHAT
THEY'RE DEPENDENT ON, WHAT WE
CAN USE TO EXPLOIT THEM AND KILL
THEM OR AT LEAST STOP THEM FROM
GROWING.
I'M GOING TO STOP THERE AND I
WANT KATE TO COME UP AND SHARE
HER STORY WITH US AS A PATIENT
WHO HAD ONE OF THESE HIGH RISK
TUMORS.
AND SHE CAME TO ME AS SOMEBODY
WHO HAD A VERY HIGH RISK TUMOR,
WE HAD AN EXTENSIVE DISCUSSION
ABOUT WHAT SHE -- YOU KNOW,
SURGERY WOULD ONLY DO SO MUCH.
AGAIN, IT ONLY REMOVES WHAT WE
CAN SEE.
IS THERE ANYTHING ELSE WE COULD
DO TO SORT OF PUT THE ODDS MORE
IN HER FAVOR.
ULTIMATELY I ENROLLED KATE ON A
STUDY WHERE SHE GOT A MONOCLONAL
ANTIBODY THAT SOUGHT TO KILL
THOSE DISSEMINATED TUMOR CELLS.
I ULTIMATELY HAD TO STOP THE
TRIAL BECAUSE WE SAW SOME
TOXICITY AND I THOUGHT IT WAS
UNFAIR FOR PATIENTS TO CONTINUE
ENROLLMENT, BUT KATE DID
EXCEPTIONALLY WELL.
THIS HAS BEEN SOMEWHAT AROUND
TWO YEARS --
>> THREE.
>> THREE YEARS.
TIME GOES BY.
SO IT'S BEEN THREE YEARS, AND
KATE HAS BECOME AN ADVOCATE, I
WOULD SAY, SHE HAD A DISEASE
CALLED CHOLANGIOCARCINOMA.
YOU GO TO THE CHOLANGIOCARCINOMA
FOUNDATION, KATE IS FRONT AND
CENTER, MENTORING PEOPLE AND
SHE'S BECOME VERY INVOLVED.
AND SO WHAT I'D LIKE TO DO IS
HAVE KATE SHARE HER EXPERIENCE,
SO I THINK PEOPLE CAN UNDERSTAND
HOW REAL THIS PROBLEM IS FOR ALL
PATIENTS WITH SOLID TUMORS.
SO KATE, I'D LIKE YOU TO SIT
HERE, IF YOU WOULD.
>> THANK YOU.
JONATHAN, AND TO NIH FOR
INCLUDING ME TODAY.
I CAN'T SAY ENOUGH ABOUT MY
TREATMENT HERE, THE
ORGANIZATION, EACH AND EVERY
PERSON WHO'S EVER INTERACTED
WITH ME IN THE LAST THREE YEARS.
NIH HAS SAVED MY LIFE.
SO I WANT TO BEGIN WITH THAT.
WHAT I WANT TO DO TODAY IS TO
TRY TO NOT ONLY TELL MY STORY,
BUT TO INCLUDE THE STORIES OF
ALL THE OTHER PEOPLE THAT I'VE
BEEN FORTUNATE TO TALK TO, WHOG
SUFFER WITH CHOLANGIOCARCINOMA,
SOME PEOPLE WITH PANCREATIC
CANCER, I HAD A LONG
CONVERSATION WITH SOMEONE I'M
MENTORING WHO IS DEALING WITH A
RECURRENCE OF COLON CANCER JUST
RECENTLY, SO THE COLON CANCER
SLIDES WERE FASCINATING FOR ME.
BECAUSE WHAT I'VE THOUGHT A LOT
ABOUT IS HOW TO HELP PATIENTS
LEARN MORE AND PROCESS WHAT
THEY'RE GOING THROUGH AS A
MENTOR OF PATIENTS.
I'M GOING TO TRY TO INCLUDE
THEIR PERSPECTIVES IN WHAT I
SAW.
MY STORY IS VERY SIMPLE, QUITE
DRAMATIC.
I HAD A TRIFECTA DIAGNOSIS IN
THE SENSE I WAS DIAGNOSED WITH
CHOLANGIOCARCINOMA BY BECOMING
VERY SICK WHEN MY TUMOR
COMPLETELY BLOCKED MY BILE DUCT,
AND I TURNED YELLOW, I WAS
HORRIBLY ILL, VERY SUDDENLY, BUT
IT WAS AT THE HEIGHT OF COVID.
IT WAS MEMORIAL DAY 2020, IF YOU
WELL REMEMBER MEMORIAL DAY 2020.
AND WE WERE ONE WEEK AWAY FROM
SETTLING AND MOVING OUT OF OUR
HOUSE OF 35 YEARS.
SO I HAD A -- A STUNNING WEEK OF
PACKING BOXES AND BEING SICK
AND, MEANWHILE, ACCESSING
DOCTORS AND TRYING TO DO
EVERYTHING OVER THE PHONE,
FINDING SURGICAL SITES, MY
DOCTORS HAD TO FIND SURGICAL
SITES WHERE THEY WOULD LET THEM
DO THE TESTS, BUT WHAT GOT ME
THROUGH THAT PERIOD WAS THAT I
WAS FORTUNATE TO HAVE EXCELLENT
DOCTORS ALREADY AT MY SIDE
INVOLVED.
AND ONE OF THE THINGS I WANT TO
POINT OUT IS THAT I'VE LEARNED
OVER THE PAST YEAR HOW RARE THAT
IS, HOW MANY PEOPLE THROUGHOUT
OUR COUNTRY, THROUGHOUT THE
WORLD COULD HAVE BEEN IN EXACTLY
MY SITUATION BUT DID NOT HAVE
ACCESS TO EXCELLENT MEDICAL CARE
AND ADVICE.
WERE NOT ABLE TO GET HOSPITAL
OUTPATIENT SURGERY CENTERS OPEN
FOR ERCPs, ET CETERA.
I ALSO HAD THE REMARKABLE GOOD
FORTUNE OF A VERY CLOSE FRIEND
NAMED DR. CYNTHIA TIFT, WHO
HAPPENS TO BE HERE AT THE NIH.
SO AFTER I HAD WORKED THROUGH MY
G.I. AND MY PRIMARY CARE DOCTOR
AND THEIR CONNECTIONS AND SOME
DOCTORS AT TWO FINE HOSPITALS,
ONE OF THEM HOPKINS IN
BALTIMORE, AND WAS LINED UP FOR
CARE, I ALSO WAS ABLE TO COME TO
NIH THROUGH MY FRIEND.
AND WITH DR. HERNANDEZ.
HE OPENED UP THIS TOPIC THAT
HE'S TALKING ABOUT TODAY OF
MICROMETASTASES AT THAT POINT,
AND IT WAS SOMETHING THAT I HAD
NOT HEARD BEFORE.
I'D HAD WONDERFUL SESSIONS WITH
TWO FINE WHIPPLE SURGEONS IN
BALTIMORE ABOUT SURGERY.
I THINK THROUGH THE FOG OF MY
ILLNESS, I REMEMBER THAT MAYBE
ONE OF THEM MENTIONED ADJUVANT
CHEMO SOMEWHERE DOWN THE LINE,
MONTHS LATER, TO PREVENT
RECURRENCE.
BUT THAT'S ABOUT ALL ANYONE
SAID.
I WAS TOO SICK AT THAT POINT TO
DO ANY RESEARCH MYSELF.
I WAS JUST PACKING BOXES.
AND FRANKLY, I WAS TOO SICK TO
BE VERY AFRAID.
MY FRIENDS AND FAMILY WERE
TERRIFIED BECAUSE THEY WENT
ONLINE AND READ THE STATISTICS.
BUT I WAS LOOKING FOR SOMEONE
WHO WOULD MAKE ME FEEL THAT I
COULD TRUST THAT DOCTOR TO MOVE
ME FORWARD WHEN I COULD NOT
UNDERSTAND ENOUGH MYSELF.
AT THIS POINT, I WANT TO SHIFT
GEARS AND TALK ABOUT THE COMMON
EXPERIENCE OF PATIENTS WHO HAVE
JUST HEARD THE WORD "CANCER."
I THINK WHAT I'VE LEARNED OVER
THE LAST THREE YEARS IS THAT THE
FIRST QUESTION IN VIRTUALLY
EVERYONE'S MIND IS, CAN YOU TAKE
IT OUT?
THAT'S THE QUESTION, AND THAT'S
THE WAY SOMEONE WHO HAS NOT GONE
THROUGH THIS EXPERIENCE AND
LEARNED SEES IT.
THERE'S A THING IN MY BODY THAT
SHOULDN'T BE THERE, AND I WANT
SOMEONE TO TAKE IT OUT.
IF THEY ARE TOLD, AS I WAS, YOU
HAVE A MALIGNANT TUMOR AND
YOU'LL HAVE A WHIPPLE SURGERY
AND IT'S POTENTIALLY CURATIVE,
THEY'RE GOING TO HEAR
POTENTIALLY CURATIVE SURGERY,
WHICH WILL TAKE IT OUT, AND THEN
WITHOUT KNOWING TH, WITHOUT
UNDERSTANDING, THEY'RE EXACTLY
IN THE POSITION THAT JONATHAN
WAS EXPLAINING, OF BEING AT RISK
IN WAYS THAT THE PATIENT MIND
DOESN'T UNDERSTAND.
EVEN IF IT'S EXPLAINED, EVEN IF
THEY THINK THEY UNDERSTAND.
THAT PHRASE, "CAN YOU CUT IT
OUT," IS, I THINK, CENTRAL TO
THE PATIENT PSYCHE.
ONLY LATER IN THE PROCESS, AFTER
SURGERY, AND THEN SPEAKING TO
PATIENTS FORTUNATE ENOUGH TO
HAVE SURGERY OFFERED, ONLY LATER
DOES THE IDEA OF RECURRENCE
BEGIN TO REALLY HAVE MEANING, I
THINK, FOR CANCER PATIENTS IN
THIS SITUATION.
AND AS JONATHAN WAS EXPLAINING,
THAT LATER CAN BE, IN MANY
CASES, TOO LATE.
WELL, THIS IS WHAT HE EXPLAINED
TO ME WHEN I CAME IN TO MEET
WITH HIM.
THREE YEARS AGO.
IN A BILIRUBIN FOG WHERE I COULD
ONLY BARELY FOLLOW, BUT WITH THE
BACKUP OF MY DOCTOR FRIEND WHO
COULD ACTUALLY LEAD THE PROTOCOL
HE PROPOSED, WHEN HE GAVE ME A
SHORTER, SIMPLER VERSION OF WHAT
HE WAS EXPLAINING TO YOU ABOUT
HIS FRUSTRATION WITH DOING A
BRILLIANT SURGERY TO BE FOLLOWED
BY RECURRENCE WITHIN A FEW
MONTHS.
WHAT I THINK IS IMPORTANT TO
SHARE IS THAT MY RESPONSE AT
THAT POINT WAS ENTIRELY
POSITIVE.
I REMEMBER THAT MY IMMEDIATE
INSTINCT WAS, THIS MAKES SENSE,
AND I HAPPEN TO BE A PRETTY
PROACTIVE PLANNER, SO THE IDEA
OF INTRODUCING THE IDEA OF
GETTING AHEAD OF THE PROCESS
MADE SENSE TO ME.
FOR OTHER PATIENTS, OF COURSE,
IT WOULD HAVE JUST ADDED MORE
FEAR, AND I'M WELL AWARE OF
THAT.
BUT I THINK THAT IT'S IMPORTANT
TO STRESS AGAIN THAT FOR MOST
PATIENTS, THIS IDEA OF A MIDDLE
GROUND, THIS MIDDLE PERIOD
BETWEEN TUMOR AND METASTASIS IS
NOT SOMETHING THAT THEY ARE
GOING TO BE ABLE TO THINK ABOUT
NATURALLY.
AND THEY DON'T WANT TO THINK
ABOUT IT.
GOING BACK TO MY STORY, I ENDED
UP HAVING A CHOICE BETWEEN THREE
WONDERFUL SURGEONS, AND I CHOSE
TO COME TO NIH PRECISELY SO THAT
I COULD TAKE PART IN THIS
EXPERIMENTAL PROGRAM THAT
OFFERED ME ATTENTION TO THAT
MIDDLE GROUND.
AND FROM THE BEGINNING, AFTER MY
FRIEND CINDY TOLD ME THAT SHE
WOULD LET ME GO THROUGH WITH
THIS AFTER SHE WROTE THE
PROTOCOL, I FELT EXCITED.
SO THERE WERE SEVERAL THINGS
THAT I FELT IN RESPONSE TO THE
IDEA OF TACKLING THESE
MICROMETASTASES THROUGH AN
EXPERIMENTAL STUDY DRUG.
THE FIRST WAS THAT IT MADE
SENSE.
THE SECOND WAS PURELY PERSONAL,
WHERE I INTENDED TO DO ANYTHING
AND EVERYTHING THAT I COULD DO,
AND WASN'T AS OVERWHELMED BY
FEAR AS A LOT PATIENTS ARE AT
THAT POINT.
THE THIRD WAS THAT I WAS TOO
SICK TO READ OR RESEARCH
ANYTHING ON MY OWN, AND I NEEDED
TO FIND SOMEONE TO TRUST.
AND I FELT INTUITIVELY THAT I
COULD TRUST DR. HERNANDEZ.
AND THE FOURTH WAS IMMEDIATE.
IT WAS A SENSE OF SATISFACTION
OF BEING PART OF SCIENTIFIC
RESEARCH.
I IMMEDIATELY FELT PART OF THIS
COMMUNITY.
AND THROUGHOUT MY ILLNESS, WHICH
INCLUDED OVER A MONTH IN THE
HOSPITAL, FOUR MONTHS OF
RECOVERY AT HOME BEFORE I COULD
DO MUCH OF ANYTHING AND A SECOND
SURGERY MONTHS LATER, IT WAS
CRUCIAL TO ME THAT I FELT LIKE
PART OF AN ONGOING COMMUNITY.
AND THAT, FOR ME, HAS TURNED
INTO WORKING AS A VOLUNTEER FOR
THE CHOLANGIOCARCINOMA
FOUNDATION.
TO FINISH UP BY GOING BACK TO
OTHER PATIENTS, I THINK WHAT
I'VE LEARNED IN THE LAST THREE
YEARS IS THAT WHEN ANYONE HEARS
THE WORD CANCER, AND I JUST
HEARD YESTERDAY FROM A FRIEND
WHO WAS JUST DIAGNOSED WITH
PANCREATIC CANCER, WHEN SOMEONE
HEARS THAT WORD, CANCER, FOR THE
FIRST TIME, NOT AS A POSSIBILITY
BUT AS A CERTAINTY, THE
IMMEDIATE YEARNING IS FOR
SECURITY.
I THINK OF A WOUNDED ANIMAL.
I'VE HAD NUMEROUS CONVERSATIONS
WITH FELLOW SURVIVORS OF
CHOLANGIOCARCINOMA AND
PANCREATIC CANCER, ABOUT THE
FACT THAT WHEN FIRST DIAGNOSED,
THEY DIDN'T WANT TO GO ANYWHERE
ELSE.
THEY DIDN'T WANT TO READ, THEY
DIDN'T WANT TO RESEARCH.
I KNOW SOME PEOPLE DO
IMMEDIATELY.
BUT I THINK THE VAST MAJORITY OF
PATIENTS TURN TO FAMILY, TURN TO
THEIR PRIMARY CARE DOCTOR, TURN
TO THE LOCAL ONCOLOGIST, THE
FAMILIAR HOSPITAL.
THEY WANT SOMEONE TO SIMPLIFY
THINGS FOR THEM, NOT COMPLICATE
THINGS FOR THEM.
AND THEY WANT TO BE SOMEPLACE
THEY FEEL FAMILIAR, WHERE THEY
FEEL THEY CAN RELAX AS MUCH AS
POSSIBLE.
THE IDEA OF MICROMETASTASES
DOESN'T FIT INTO THAT NATURALLY.
SO THAT BECOMES A CHALLENGE, IN
MEETING PATIENTS WHERE THEY ARE,
HOW TO ADD ANOTHER LEVEL BEHIND
CAN YOU CUT IT OUT, OR HOW CAN
WE PREVENT IT FROM RECURRING?
BUT ON THE OTHER HAND, THE LAST
THING I'LL SAY IS THAT NA IN THE
LAST THREE YEARS, WHENEVER I
TALK WITH PATIENTS AND I'M ABLE
TO TELL MY STORY AND TELL THEM
THE STORY THAT NOBODY'S EVER
HEARD OF, THEY'RE THRILLED.
THEY'RE FASCINATED.
THEY'RE EXCITED.
PEOPLE WHO WENT NO FURTHER THAN
THE DOCTOR AT THE CORNER WITH
THEIR OWN DIAGNOSIS ARE SUDDENLY
ASKING QUESTIONS, WANTING TO
KNOW WHAT THEY CAN READ, AND
WISHING THEY HAD THAT
OPPORTUNITY.
SO I THINK THAT'S WHERE THE
CHALLENGE GOING FORWARD FOR
CLINICIANS LIES, TO THE DEGREE
THAT THEY CAN WORK WITH THE
SCIENCE TO ADDRESS THAT MIDDLE
GROUND, IS IN FINDING WAYS TO
DRAW PATIENT ATTENTION AND
PATIENT CURIOSITY AND PATIENT
TRUST ALONG WITH THEM.
I'M GOING TO FINISH BY SAYING
THAT THE IRONY OF ALL OF THIS IS
THAT I'VE SPENT THE LAST YEAR OR
TWO TALKING WITH -- WHEN I SEE
JONATHAN, ABOUT MY CASE AND WHY
I'M WELL AND -- WHY I'M WELL AT
THIS POINT, THREE YEARS LATER,
AS FAR AS WE KNOW, AND HE ALWAYS
EXPLAINS IT AS GOOD FORTUNE, OR
LUCK OR MYSTERY OR THE FACT THAT
IT WAS EARLY OR THAT IT'S A RARE
OUTCOME.
I SEE IT AS A COMBINATION OF
BRILLIANT SURGERY AND AN
EXPERIMENTAL TRIAL PRODUCED BY
LEADING SCIENTISTS AT NIH.
AND THAT'S WHAT I TELL PEOPLE,
AND THAT'S WHAT I -- HOW I
INTEND TO CONTINUE TO TELL MY
STORY GOING FORWARD.
SO THANK YOU.
>> THANK YOU, KATE.
>>I ALWAYS SAY
THERE'S ACES IN EVERY DECK, AND
I TOLD YOU FROM THE BEGINNING I
THOUGHT YOU WERE AND I WAS RIGHT
ABOUT YOU, AND SOMETIMES I'M
RIGHT FOR OTHER REASONS AND I
DON'T LIKE IT AND I KNOW THERE
ARE PEOPLE WITH ISSUES, AND THIS
IS WHY WE COME TO WORK EVERY
DAY.
WITH THE TIME I HAVE LEFT, WHAT
I'D LIKE TO DO IS, I'M
FRUSTRATED BY THE PROBLEM AND BY
THE LACK OF THERAPEUTIC
OPPORTUNITIES, SO I WANT TO SHOW
YOU WHAT I'M DOING WITH IT,
DOING ABOUT IT.
SO WHAT I SORT OF CAME UP WITH,
AND I DO OPERATE ON PATIENTS
WITH METASTASES QUITE
FREQUENTLY, AND I'LL DO LIVER
OPERATIONS, INSTEAD OF GIVING
THIS SPECIMEN TO PATHOLOGY, WHAT
I'VE COME UP WITH IS, WHAT IF WE
INSTEAD TOOK IT DOWN THE HALL TO
THE LAB AND CREATED A PERFUSION
MACHINE SUCH THAT WE COULD KEEP
THIS PIECE OF TISSUE WITH A
MACRO METASTASES AS WELL AS A
MICRO -- ALL OF THE -- ALL OF
THE MICRO METASTASES PRESENT
OUTSIDE OF A GIVEN PATIENT, WE
KNOW THOSE CELLS ARE GOING TO BE
THERE, ALREADY SOME HAVE BEGUN
TO OUTGROW, WE CAN PUT IN SOME
ANTIBODIES TO HELP IDENTIFY
THEM, AND THEN WE COULD BEGIN TO
UNDERSTAND WHAT THESE MICRO
METASTASES OR DISSEMINATED TUMOR
CELLS ARE ACTUALLY LIKE.
ARE THERE ANY THERAPEUTIC
VULNERABILITIES WE COULD USE TO
EXPLOIT.
AND THIS WAS A CONCEPT THAT I
SORT OF THOUGHT OF SHORTLY AFTER
ARRIVING ABOUT SIX YEARS AGO.
WE FINALLY MADE THIS HAPPEN
AFTER A LOT OF MONEY AND A LOT
OF TIME, AND THIS IS SORT OF
WHAT IT LOOKS LIKE.
WE SA CALL THIS THE TUMOR BEARIG
ORGAN MACHINE, PRIMARILY USED
FOR LIVER BUT WE CAN USE OTHER
ORGANS.
WE HAD TO REBUILD THE PATIENT'S
BODY AROUND THIS.
YOU COULDN'T JUST BUY A PUMP AND
AN OXYGENATOR.
WE TRIED THAT, IT WOULD HAVE
BEEN WAY SIMPLER BUT IT DIDN'T
WORK.
I'M GOING TO TAKE A FEW MOMENTS
TO SHOW YOU HOW WE DO THIS.
WE CREATED A HEART AND A PUMP,
AND FOR THE LIVER, THE LIVER HAS
TWO OUTFLOW SYSTEMS, WE USED
BOTH OF THOSE.
OF COURSE THERE'S LUNGS, WE USE
OXYGOXYGENATORS, WE LEARNED ALLF
THESE THINGS THE HARD WAY.
OF COURSE THERE WILL BE A
KIDNEY, SO YOU HAVE TO HAVE
FILTRATION, AND WE SORT OF
RIGGED THIS UP WITH VARIOUS PAIS
PUMPS, WE ALSO REMAKE THE
PANCREAS INSOFAR AS INSULIN AND
GLUCAGON, WE CAN TELL ABOUT THE
GLUCOSE UTILIZATION.
WE HAVE VASOPRESSOR SUBSTANCES
AVAILABLE TO USE, SIMULATING THE
ADRENAL GLANDS, AND THEN WE ALSO
HAVE THE G.I. TRACTS, WE HAVE
TPN AND VI BILE SALTS, AND THISS
INTEGRATED INTO A VERY
COMPLICATED COMPUTER SYSTEM THAT
WE WROTE THAT'S SEMI AUTOMATED
SO WE CAN UTILIZE THIS IN A WAY
THAT SOMEBODY DOESN'T HAVE TO
SLEEP NEXT TO IT ALL THE TIME.
ADMITTEDLY THEY DO AND THAT'S
WHAT THE SURGERY RESIDENTS DO
FOR U BUT IT'S A WORTHWHILE
CAUSE AND THEY'RE COMMITTED AND
SO AM I.
AND SO THIS IS SOMEBODY WITH A
METASTATIC NEUROENDOCRINE TUMOR.
I HAD TO CUT OUT HALF OF HER
LIVER IN ORDER TO GET THIS TUMOR
OUT, AND INSTEAD OF GIVING IT
STRAIGHT TO PATHOLOGY, WE GOT IT
ON THE BACK TABLE, WALKED TO THE
LAB.
WITHIN 10 MINUTES, IT WAS ON OUR
PERFUSION MACHINE, AND WE WERE
ABLE TO PERFUSE THIS ORGAN.
POSTOPERATIVE DAY NUMBER 5, I
WALKED THAT PATIENT BACK DOWN TO
THE LAB AND HER LIVER WITH HER
TUMOR IN IT AND ALL OF THOSE
MICRO METASTASES IS BEING
PERFUSED BEHIND HER.
AND SO I THINK THIS IS THE FIRST
WAY IN HUMANS WE COULD EVER
REALLY LOOK AT THIS.
AT LEAST IN ANY REAL WAY.
SO THIS IS HER LIVER
ENVIRONMENT.
I'M NOT SHOWING YOU ANY MICRO
METASTASES IN THIS PICTURE, BUT
THIS IS THE OSTENSIBLY NORMAL
LIVER THAT WE KNOW IS GOING TO
HAVE MICRO METASTASES IN IT.
THIS IS HER TUMOR AFTER ABOUT A
WEEK, AND IT LOOKS PRETTY
NORMAL.
AND SO NOW WE HAVE THE ABILITY
TO UNDERSTAND THE TUMOR
VULNERABILITIES, MATT CROW THE O
METASTASES AND THE POTENTIAL TO
FIND THOSE MACRO METASTASES.
WE'VE MADE THE HAYSTACK MUCH
SMALLER AND WE'RE ACTIVELY
LOOKING FOR THERAPEUTIC
VULNERABILITY SO I CAN COME UP
WITH NEW THERAPIES TO OFFER
PATIENTS LIKE KATE.
THAT'S ALL I WANT TO SHARE WITH
YOU, AND I SLIGHTLY WENT OVER
TIME AND I APOLOGIZE, BUT I
APPRECIATE THE OPPORTUNITY TO
SPEAK.
>> THANK YOU VERY MUCH,
JONATHAN.
THAT'S VERY EXCITING.
NOW WE'RE GOING TO GO ON TO
KANDICE TANNER.
KANDICE?
>> SO THANK YOU SO MUCH FOR THE
OPPORTUNITY TO SHARE OUR, I
GUESS, PERSPECTIVE IN TERMS OF
HOW WE APPROACH METASTASIS.
AND WE'VE ALREADY HAD SOME
EXCELLENT INTRODUCTIONS INTO THE
TOPIC, BUT WE'RE GOING TO PURSUE
IT FROM A DIFFERENT ANGLE IN
TERMS OF HOW MICROENVIRONMENTAL
FACTORS REGULATE THIS VERY
IMPORTANT PROCESS AND
UNFORTUNATELY LETHAL PROCESS OF
CANCER, AND WE'RE GOING TO
INTRODUCE CONCEPTS THAT PHYSICAL
PROPERTY, PHYSICAL
CHARACTERISTICS OF THESE TISSUES
AND MATRIX COMPONENTS WITHIN
THIS MICROENVIRONMENT ARE
IMPORTANT.
SO YOU MAY BE SURPRISED THAT
PHYSICS CAN PLAY A ROLE IN TERMS
OF CANCER BIOLOGY, SO LET'S
FIRST INTRODUCE THIS.
FIRST MY DISCLOSURES, AS WELL AS
THE OBJECTIVES OF TODAY.
SO IN TERMS OF ORIENTATION,
WE'RE LOOKING AT A
HISTOPATHOLOGY SLIDE HERE, AND
IT'S SHOWING A PROGRESSION, SO
THIS IS FROM A TISSUE BIOPSY
WHERE WE HAVE NORMAL EPITHELIUM,
THAT'S SEPARATE BID CONNECTIVE
TISSUE BY THIS SPECIALIZED
BASEMENT MEMBRANE, AND AS A
FUNCTION OF MALIGNANCY, SO FROM
LEFT TO RIGHT, WE'RE MOVING FROM
NORMAL TO FULL TUMORS, INDICATED
BY THESE SIMPLY MARCATIONS.
THERE ARE TWO OBVIOUS PHYSICAL
CHARACTERISTICS THAT YOU CAN
APPRECIATE FROM THESE BIOPSIES.
ONE IS THE SIZE OF THE CELLS IN
TERMS OF THESE NORMAL
COMPARTMENTS, AS WELL AS IN THE
STROMAL OR CONNECTIVE TISSUE ARE
ALTERED.
THE SECOND THING IS THAT THE
ARCHITECTURES IN TERMS OF HOW WE
DEFINE THESE TISSUE BOUNDARIES
ARE ALSO ALTERED AS A FUNCTION
OF MALIGNANCY.
AND AS A THIRD PROPERTY THAT WE
AND OTHERS HAVE SHOWN, THAT IT
IS ALSO ALTERED AS A FUNCTION OF
THIS TRANSITION FROM NORMAL TO
MALIGNANCY.
AND THAT IS IN THE SENSE THAT
MECHANICAL PROPERTIES OF THESE
TISSUES ALSO CHANGE DURING THIS
PROGRESSION.
SO THE IDEA THAT MECHANICAL
PROPERTIES IN ITSELF CAN BE USED
TO DELINEATE NORMAL TISSUES FROM
THAT OF CANCERS HAS BEEN KNOWN
SINCE ANTIQUITY.
IN EARLY EGYPTIAN PERIODS, IT
WAS SHOWN IN PAPYRUS SORT OF
MARKINGS THAT IF ONE USES SIMPLE
TOUCH, ONE CAN DIFFERENTIATE
THAT A CANCER MASS HAS A
DIFFERENT PHYSICAL OR MECHANICAL
PROPERTY COMPARED TO NORMAL
TISSUES.
BUT HOW DO WE THEN RECONCILE
THESE SORT OF ANECDOTAL, SORT OF
GROSS TYPES OF DATA AND
RE-CREATE IT IN A LAB?
SO YOU MAY HAVE HEARD OF THREE
DIMENSIONAL CULTURE SYSTEMS OR
ORGANORGANOID SIM TELLS, WITH TE
ABILITY TO RE-CREATE TISSUES
USING THESE HYDROGEL MODELS.
ON THE LEFT WE'RE LOOKING AT THE
RECREATION OF MAMMARY EPITHELIAL
ASSAY, WE CAN SEE THE EVOLUTION
AND DIFFERENT TYPES OF MOTILITY,
BUT MORE IMPORTANTLY, WE COULD
USE THESE AS SCREENS TO
RE-CREATE THESE TUMOR TISSUES
THAT JONATHAN JUST SPOKE ABOUT.
BUT ONE OF THE THINGS THAT
ALLOWS US TO DO IS TO BE ABLE TO
USE OPTICAL TECHNIQUES THAT ARE
SHOWN BELOW.
I'M GOING TO TALK BRIEFLY ABOUT
THEM LATER ON.
BUT JUST AS AN EXAMPLE, BY USING
THESE ORGANOID SYSTEMS AS WELL
AS OPTICAL BASED SYSTEMS, WE AND
OTHERS HAVE BEEN ABLE TO
IDENTIFY THESE MECHANICAL
CHANGES THAT OCCUR AS A FUNCTION
OF MALIGNANCY.
THE QUESTION IS -- WHAT EXCITED
ME, THIS CAN ALSO BE DONE IN THE
CLINIC RIGHT NOW, ALBEIT
DIFFERENT LENGTH SCALES, NOT
QUITE AT THE MICRO SCALE WE DO
IN TISSUES BUT IN MILLIMETER
SCALES IN TERMS OF IN VIVO.
AND ONE OF MY COLLEAGUES AND
COLLABORATORS USES ANOTHER
OPTICAL BASED TECHNIQUE KNOWN AS
MAGNETIC RESONANCE ELASTOGRAPHY
WHERE YOU CAN PROBE THE ABILITY
IF THESE TUMORS HAVE DIFFERENT
PHYSICAL OR MECHANICAL
PROPERTIES COMPARED TO NORMAL
TISSUE COUNTERPARTS.
SO I'VE SHOWN YOU THAT WE COULD
DO THESE MEASUREMENTS IN CULTURE
MODELS.
WE COULD DO THESE MEASUREMENTS
IN HUMANS.
BUT WHY YET IS THIS NOT BEING
USED ACTIVELY AS A DIAGNOSTIC
MODEL?
AND ONE OF THE REASONS BEING IS
THAT WE STILL CANNOT UNDERSTAND
THE BIOLOGY THAT DRIVES THESE
CHANGES IN A PREDICTABLE MANNER.
SO THIS IS ONE OF THE
OUTSTANDING QUESTIONS IN WHAT WE
WOULD CALL A FIELD OF CANCER
MECHANOBIOLOGY.
SO I'VE SPOKEN TO YOU ABOUT THE
ABILITY TO SEE THESE PHYSICAL
PROPERTIES, HOW THEY'RE USED
RIGHT NOW IN TERMS OF THEIR
STANDARD TECHNIQUES, BUT I
HAVEN'T SPOKEN TO YOU ABOUT
METASTASIS AND WHAT ROLE IT MAY
PLAY IN DRIVING THIS PROCESS.
SO WE'VE ALREADY HAD THIS
INTRODUCTION SO I'M GOING TO
RE-INTRODUCE THE CONCEPT FOR YOU
SO THAT YOU CAN LOOK AT IT FROM
A DYNAMIC PERSPECTIVE.
THIS IS A VERY CRUDE SCHEMATIC
OF A TUMOR, TUMOR CELLS ARE
SHOWN IN PURPLE.
TO ORIENT YOU, THIS IS SOME
EXAMPLE OF, IN THIS CASE, A
CONDUIT, A BLOOD VESSEL, AND
THESE ARE BLOOD CELLS, AND ONE
THING THAT YOU COULD APPRECIATE
THAT YES, METASTASIS DESCRIBES
THE DISSEMINATION FROM A PRIMARY
SITE WITHIN SOME CONDUIT, SO IN
SOME CASES, EVEN ALONG NERVES
AND SO FORTH, TO BE ABLE TO
SURVIVE AT A DISTANT SITE.
AS THIS MOVIE LOOPS, I WANT YOU
TO APPRECIATE THAT IT'S A
DYNAMIC PROCESS, THAT THESE
CELLS UNDERGO DIFFERENT CHANGES
IN TERMS OF THEIR CELL SHAPE.
THEY ENCOUNTER DIFFERENT CELL
TYPES.
AND HENCE THEY WILL BE EXPOSED
TO DIFFERENT PHYSICAL
ENVIRONMENTAL PRESSURES THAT MAY
INFLUENCE THE CELL'S ABILITY TO
SURVIVE OR GET -- ACQUIRE TRAITS
THAT MAY ENHANCE SURVIVABILITY
AT THEIR DISTANT SITES.
WE'VE ALREADY INTRODUCED THIS
CONCEPT THAT METASTASIS REMAI
REMAINS -- A MAIN CAUSE OF --
WHERE 90% OF PATIENTS WITH
METASTATIC DISEASE WILL SUCCUMB
WITHIN FIVE YEARS.
SO FOR US, THE QUESTION THEN,
HOW CAN WE THEN BRING THIS IDEA
OF RE-CREATING THIS DYNAMIC
PROCESS INTO SOME OF THE MODEL
SYSTEMS THAT WE INTRODUCED
EARLIER.
SO THERE'S ONE MORE THING I NEED
TO TELL YOU ABOUT METASTASIS.
NOT ONLY IS IT DYNAMIC, NOT ONLY
DO THESE CELLS ENCOUNTER
DIFFERENT CELL TYPES AS THEY GO
ABOUT THEIR JOURNEY.
IS THAT HOW THEN DO WE RE-CREATE
THIS PROCESS?
IN TERMS OF BEING ABLE TO GET
THAT.
SO I'VE INTRODUCED THIS ORGANOID
MODEL.
I'VE INTRODUCED THE CONCEPT NOW
THAT I'M GOING TO INTRODUCE TO
YOU ANIMAL MODELS, IN THIS CASE,
WE USED ZEBRAFISH, AND HOW COULD
WE THEN BUILD IN THE COMPLEXITY
OF THESE DYNAMIC PROCESSES THAT
I JUST SHOWED YOU IN THE
SCHEMATIC.
SO AS A REMINDER, THESE ARE
THREE DIMENSIONAL HYDROGELS.
WHAT IS NOT SPE SEEN IN BLACK SS
HERE IS THAT THIS IS A MATRIX
THAT USUALLY REPRESENTS THE
CHEMISTRY AND BIOPHYSICAL
PROPERTIES THAT THESE CELLS
WOULD SEE IN AN ORGAN-SPECIFIC
MANNER.
AND I AS I PLAY THIS MOVIE HERE,
NOW, TO BE ABLE TO BUILD IN
THESE CONDUITS WHERE THESE
PHYSIOLOGICAL FORCES SUCH AS
BLOOD FLOW OR LYMPHATIC FLOW CAN
INFLUENCE AND IMPART FORCES ON
TO THESE CELLS, WE'RE USING A
LARVAL ZEBRAFISH.
SO TO ORIENT YOU, THIS IS NOW
THE HEAD OF THE FISH, THIS IS
ITS EYE, BLOOD VESSELS ARE IN
RED -- ARE IN GREEN, AND WHAT
YOU SEE IN HERE ARE HUMAN BREAST
CANCER CELLS THAT WERE
INTRODUCED INTO CIRCULATION AND
WE'RE ABLE TO FOLLOW THESE CELLS
WITH SINGLE CELL RESOLUTIONS AS
THEY TRAVERSE WITHIN THESE
CONDUITS, AND THEN WHAT YOU'RE
LOOKING AT IS THE ABILITY TO
FOLLOW VERY EARLY STAGES OF
EXTRAVASATION, NAMELY WHEN THESE
CELLS HAVE LEFT THESE BLOOD
VESSELS, IN THIS CASE, AND ENTER
INTO THE HEAD OF THE FISH.
SO THESE ARE NO MODELS THAT MO E
NOW MODELS THAT ALLOW US TO GET
TO EARLY STAGES THAT AS JONATHAN
POINTED OUT ARE NOT OPTICALLY
ACCESSIBLE RIGHT NOW IN HUMANS.
OF COURSE WE'D LIKE TO GET TO
THIS STAGE, BUT THIS IS WHERE
WE'RE AT TODAY.
BUT THERE'S ONE MORE THING I
NEED TO TELL BUT ME ABOUT META,
HERE I'M SHOWING YOU FOUR
DIFFERENT EXAMPLES, AND BASED ON
WHERE THESE TUMORS ORIGINATED,
IF WE FOCUS ON PROSTATE CANCER,
SOME MOLECULAR SUBTYPES OF
PROSTATE CANCER, PREFS LENGSLY
GO TO BONE, WHEREAS LUNG AND
BREAST CANCERS ARE FAIRLY
PROMISCUOUS IN THAT THEY CAN
COLONIZE MANY SITES SUCH AS THE
BONE, LIVER, LUNG AND BRAIN,
ALBEIT WITH DIFFERENT LATENCIES
AND ALSO TO SOME EXTENT BASED ON
THE MOLECULAR SUBTYPE.
SO THIS IDEA THAT THERE'S SOME
TROPISM IN THAT CELLS CAN ONLY
COLONIZE AND SURVIVE IN DISTANT
ORGANS HAVE ALREADY BEEN
DESCRIBED IN THAT HE COULD
FOLLOW THE OBSERVATION THAT
TUMOR CELLS, IF ONE CAN
APPROXIMATE THEM AS IF THEY WERE
SEEDS, WITH SOME GIVEN INTRINSIC
PROPERTIES, ONLY BEFELL ON
CONGENIAL SOIL, WHICH WOULD NOW
BE TH THE DISTANT SITES AND THAT
WHICH DRIVE ACROSS
COMPASSIBILITY, THAT ONLY THEN,
A SUCCESSFUL LESION EMERGES.
SO SINCE THAT EARLY OBSERVATION
IN 19TH CENTURY, YOU KNOW, THERE
ARE MANY SORT OF LIKE, I WOULD
SAY, SEMINAL WORKS BUILT ON THIS
FROM THE ORIGINAL FINDINGS IN
BREAST CANCERS TO OTHER TYPES OF
CANCERS, IN THAT FIGURING OUT
ONE OF THOSE TWO MAIN INTRINSIC
OR SEED PROPERTIES, VERSUS ONE
OF THOSE PROPERTIES THAT ARE
COMPATIBLE OR NEED TO BE
COMPATIBLE IN SOIL FOR THE ORGAN
OF THE SECONDARY OUTGROWTH.
SO THEY'VE SHOWN THERE'S SOME
GENE SIGNATURE THAT REGULATES
THIS PROCESS AND IN TERMS OF THE
CELL'S AVAILABILITY TO TALK TO
THE MICRO VIERPT, THIS ALSO, MIE
WITH CHEMOKINES OR THAT WE
RECEIVE FROM THE SOIL OR
SECONDARY SITE CAN THEN DIRECT
THIS COMPATIBILITY.
MORE RECENTLY, THE IDEA THAT
TUMOR CELLS SECRETE THESE
PACKETS OF EXOSOMES AND THAT
WHEN THEY GET TO THESE SECONDARY
SITES, MAKE THE ORGAN MORE
ACCESSIBLE FOR A SUCCESSFUL
OUTGROWTH OF TUMOR CELLS ONCE IT
GETS THERE, KNOWN AS THE
PREMETASTATIC NICHE.
SO THESE ARE SOME OF THE FACTORS
THAT HAVE SINCE BEEN DETERMINED
BUT WE'RE STILL NOT GETTING THAT
PREDICTABILITY IN TERMS OF COULD
WE REALLY PREDICT IF, ONE, A
TUMOR WOULD METASTASIZE IN A
GIVEN PATIENT, AND, MORE
IMPORTANTLY, WHERE WOULD IT
METASTASIZE TO.
SO WE PUT FORWARD THE HYPOTHESIS
THAT BECAUSE CELLS CAN UNDERGO
DIFFERENT FORCES AND DIFFERENT
PHYSICAL PROPERTIES CAN DIRECTLY
CHANGE GENE EXPRESSES, THAT THIS
MIGHT BE ONE OF THE MISSING
DETERMINANTS THAT CAN PLAY A
ROLE IN THIS NON-RANDOM
SELECTION DURING METASTASIS.
SO I'VE TOLD YOU THAT WE CAN USE
ZEBRAFISH AS A MODEL TO
RE-CREATE SOME OF THE
PHYSIOLOGICAL PRESSURES, BUT THE
IDEA IS THAT A MODEL NEEDS ALSO
TO BE RELEVANT FOR
HUMAN-SPECIFIC DISEASE.
SO I'M GOING TO INTRODUCE A FEW
CONCEPTS WHERE WE THINK THAT
SOME ASPECTS OF HUMAN RELEVANT
DISEASE CAN BE RECAPITULATED,
ESPECIALLY GIVEN THIS
ORGAN-SPECIFIC COLONIZATION.
SO IN THIS SCHEMATIC, WE'RE
LOOKING AT TWO DIFFERENT CLONES
OF A BREAST CANCER CELL LINE
THAT REPRESENTS A SUBTYPE KNOWN
AS TRIPLE NEGATIVE BREAST
CANCERS.
AND THEY EXIST SUCH THAT IF YOU
INTRODUCE THEM INTO MICE, A
BRAIN TARGETING CLONE GOES TO
THE BRAIN WHEREAS IF YOU
INTRODUCE BONE MARROW -- IT GOES
TO THE BONE MARROW.
SO IF WE CAN RE-CREATE THIS
ASPECT IN TERMS OF ORGAN
SPECIFIC COLONIZATION, WE SIMPLY
ASK THE QUESTION, IF WE
INTRODUCE THESE CLONES DIRECTLY
INTO THE FISH, DO WE THEN SEE
THE SAME PATTERN OF COLONIZATION
WHERE BRAIN TARGETING GOES TO
THE BRAIN AND BONE MARROW
TARGETING GOES TO THIS BO BONE
MARROW NICHE.
SO WHAT DID WE FIND?
HERE WE'RE LOOKING AT
MICROGRAPHS.
LET ME ORIENT YOU.
HERE'S THE HEAD OF THE FISH,
HERE IS ITS EYE.
AND WHAT WE OBSERVED IS THAT
FIVE DAYS AFTER INJECTION, WE
SEE THAT BRAIN TARGETING CELL
SHOWS MULTIPLE SITES OF
EXTRAVASATION AND GROWTH IN THE
HEAD OF THE FISH.
WHEREAS THE CLONE THAT'S HOME TO
THE BO BONE MARROW, THEY'RE DEVD
OF ANY CELLS.
TO BE SURE THIS IS REALLY A
NON-RANDOM SELECTION, WE NEED TO
QUANTIFY IN THE SAME FISH IF
THESE CELLS ARE REDIRECTED TO
THE OTHER ORGANS.
SO WHEN WE CHECK WITH BRAIN
TARGETING CELLS FOR OUR BONE
MARROW NICHE OF THE FISH, WE DO
SEE SOME BLUE CELLS PRESENT BUT
THEY'RE LARGELY DEAD OR DYING.
THEY HAVE MI MIXED TRAF SATED --
HAVE INDEED WENT INTO THE BONE
MARROW NICHE AND ARE ACTIVELY
GROWING THERE.
SO I'M SHOWING YOU FOR -- BUT
WHAT IS COMING FOR BASIC SCIENCE
APPLICATIONS WE HAVE TO PROVE
THIS FOR MULTIPLE CLONES AND
THIS IS INDEED THE CASE.
BUT MOVING FORWARD, I'M JUST
GOING TO SHOW YOU SOME OF THESE
DATA.
SO ONE OF THE THINGS THAT WE
THINK IS THAT TUMOR CELLS NEED
TO GET STUCK.
SO THESE ARE NOW WHEN THESE
BLOOD VESSELS, ALL LYMPHATIC
VESSELS SOUGHT TO GET INTO THESE
VERY NARROW SPACES, WHERE THE
CELL DIAMETER IS COMPARABLE
INSIDE TO THE WIDTH OF THE
VESSELS.
AND WHEN WE FIRST FOCUSED HERE
JUST IN THE INTEREST BECAUSE
THIS IS SUPPORTED TO BE AN
OVERVIEW, WE'VE NOTICED THAT IF
WE UNDERSTAND HOW THESE CELLS
INTERACT WITH THESE ENT THEEL EL
CELLS AT THIS INTERFACE -- HOW
DO WE FINE THAT LESS DEFINED --
CONCEPTS HOW IN ADDITION TO
GENETIC MODULATION, THAT
BIOPHYSICAL PROPERTIES MAY PLAY
A ROLE.
SO LET'S START WITH THE
FOLLOWING SCHEMATIC.
ON YOUR LEFT, I'M SHOWING YOU
NOW WWHEN A CELL GETS STUCK IN A
BLOOD VESSEL THAT'S COMPARABLE
IN SIZE, AND THE CELL ITSELF CAN
BE FINE AS IF IT HAS MATERIAL
PROPERTIES JUST AS IF YOU WERE
PICKING UP THIS BOTTLE THAT HAS
SOME GIVEN SOFTNESS OR STIFFNESS
VERSUS JUST LIKE -- A CELL HAS
THAT DIFFERENT TYPE OF MATERIAL,
WHICH I'M GOING TO INTRODUCE
WHAT WE MEAN BY THAT LATER.
BUT BY UNDERSTANDING CELLS'
MECHANICAL PROPERTY IN ASSIGNING
THAT MECHANICAL SIGNATURE, THESE
CELLS, IN ORDER TO MAINTAIN CELL
SHAPE, OR THE ABILITY TO BE ABLE
TO GET OUT, THEY ALSO WOULD BE
INFLUENCED BY THE MECHANICAL
PROPERTIES OF THESE BLOOD
VESSELS THAT THEY'RE STUCK IN.
SO I WANT YOU TO THINK ABOUT IF
A CELL IS IN A TUBE AND IS
TRYING TO GET OUT, WHEN THE
FORCES THAT ARE IMPARTING ON
THESE CELLS AT THAT TUBE IS
GOING TO INFLUENCE THE CELLS'
ABILITY TO MAINTAIN ITS SHAPE OR
THE ABILITY TO OVERCOME TO GET
OUT SO ONE OF THE LIMITING STEPS
IN MOVING THIS FORWARD IS THAT
WHAT DO WE MEAN AND HOW DO WE
MEASURE WHAT CELLS SENSE ONCE
THEY GET INTO THESE IN VIVO-LIKE
SITUATIONS.
, OPTICAL TWEEZERS HAD BEEN
USED, IN FACT THE NOBEL PRIZE IN
PHYSICS HAD BEEN OPTICAL
TWEEZERS HAS BEEN GIVEN A FEW
YEARS AGO NOW,, AND WE'RE GOING
TO INTRODUCE THIS CONCEPT IN
THESE VERY COMPLEX MECHANICAL
PROPERTIES KNOWN AS A SHARED MOD
MODULUS.
BY DOING THIS, WE COULD THEN
UNDERSTAND THIS RELATIVE BALANCE
BETWEEN THE CELLS' ABILITY TO
MAINTAIN CELL SHAPE AND TO GET
OUT.
A SECOND PHYSICAL PROPERTY THAT
THESE CELLS ENCOUNTER ONCE
THEY'RE IN THESE SORT OF
CAPILLARY BEDS IS THAT THE
ABILITY TO BIND IN TERMS OF
RECEIVING QUEUES EITHER BY -- BY
RECEPTOR LIGAND PARENTS,
PHYSICAL OR -- PROPERTIES, ALSO
REGULATED BY THE MEMBRANE
PROPERTIES.
SO SO IF THE CELL IS IN THESE
CURVED TYPES OF BEHAVIORS AND
THE MEMBRANES WOULD THEN BE
INFLUENCED BY THAT CURVATURE AND
IT COULD INFLUENCE HOW THESE
DIFFERENT RECEPTORS CLUSTER AT
THE CELL SURFACE THAT THEN DRIVE
DOWNSTREAM SIGNALING EFFECTS.
IN ADDITION, NOT ONLY DOES IT
INFLUENCE THE MEMBRANE
STRUCTURES IN TERMS OF
CLUSTERING, IT MAY ALSO DRIVE A
PREFERENCE FOR ONE TYPE OF
RECEPTOR VERSUS THE OTHER,
BECAUSE THESE HAVE BEEN SHOWN TO
BE ALSO SENSITIVE TO DIFFERENT
PHYSICAL PROPERTIES.
SO WHAT WE CAN THEN DO BECAUSE
WE HAVE THE SINGLE CELL
RESOLUTION IS DEFINE THESE
ARCHITECTURAL CHANGES, AND THEN
MOVE FORWARD IN TERMS OF HOW DO
THEY THEN INFLUENCE CELLS'
ABILITY TO SENSE AND RESPOND TO
THESE QUEUES AND IF THESE ARE,
INDEED FACTORS IN DRIVING THE
NON-RANDOM SELECTION THAT WE
OBSERVED.
SO I INTRODUCED MECHANICAL
PROPERTIES BUT I DIDN'T REALLY
GET INTO WHAT DOES IT MEAN, THE
COMPLEXITY OF IT, AND HOW COULD
WE POSSIBLY DEFINE THEM SO THAT
IN THE EVENT WE COULD USE IT AS
A POTENTIAL BIOMARKER.
SO TISSUES ARE NEITHER JUST
SIMPLY ELASTIC OR SIMPLY SOLID.
THEY SHOW A COMBINATION OF THE
TWO, WHICH IS KNOWN AS
VISCOELASTICITY.
SO AS I PLAY THIS MOVIE, THIS IS
A FLUID REPRESENTATIVE OF WHAT A
VISCOELASTIC MATERIAL BEHAVES
LIKE, AND YOU SEE AS A FUNCTION
OF HOW IN THIS CASE A FINGER
INTERROGATES THIS MATERIAL, ON
YOUR LEFT YOU SEE THAT AT HIGH
FREQUENCIES, SO VERY FAST
TAPPING, THE MATERIAL BEHAVES AS
IF IT HAS MORE SOLID-LIKE
PROPERTIES.
WHEREAS, IF YOU THEN LOOK AT THE
SAME MATERIAL WHERE YOU PROBE AT
LOWER FREQUENCIES, SO LONGER
TIME SCALES, THIS MATERIAL
BEHAVES MORE LIQUID-LIKE.
SO THE IDEA NOW THAT DEFINING
THESE TWO PROPERTIES CAN BE
SHOWN IN THIS FORMULA BELOW,
WHERE THE RELATIVE CONTRIBUTIONS
ARE GIVEN BY THE STORAGE, AND
IMAGINARY -- THAT GOES THROUGH
THIS LOSS MODULUS.
BY UNDERSTANDING THESE THINGS,
NOT ONLY CAN WE DEFINE EITHER
THE MECHANICAL PROPERTIES OF
THESE CELLS, THE IDEA IS ONCE WE
MEASURE THEM, AND LINK THAT TO
BIOLOGICAL SIGNATURE, THEN MAYBE
THEY MAY GIVE A HINT IN TERMS OF
BIOMARKERS FOR THERAPY.
SO GOING BACK TO THE
DEMONSTRATION OF IF THE LARVAL
ZEBRAFISH CAN RECAPITULATE SOME
ASPECTS OF HUMAN DISEASE, ONE OF
THE THINGS WE ASK SIMPLY IS AS A
FUNCTION OF WHERE THESE CELLS
HOME TO, WHETHER THEY WENT TO
BRAIN VERSUS A BONE MARROW,
COULD WE USE THAT AS OUR METRIC
IN ITSELF, JUST LIKE SOME GENE
SIGNATURE, TO BE ABLE TO
DETERMINE OR MATCH A MECHANICAL
SIGNATURE TO THAT PROCESS.
SO ON THE Y AXIS WE SIMPLY SHOW
YOU THE -- ON THE X AXIS ARE
FREQUENCIES, AND WHAT I WANT YOU
TO TAKE AWAY TB FROM THIS, WE CN
DEFINE A FACTOR HERE THAT THEN
ALLOWS US TO THEN USE THIS AS A
METRIC TO DEFINE A MECHANICAL
PHENOTYPE.
SO THIS CROSSOVER FREQUENCY
SIMPLY TELLS ME WHEN A MATERIAL
BECOMES MORE SOLID-LIKE VERSUS
LIQUID-LIKE.
AS IT SHIFTS FROM LEFT TO RIGHT,
IF IT GOES TO THE LEFT THAT,
MEANS MATERIAL HAS MORE
LIQUID-LIKE PROPERTIES.
IF IT GOES TO THE RIGHT, IT
ALLOWS US TO TELL US IT'S MORE
SOLID-LIKE BUT MORE IMPORTANTLY,
IT GIVES US A QUANTITATIVE
PARAMETER THAT ASSIGNS A
MECHANICAL PHENOTYPE.
SIMPLY LIKE IF YOU ARE TRYING TO
ASSIGN A GENE EXPRESSION, THIS
GIVES US THE SAME MECHANICAL
SIGNATURE.
SO JUST AS A REMINDER WHAT SOLID
LIKE AND LIQUID LIKE MEAN, WHAT
WE COMPARE, THIS IS NOW THE
PARENTAL CLONE FROM WHICH EACH
OF THESE CLONES WERE DERIVED, WE
SEE NOW THAT THE CLONE TO THE
BONE MARROW, MORE LIQUID-LIKE,
VERSUS THE CLONE THAT WENT MORE
TO THE BRAIN.
SO WE CAN SEE IN ADDITION TO
GENE EXPRESSION CHANGES THAT I
DIDN'T SHOW YOU EARLIER BUT WE
KNOW EXIST BETWEEN CLONES, THAT
THERE'S A MECHANICAL SIGNATURE
THAT CAN BE PULLED OUT AND THIS
IS QUITE EXCITING FROM THE
PRIMARY TUMOR.
BUT NOW WE WANT TO GET BACK TO
THIS IDEA OF IS THIS THEN
INDICATIVE OR AN ADVANTAGE IN
TERMS OF BEING ABLE TO GET OUT
INTO THESE SECONDARY SITES.
SO CAN WE GO BACK TO OUR FORCE
BALANCE TO UNDERSTAND WHAT TYPES
OF PRESSURE OR I WOULD SAY
RESISTANCE THESE ENDOTHELIAL
BARRIERS HAVE AT THESE SECONDARY
SITES.
AND WHILE I'M SHOWING YOU DATA
IN A DIFFERENT FORM WHERE NOW WE
HAVE THIS MAGNITUDE OF THE
COMPLEX MODULUS, THE CROSSOVER
FREQUENCY -- ONE CAN APPRECIATE
THAT THERE ARE NO DIFFERENCES AS
A FUNCTION OF WHERE THESE
ENDOTHELIAL CELLS -- THE
MECHANICAL PROPERTIES OF THE
ENDOTHELIAL CELLS.
SO AT LEAST WE COULD SAY AT THE
AGES AT WHICH WE SEE THESE
EXTRAVASATION EVENTS ARE
NON-RANDOM, AT LEAST THAT
MECHANICAL PROPERTY WAS
CONSTANT.
INSTEAD NOW, LET'S INVESTIGATE
THE SECOND ASPECT OF THE CELLS'
ABILITY TO RESPOND TO THESE
QUEUES VIA THE INFLUENCE ON
MEMBRANE DYNAMICS.
AND WHAT WE DID IS THAT IF WE
QUANTIFIED IN TERMS OF THE
CURVATURE THAT THESE CELLS SAW,
IS THAT THE BONE MARROW NICHE --
PLEXUS IS MUCH MORE HIGHLY
CURVED COMPARED TO THAT OF THE
BRAIN, AND WE USE THESE
INTERSEGMENTAL VESSELS AS A
CONTROL.
AND WITH THAT, WE SIMPLY ASK
THEN, COULD THAT BE ONE OF THE
REASONS WHERE MOST OF THE BRAIN
TARGETED CELLS PREFER TO GET
STUCK IN THE BRAIN ENVIRONMENT
VERSUS THE VASCULAR PLEXUS.
AND TO OUR SURPRISE, WHAT WE
FOUND IS THAT INDEPENDENTLY OF
THE CELL TYPE, SO LET ME TALK
YOU THROUGH THIS VERY BUSY
CURVE, IS THAT WE'RE NOW
QUANTIFYING VERY EARLY STAGES.
SO THIS IS THE FIRST 12 HOURS
AFTER WE DIRECTLY INTRODUCE THE
LESIONS INTO THE CIRCULATORY
SYSTEM.
WHAT WE OBSERVED IS THAT
INDEPENDENTLY OF CELL TYPE, SO
HERE ARE TWO DIFFERENT CLONES,
AND 10-MICRON DIAMETER BEADS
THAT SHOULD NOT HAVE A RECEPTOR
THAT'S BIASED FOR ONE ORGAN
VERSUS ANOTHER, THAT MOST OF
THEM GET STUCK, INDICATING THAT
THE ARC 10 TOUR ARCHITECTURE THE
CHAOTIC ACTUALLY ACTS AS A FIRST
PASS TO GET THESE CELLS
PREFERENTIALLY STUCK IN ONE
ORGAN VERSUS THE OTHER.
BUT WHY, THEN, DO WE OBSERVE
THAT BRAIN TARGETING CELL
PREFERS TO GO TO THE BRAIN IN
TERMS OF EXTRAVASATION, AND THE
BONE MARROW TARGETING CELL THEN
PREFERS TO EXTRAVASATE, WHEREAS
THIS INITIAL STEP TELLS US THAT
THEY TEND TO GET STUCK IN THIS
HIGH HIGHLY CURVED AREA, AND ITS
BACK TO, ONE, THE ASSUMPTION
THAT THESE SECTORS THAT ARE
PRESENT ON THESE CELLS TO BE
ABLE TO RESPOND TO THIS QUEUE,
ARE THEY EVEN CONSTANT, AND
WOULD THEY BE EXPRESSED IN THE
SAME WAY, AND WOULD THEY RESPOND
TO THESE QUEUES IN A DIFFERENT
WAY?
SO FOR THAT, WE PERFORMED
PROTEOMIC ANALYSIS THAT THEN
IDENTIFIED THAT THERE IS INDEED
A DIFFERENCE IN DIFFERENT
RECEPTORS THAT ALLOW CELLS TO
RESPOND TO DIFFERENT QUEUES, AND
NAMELY ONE OF THEM IS INTERGRIN
BETA 1, WHICH IS UPREGULATED IN
THE BONE MARROW HOMING CELLS
COMPARED TO BRAIN TARGETING
CELLS, AND THE LAST IS
UNCONVENTIONAL MYOSIN 1B
TARGETING BRAIN CELLS VERSUS THE
BONE MARROW TARGETING CELLS.
IN THE INTEREST OF TIME I'M JUST
GOING TO SHOW YOU SOME SNAPSHOTS
OF THIS UNCONVENTIONAL MYOSIN
1B.
WE INDEED CONFIRM THIS HAD IS
LOCALIZED IN BRAIN TARGETING
CELLS LARGELY DEVOID IN BONE
MARROW CELLS AND AS YOU CAN SEE,
THERE'S A DIFFERENCE IN THIS
MEMBRANE DYNAMICS GOING BACK TO
THIS CONCEPT OF HOW THESE
ARCHITECTURES CAN REGULATE
MEMBRANES AND, THEREFORE, THE
ABILITY TO BIND.
WHEN WE SILENCE, WE FIND THESE
CELLS ARE NO LONGER ABLE TO
COLONIZE THE BRAIN, INSTEAD --
SO JUST BY TUNING THESE CELLS'
ABILITY TO SENSE THESE QUEUES BY
THESE RECEPTORS, WE COULD THEN
CHANGE THEM.
WE WANT TO MAKE SURE THIS ISN'T
ZEBRA CELL SPECIFIC, SO WE TOOK
PARENTAL CELLS AND DID THE SAME
SILENCING AND WHAT WE OBSERVED
IS THAT THERE'S A DISTINCTION
BETWEEN A REDUCTION IN CELLS'
ABILITY TO COLONIZE THE BRAIN
COMPARED TO THE CONTROL.
SO WHAT I THINK I'D LIKE TO
INTRODUCE IS THAT YOU MAY HAVE
HEARD OF MOUSE MODELS, YOU MAY
HAVE HEARD OF 3D ORGANOID MODEL,
BUT THERE ARE OTHER PRE-CLINICAL
MODELS OUT THERE THAT CAN
RECAPITULATE SOME ASPECTS OF
HUMAN DISEASE.
AND IN THIS CASE BY USING CELLS
THAT RECAPITULATED THIS
NON-RANDOM TROPISM, WE CAN
IDENTIFY THAT IN ADDITION TO
GENE EXPRESSION CHANGES, THAT A
MECHANICAL SIGNATURE MAY INDEED
BE PROMISING IN TERMS OF
DEFINING THESE CELL TYPES
A PRIORI.
WE ALSO INTRODUCE A CONCEPT THAT
THIS SELECTION CAN OCCUR AT
ENDOTHELIAL INTERFACES AND BY
UNDERSTANDING HOW CELLS GET IN
AND OUT OF THESE DIFFERENT
ARCHITECTURAL COMPLEXITIES MAY
ALSO DRIVE WHY METASTASIS, ONE,
IS AN INEFFICIENT PROCESS, BUT
WHEN IT DOES WORK, WHY IT
ACTUALLY DOES WORK.
NOW, THERE ARE A FEW CAVEATS.
REMEMBER WE'RE TRYING TO
RECAPITULATE SOME ASPECTS OF
HUMAN DISEASE.
WHEN WE PLACE HUMAN BREAST
CANCER CELLS IN ZEBRAFISH THERE
ARE THINGS WE NEED TO TAKE INTO
CONSIDERATION.
WHILE WE COULD RECAPITULATE THE
PHYSIOLOGICAL FORCES SUCH AS
BLOOD FLOW AND BLOOD VESSELS, WE
DON'T HAVE TO WORRY ABOUT STOKES
CONSERVED IN MAY MAILIAN BRAIN,
FISH IS ACTIVELY GROWING.
AND WHILE THERE'S A PRESENCE OF
THE INNATE IMMUNE SYSTEM, THE
REASON WHY WE CAN GET HUMAN
CANCER CELLS TO SURVIVE AT THESE
STAGES IS THAT THE ADAPTIVE
IMMUNITY IS NOT PRESENT YET AND
ONLY MATURES LATER ON.
SO THERE'S THIS WINDOW THAT
ALLOWS US TO LOOK AT THESE SORT
OF EXTRAVASATION PROCESSES.
LIMITATIONS ARE THAT WE CAN'T
LOOK AT THESE BIG METASTASES,
ONLY THESE EXTRAVASATION EVENTS
AND THE IDEA IS THAT HOW CAN WE
THEN FOLLOW THIS PROCESS FROM
THE BEAUTY OF THE FISH WHICH IS
SINGLE CELL DISSEMINATION AND
STILL MAINTAIN THE ABILITY TO
HAVE THIS VISUALIZATION AND
MANIPULATION THAT I MENTIONED,
BUT MORE IMPORTANTLY, FOLLOW TO
FRANK LESIONS.
HOW DO WE GET FROM HERE TO HERE?
SO THIS IS NOW THE ADULT FISH ON
YOUR RIGHT AND HERE WE'RE
SLIGHTLY -- WE'RE CHANGING
MODELS HERE, AND THAT WAY WE'RE
USING A HUMAN RELEVANT MELANOMA
MODEL DRIVEN BY THE SAME GENETIC
DRIVERS THAT ARE FOUND IN
ZEBRA -- IN HUMAN MELANOMAS, IN
FACT, ONE OF THE FIRST ANIMAL
MODELS OF ME MELANOMA WAS DONE N
FISH AND WE'RE ABLE TO BRING
THIS SORT OF RESOLUTION TO HERE,
WHERE YOU SEE THE -- HEAD AND
THE TAIL OF THE FISH.
SO FOR THAT, WE HAD TO BE A BIT
CREATIVE.
SO WHAT WE DESIGNED IN
COLLABORATION IS THAT THE
ABILITY TO SOLVE ONE OF THE
ISSUES THAT EXISTED IN THE
ZEBRAFISH FIELD IS HOW DO WE
KEEP THIS FISH ALIVE AND MORE
IMPORTANTLY, ALIVE LONG ENOUGH
SO THAT WE COULD MAINTAIN THIS
SINGLE CELL RESOLUTION THAT I
SHOWED YOU EARLIER.
JUST TO ORIENT YOU HOW THIS IS
DONE, IT'S A MICRO FLUID DEVICE
WHERE WE HAVE AN ORAL LAVAGE
INTO THE FISH.
THIS FISH DOESN'T HAVE STRIPES,
THIS IS A MUTANT FISH, AND MORE
IMPORTANTLY, WE CAN GET LONG
TERM SURVIVAL, THE FISH STAYS
ALIVE AND WE CAN DO LONGITUDINAL
FOR SEVERAL DAYS.
SO WITH THIS IN MIND, ONE OF THE
TECHNIQUES I SHOWED YOU BEFORE,
WE CAN BRING THIS INTO THE ADULT
FISH AND MORE IMPORTANTLY, INTO
METASTATIC LESIONS THAT WERE NOT
POSSIBLE.
SO JUST AS A REMINDER, WE STILL
HAVE THE ABILITY TO DO
MECHANICAL PROPERTIES, WE STILL
HAVE THE ABILITY TO THEN LOOK AT
WHAT MAY BE RELEVANT IN THE
HUMAN DISEASE.
SO I'D LIKE TO KIND OF INTRODUCE
A FEW CONCEPTS HERE QUICKLY TO
WRAP UP.
YOI SHOWED YOU MECHANICAL CHANGS
CAN PLAY A ROLE BUT ULTIMATELY
IF THIS WERE INDEED GOING TO BE
USED AS A BIOMARKER, WE STILL
NEED TO UNDERSTAND WHAT DOES IT
MEAN -- RELATIVELY SOLID VERSUS
LIQUID LIKE, IS THAT INDICATIVE
OF A BIOLOGICAL PROCESS?
AND HERE I'M SHOWING YOU NOW
THAT WHAT WE THINK MAY BE AN
IMPORTANT ROLE IS THAT CELLS --
THAT MECHANICAL SIGNATURE MAY BE
A FUNCTION OF THE METABOLIC
STATE OF THE CELL.
SO HERE ON THE Y AXIS, THIS GOES
BACK TO DEFINING HOW SOFT OR
STIFF A MATERIAL IS, AND EACH OF
THESE INDIVIDUALS CURVES ARE
SHOWN ON THE RIGHT HERE, GIVEN
PH KNOWN TO GIVE A DIFFERENT
METABOLIC TYPE OF STATE, MEANING
HOW THESE CELLS METABOLIZE
ENSOMETIMES.
AND BY USING THIS, WE SEE THAT
AS A FUNCTION OF CHANGE IN THE
PH IN A SENSE, WE ALSO MODULATE
MECHANICAL PROPERTY AS SHOWN
HERE WHERE THE MOST ACIDIC PH IS
STIFFER THAN THAT OF THE MOST
BASIC IN OUR DYNAMIC RANGE.
SO I HYPOTHESIZED THAT MAYBE,
GOING BACK TO TRY TO LINK THESE
PHYSICAL PROPERTIES, THAT THEY
ARE INDEED INDICATIVE OR MAY BE
INDICATIVE OF BIOMARKER OF THIS
METABOLISM AND CAN BE USED IN
CONCERT IN TERMS OF TESTING THIS
RULE OF DRIVING ORGAN-SPECIFIC
METASTASIS.
SO THESE ARE THE TWO QUESTIONS
WE'RE TRYING TO ADDRESS RIGHT
NOW AND QUITE FRANKLY I'M
PUTTING IT OUT THERE IN TERMS OF
DIRECTIONS OF THE LAB AND I
THINK TO SOME EXTENT THE FIELD
WILL START TO GET INVOLVED IN
THESE TYPES OF MEASUREMENTS.
BUT THE IDEA IS THAT HOW CAN WE
THEN LINK, WE HAVE A LOT OF
MICRO SCALE TECHNIQUES THAT WE
AND OTHERS HAVE DEVELOPED, MY
COLLEAGUE IN GERMANY HAS THE
ABILITY TO MEASURE THESE THINGS
DIRECTLY, HOW CAN WE THEN REALLY
TRY TO BRIDGE THESE GAPS.
SO IN MY LAB, WE HAVE BEGUN
TESTING THESE MECHANICAL
PROPERTIES OF THESE TISSUES AND
THESE LESIONS THAT I SHOWED YOU
EARLIER ON, WE ALREADY FOUND
SOME LINKS BETWEEN MECHANICAL
PROPERTIES AND BY USING A
PROCESS KNOWN AS FLUORESCENT
LIFETIME -- METABOLIC STATE, AND
MY COLLEAGUE IN COLLABORATION,
WE'LL TRY TO DO THESE
MEASUREMENTS WHERE WE COULD MAP
THESE MECHANICAL MEASUREMENTS
DONE WITH MAGNETIC RESONANCE EE
LAS TOGRAPHY WITH PET IMAGING
THAT ALSO GIVES US A READOUT OF
THE METABOLIC STATES OF THESE
TUMORS.
SO JUST TO KIND OF BUILD IN TO
WHAT WE'VE DONE IN TERMS OF THIS
IN VITRO MODEL, SORRY THIS IN
VIVO MODEL, THE ZEBRAFISH
SYSTEM, AND WE'VE SEEN THAT
THERE'S A CORRELATION BETWEEN
THE CELLS, TUMOR CELLS IN TERMS
OF THEIR BRAIN -- THEIR ORGAN
LOCATION, BRAIN METASTASES,
SKELETAL METASTASES, THAT IS
ALSO CORRELATED WHERE WE SEE A
HIGHER RATE OF GLYCOLYSIS IN THE
BRAIN METASTASES VERSUS A HIGHER
OXIDATIVE -- IN SKELETAL
METASTASES, SO THIS IS EXCITING
BECAUSE IT AGAIN STARTS TO
BRIDGE THESE CONCEPTS OF WHAT
DOES IT MEAN TO HAVE A
MECHANICAL PROPERTY AND HOW CAN
WE THEN CORRELATE THAT TO SOME
BIOLOGY.
AND I'D LIKE TO JUST LEAVE WITH
A LAST TWO CAVEATS.
WE STARTED OFF BY BEING ABLE TO
VISUALIZE THE CELLS' ABILITY TO
INTERACT WITH ITS
MICROENVIRONMENT.
SO WHILE THESE QUANTITATIVE
MULTIPLEX MEASUREMENTS ARE
INDEED INDICATIVE, ULTIMATELY,
THERE'S SO MUCH POWER IN SEEING
THINGS THAT WE CANNOT SEE AT THE
SINGLE CELL RESOLUTION AND
LESIONS IN VIVO IN THE HUMAN.
SO THE ZEBRAFISH IS POWERFUL IN
THAT THE IMMUNE SYSTEM IS
CONSERVED WITH THE HUMAN SYSTEM
FOR MANY ASPECTS, MAINLY, IN
THIS CASE YOU'RE LOOKING AT
T-CELLS.
AND ONE OF THE THINGS YOU CAN
APPRECIATE IN THE T-CELLS I
FOUND IN THESE DIFFERENT
METASTATIC LOCATIONS IS THAT
THERE'S A DIFFERENCE IN THE WAY
THAT THEY MOVE, THERE'S A
DIFFERENCE IN THEIR MORPHOLOGY.
DO YOU SEE THESE TYPES OF --
THAT WE OBSERVE THEM, AND MORE
IMPORTANTLY, WHEN WE TRY TO MAP
THIS SINGLE CELL SEQUENCING, WE
OBSERVE THAT THERE ARE DIFFERENT
FLAVORS OF THE IMMUNE
INFILTRATES.
AND WHILE THIS IS POWERFUL IN
TERMS OF GENE EXPRESSIONS THAT
MAY BE DISTINCT OR
DIFFERENTIALLY EXPRESSED, RIGHT
AWAY, YOU COULD SEE THAT EVEN IN
THESE TUMORS, THERE'S A
HETEROGENEITY IN TERMS OF THEIR
MOTILITY, HETEROGENEITY IN TERMS
OF A MORPHOLOGY, SO IT BRINGS
BACK THIS CONCEPT OF WHEN WE GET
THESE TYPES OF DATA, HOW MUCH
HAD THEY REALLY -- ARE THEY
INDICATIVE OF WHAT'S GOING ON IN
THE TUMOR AND HOW THIS MAY
IMPACT ANY OF OUR THERAPEUTIC
TARGETS.
SO I JUST WANT TO WRAP UP IN
SAYING THAT SOME OF THE GOALS
THAT WE HAVE, BECAUSE OF THE
FACT METASTATIC DISEASE IS STILL
OF CLINICAL RELEVANCE, IS CAN WE
THEN USE SOME PRE-CLINICAL
MODELS TO REALLY RE-CREATE SOME
ASPECTS OF THIS HUMAN DISEASE,
BE REALISTIC IN TERMS OF WHAT WE
CAN RE-CREATE AND BE TRANSPARENT
ON WHAT WE'RE NOT RE-CREATING,
AND THEN MOVE TOWARDS JUST
DEFINING THESE MECHANICAL
PROPERTIES, IN THE REALM OF
BASIC BIOLOGY IN TERMS OF
MECHANOBIOLOGY, BUT TRYING TO
UNDERSTAND THEN, HOW COULD WE
THEN LINK THIS SORT OF SIGNATURE
INTO WHAT'S CLINICAL BIOMARKERS.
JUST TO RECAP, CAN WE USE IT
RELIABLY TO DIFFERENTIATE NORMAL
TISSUES FROM CANCERS?
WE COULD DO THAT, BUT HOW COULD
WE DO IT FUNCTIONALLY?
CAN WE THEN USE THIS TO
UNDERSTAND WHAT HAPPENS IN THE
SELECTION OF SITES OF
METASTASIS?
AND THEN I WOULD SAY THIS IS MY
PIE IN THE SKY GOAL, WOULD IT BE
USEFUL IN TERMS OF UNDERSTANDING
WHAT REGULATES THERAPY
EFFECTIVENESS?
SO OBVIOUSLY I DON'T DO THIS
WORK ALONE.
I'M REALLY FORTUNATE TO BE HERE
IN THE INTRAMURAL PROGRAM.
OF COURSE I LIKE TO THANK MY
FUNDING SOURCES, MY ALUMNI, AS
WELL AS THE PEOPLE WHO CURRENTLY
WORK IN THE LAB.
AND WITH THAT, I'M HAPPY TO TAKE
ANY QUESTIONS, AND THANKS AGAIN
FOR THE OPPORTUNITY.
>> WELL, THANK YOU BOTH FOR VERY
STIMULATING TALKS COVERING VERY
DIFFERENT ASPECTS OF THIS
COMPLICATED PROBLEM.
WE'VE GOT ENOUGH QUESTIONS TO
KEEP THIS GOING FOR ANOTHER
COUPLE OF HOURS, SO I'M GOING TO
TRY AND CONDENSE SOME OF THEM
INTO CERTAIN AREAS.
SO THERE ARE A WHOLE SERIES OF
QUESTIONS ABOUT THE IDEA OF
DORMANCY, OF DORMANT CELLS, AND
I SEEM TO RECALL THAT IT KIND OF
CAME TO LIGHT WHEN PATIENTS WHO
WERE SUCCESSFULLY SUPPOSED
LIQUEURED OF CERTAIN CANCERS, I
THINK IT WAS BREAST CANCER, IN
LATER YEARS, DONATED A KIDNEY
FOR A SIBLING OR SOMEONE WHO WAS
MATCHED, AND THEN LO AND BEHOLD,
IT TURNED OUT THAT THE KIDNEY,
WHICH HAD NOT BEEN KNOWN TO HAVE
ANY UNUSUAL CELLS IN IT, WAS THE
SOURCE OF A VERY ACTIVE BREAST
CANCER.
NOW, I THINK I'VE GOT THAT RIG
RIGHT.
BUT THE CONCEPT OF DORMANCY,
MAYBE YOU'D EACH LIKE TO BRIEFLY
COMMENT ABOUT IT.
THE SPECIFIC QUESTIONS PEOPLE
HAVE ASKED, WHAT DO WE KNOW
ABOUT THE GENETICS, ABOUT THE
METABOLISM?
IS THERE ANY WAY WE COULD
IDENTIFY DORMANT CELLS BY ANY
IMAGING TECHNIQUE, AND DORMANT
CELLS IN THE IN VITRO MODELS OR
IN THE ORGANOIDS BEING CREATED
AND FOLLOWED?
CAN YOU BRIEFLY -- I'M SURE WE
CAN HAVE A WHOLE SESSION ON
DORMANCY, BUT IT WOULD BE, I
THINK, OF GREAT INTEREST TO HEAR
YOUR VIEWS ABOUT THIS.
SO JONATHAN, YOU WANT TO GO
FIRST?
>> SURE, THAT'S A VERY BIG
QUESTION.
THIS PROCESS IS INVALUABLE IN
MOUSE MODELS.
WHEN I SHOWED UP HERE, I SORT OF
HAD THIS IDEA THAT I WOULD SEW
WINDOWS ON THE MOUSE LIVER AND
GLUE THE LIVER UP AND WE COULD
DO ALL SORTS OF MANIPULATION
INCLUDING INJECTING VARIOUS CELL
LINES.
I ULTIMATELY SETTLE OED ON THE T
THAT IF YOUR ANGLE IS HEAVILY
TRANSLATIONAL, THEN I'M JUST NOT
SURE THAT THIS WOULD ACCURATELY
PREDICT ANYTHING IN PEOPLE SUCH
THAT IT WOULD BE SOMETHING WE
SHOULD FOLLOW PHARMACOLOGICALLY
AND TRY AND MANIPULATE.
SO THE LONG AND SHORT OF THIS
IS, IT'S VERY HARD TO IDENTIFY,
I'LL CALL THEM DORMANT
DISSEMINATED TUMOR CELLS IN
PEOPLE.
IT HAS BEEN DONE BY DOING BONE
MARROW ASPIRATES AND IDENTIFYING
SMALL NUMBERS OF CELLS, THIS IS
IN BREAST CANCER, BUT IT'S
REALLY HARD, AND THEN I THINK
THE QUESTION REALLY RELATES TO,
WHAT CAN WE LEARN ABOUT THEM?
I THINK YOU CAN GARNISH SOME
INFORMATION ABOUT THE GENETICS
OF MACRO METASTASES AND YOU
KNOW, IT'S UNLIKELY THAT IF YOU
WERE TO SINGLE CELL SEQUENCE AN
ENTIRE MICRO METASTASES, YOU
MUST PICK UP THE HE GENETICS OF
A MICRO METASTASIS AT SOME
POINT.
I DON'T THINK GENETICS IS GOING
TO CAPTURE THE PROBLEM.
THIS IS A PLASTIC STATE.
CLEARLY, THE DORMANCY PART, YOU
LEAVE A PRIMARY TUMOR WHERE
YOU'RE LIKELY TO BE GROWING AT
LEAST AT SOME POINT, YOU WERE
DIVIDING, AND YOU END UP IN THIS
PLACE, AND YOU STOP.
YOU DIDN'T CHANGE YOUR GENETICS
IMMEDIATELY.
YOU PROBABLY WENT THROUGH AN
EPIGENETIC REPROGRAMMING EVENT
WHERE YOU WERE SORT OF NOT DOING
ANYTHING OR YOU WERE SORT OF IN
AN ENVIRONMENT THAT WASN'T QUITE
FAVORABLE FOR YOU AND SO YOU
DECIDED NOT TO DO ANYTHING.
THIS DOESN'T REALLY MEAN CHANGES
IN GENETICS.
SO THE SECOND PART OF THE
QUESTION WAS DOES IT MEAN
CHANGES IN METABOLISM.
I WOULD SAY THE ANSWER IS YEAH,
I WOULD SAY THE ANSWER IS HIGHLY
LIKELY TO BE YES, YOU DEFINITELY
HAVE CHANGE IN METABOLISM,
AGAIN, CAPTURING THAT INTO --
WAYS IS REALLY HARD.
IT'S GOING TO BE REALLY HARD TO
DO IN A PERSON, ALTHOUGH I
CERTAINLY WOULD BE AB LOVE TO BE
ABLE TO DO THAT ZEBRAFISH STUFF
IN A PERSON.
THAT'S GOING TO BE TOUGH, BUT
WHAT IF WE SEPARATE THE ORGAN
THAT HAS A LOT OF METASTASES
FROM THE PERSON SUCH THAT WE CAN
DO A LOT OF ME NIP LATING.
BUT EVEN THEN, STILL A BIG PIECE
OF TISSUE IS NOT SEE-THROUGH,
IT'S JUST VERY DIFFICULT, BUT
THAT'S SORT OF WHERE WE ARE IN
WORKING WITH THIS.
SO I WOULD SAY DO WE HAVE ANY
IDEA OF WHAT DORMANT
DISSEMINATED TUMORS ARE LIKE
METABOLICALLY?
NO, I DON'T FEEL LIKE I KNOW THE
ANSWER TO THAT QUESTION.
GENETICALLY I THINK YOU CAN
INFER THIS, BUT I DON'T THINK
GENETICS IS GOING TO ANSWER THE
QUESTION.
>> KANDICE, WHAT IS YOUR VIEW?
>> DORMANCY IN ITSELF IS THAT
YOU HAVE SINGLE QUIESCENT CELLS
THAT HAVE SUCCESSFULLY
EXTRAVASATED, AND THAT THEY'RE
ABLE TO, QUOTE-UNQUOTE, BE --
RESIDE AND RESIST ANY SORT OF
IMMUNE SURVEILLANCE, RIGHT?
SECOND ASPECT IS THAT YOU COULD
HAVE THESE CELLS THAT CAN DIVIDE
TO SOME EXTENT, BUT THEN THEY
MANAGE, EITHER BY SOME BALANCE
BETWEEN DEATH AND SURVIVABILITY,
THAT KEEPS IT BELOW SOME
CRITICAL MASK.
SO I THINK THAT GOING BACK TO
WHAT HAS BEEN SHOWN IN
PRE-CLINICAL MODELS, AND THESE
ARE MOUSE MODELS, AND SOME OF
THE WORK WE WANT TO ILLUSTRATE
STARTS WITH ANNE CHAMBERS, WHO
WAS AT UNIVERSITY OF TORONTO,
WHO LOOKED AT SOME OF THESE
FACTORS THAT COULD EITHER BE
CELLULAR BASED VERSUS THAT OF
THE MICROENVIRONMENT.
JEFF BREEN HEJEFF GREEN HERE ATI
BEFORE HE RETIRED LOOKED AT WHAT
COULD WEAKEN THESE CELLS, THEY
WERE MICROENVIRONMENT TALL
FACTORS, AND THEN MORE RECENTLY,
A COLLEAGUE OF MINE HAS REALLY
EXTENSIVELY LOOKED AT THESE
GENETIC FACTORS IN AN
ORGAN-SPECIFIC FACTOR, MEANING
ORGAN CELLS THAT ARE RESIDENT IN
ONE ORGAN MAY HAVE SOME GENETIC
SIGNATURE THAT'S DISTINCT FROM
ANOTHER ORGAN.
SO I DO THINK IT'S POSSIBLE IF
WE RELY ON WHAT HAS BEEN SHOWN
IN THE PRE-CLINICAL MODEL
SYSTEMS.
NOW IN TERMS OF WHAT MAY DEFINE
THESE ESCAPE MECHANISMS, THAT
WOULD I PREDICT IF THEY REMAIN
DODORMANT OR SO FORTH, I THINK E
EVIDENCE IS THERE THAT SOMETHING
THAT -- STROMAL CHANGES IN THE
MICROENVIRONMENT CAN THEN
REACTIVATE THESE DOOR MALL
CELLS.
ONE OF THESE -- I WOULD SAY TGF
BETA HAS BEEN IMPLICATED IN
TERMS OF THESE CELLS BEING ABLE
TO WEAKEN FROM THESE DORMANT
CELLS AND THE HE ABILITY TO
REMODEL AND CREATE -- SECRETE
DIFFERENT TYPES OF PROTEINS LIKE
FIBROME CAN TIN.
AT LEAST FROM THE PRE-CLINICAL
SIDE, OF COURSE JONATHAN IS A
SURGEON, I'M JUST A PHYSICIST,
THERE IS EVIDENCE THAT YOU CAN
AT LEAST DELINEATE SOME OF THESE
PORE TANT DETERMINANTS, NOW
TRYING TO TRANSLATE THAT INTO
THE HUMAN STUDIES, GOES BACK TO
THE LIMITATIONS OF HOW DO WE
THEN IMAGE THESE THINGS TO THEN
REALIZE, THE ASSUMPTION IS CELLS
HAVE DISSEMINATED ONCE A PRIMARY
TUMOR IS PRESENT AND THE
QUESTION BECOMES THEN HOW DO WE
ISOLATE THEM OR AT LEAST KNOW
THAT THEY'RE PRESENT TO BACK UP
SOME OF THESE PRE CLINICAL
STUDIES.
SO I THINK THAT THE ANSWER IS
STILL OPEN-ENDED.
OBVIOUSLY AT THE PRE-CLINICAL
MODEL, WE STILL HAVE TO SHOW THE
RELEVANCE BUT THE EVIDENCE IS
MOUNTING THAT THERE IS GOING TO
BE A SIGNATURE THAT ALLOWS US
THEN TO TEST THESE IN CLINICAL
TRIALS.
>> SOUNDS TO ME IT'S A LITTLE
BIT LIKE STAR TREK, WHEN THE
SHIELDS ARE UP, NOTHING MUCH IS
HAPPENING, BUT THERE'S
RESISTANCE, AND WHEN THE SHIELDS
ARE DOWN, YOU CAN MOVE, YOU CAN
SPREAD, BUT YOU'RE ALSO
VULNERABLE.
>> I DON'T KNOW, THAT'S JUST MY
NAIVE INTERPRETATION.
I THINK THAT WE STILL -- WELL,
LET ME SPEAK FOR MYSELF, I THINK
THAT I DON'T UNDERSTAND HOW DO
CELLS EVEN RESPOND TO DIFFERENT
CELLS IN THEIR OWN ENVIRONMENT,
SO MUCH LESS FOR WHAT HAPPENS
UNDER PERTURBATIONS.
I THINK THESE ARE VERY COMPLEX
QUESTIONS AND WE'RE JUST
SCRAPING THE SURFACE OF THEM
QUITE FRANKLY.
>> SO ANOTHER QUESTION THAT POPS
UP DEALS WITH METABOLIC
DIFFERENCES.
GENERALLY SPEAKING, CANCERS ARE
SAID TO ANABOLIC.
WHAT ABOUT METASTASES OR THE
CIRCULATING CELLS IN THE BODY,
OR, AS YOU MENTIONED, THIS
FASCINATING PH RELATIONSHIP
WHICH USUALLY IMPLIES THAT THERE
ARE PATHWAYS AND METABOLIC
MECHANISMS THAT ARE AT WORK,
CREATING THAT.
SO IN BRIEF, WHAT DO WE -- DO WE
KNOW MUCH ABOUT THE DIFFERENT
METABOLISM THAT'S OCCURRING IN A
METASTATIC CELL IN A FULL BLOWN
METASTASES AS COMPARED, SAY, TO
THE PRIMARY TUMOR?
IS THIS A RELEVANT QUESTION?
WE'VE BEEN ASKED THIS SEVERAL
TIMES HERE.
>> I THINK IT'S A VERY RELEVANT
QUESTION.
I'LL ANSWER WITH SOME WORK WE'VE
BEEN DOING WITH MOUSE MODELS IN
THE LAB WITH PANCREAS CANCER.
THAT IS, IF YOU SIMULATE A
METASTASIS MODEL IN THE LIVER,
WHAT A CELL HAS TO DO WHEN IT'S
LEFT A PRIMARY TUMOR IS IT HAS
TO COPE WITH THINGS.
ONE THE NUTRIENT ENVIRONMENT IS
GOING TO BE DIFFERENT, AND TWO
IS THE OXIDATIVE STRESS IS GOING
TO BE DIFFERENT.
THE THIRD PART OF THIS IS YOU
HAVE TO EVADE THE IMMUNE SYSTEM.
ONCE YOU LEAVE A PRIMARY TUMOR
AND YOU END UP IN A FOREIGN
LAND, I USED TO SAY IF YOU
DROPPED ME IN RURAL CHINA, I
DON'T SPEAK THE LANGUAGE, I'VE
GOT TO HELP -- GET THE LOCAL
PEOPLE, I'VE GOT TO LEARN HOW TO
GET FOOD, I HAVE TO SPEAK THE
LANGUAGE, I HAVE TO INTERACT
WITH PEOPLE.
ALL OF THOSE THINGS THAT
METASTATIC TUMOR CELL HAS TO DO
AS WELL.
AND SO THERE ARE GENE
SIGNATURES, EPIGENETIC CHANGES
THAT OCCUR THAT ALLOW THAT CELL
TO INTAKE NUTRIENTS, TO HAVE TO
DEAL WITH NEW OXIDATIVE STRESS.
PRIMARY TUMORS ARE VERY HYPOXIC.
THEY DON'T HAVE A LOT OF BLOOD
VESSELS.
IF YOU LOOK AT THEM UNDER A
MICROSCOPE, YOU ALMOST WONDER
HOW THE THING DOESN'T DIE.
THERE'S NOT A LOT OF BLOOD
VESSELS.
BUT WHEN YOU GO INTO THAT
CIRCULATION, YOU'RE IN A LOT
MORE OXYGEN INTENSIVE, YOU HAVE
TO SORT OF DEAL WITH THAT TOO,
THEN YOU END UP IN A PLACE LIKE
THE LIVER OR LUNG WHERE THE
OXYGEN IS MUCH HIGHER.
YOU HAVE TO DEAL WITH ALL OF
THESE THINGS SIMULTANEOUSLY OR
YOU DIE IF YOU'RE THAT TUMOR
CELL.
SO WE HAVE IDENTIFIED A CERTAIN
STRESS RESPONSE THAT THESE
DISSEMINATED TUMOR CELLS ARE
LIKELY TO EMPLOY IN ORDER TO
DEAL WITH ALL THESE THINGS
SIMULTANEOUSLY.
THE TARGETTABILITY OF THIS IS
UNCLEAR TO ME AT PRESENT, BUT
THESE ARE THINGS THAT HAVE TO
BE -- YOU HAVE TO DO THIS IF
YOU'RE GOING TO SURVIVE.
AND TO I GUESS I'LL ANSWER THE
QUESTION THAT WAY.
>> SO I GUESS IT MUST BE OVER 40
YEARS AGO, A MAJOR ISSUE
INVOLVED IN CANCER ITSELF AS
WELL AS METASTASIS WAS THE ROLE
OF ANGIOGENESIS, AND THE
POTENTIAL CLINICAL THERAPEUTIC
EFFECT OF ANTIANGIOGENIC
COMPOUNDS.
THINGS AS I RECALL, THINGS
CALLED ENDO STATIN AND
ONCOSTATIN AND SO FORTH.
THAT SEEMS TO HAVE DISAPPEARED
ENTIRELY FROM DISCUSSIONS OF ME
TAS CYST AND TUMOR.
METASTASIS AND TUMOR.
DO YOU WANT TO COMMENT AS TO WHY
IS THERE NO ROLE OF -- IS IT
WRONG THAT THE TUMORS AND
METASTASES ARE DEPENDENT UPON
THEIR BLOOD SUPPLY, AND IF YOU
COULD INTERFERE WITH IT, THAT
YOU WOULD BE INHIBITING THEIR
GROWTH?
WHY IS THAT SORT OF NO LONGER
CONSIDERED?
>> SO THIS ALL STARTED WITH
FOLKMAN, WHO COINED THIS TERM
ANGIOGENESIS AND OTHERS HAVE
BUILT ON THESE FINDINGS, AND
QUITE FRANKLY, I THINK THAT
THERE IS SORT OF A -- FROM MY
UNDERSTANDING, IT'S A MIXED BAG
IN TERMS OF USING
ANTIANGIOGENIC, I WILL SAY --
WELL, INHIBITORS OF
ANGIOGENESIS, IN THE SENSE THAT
DEPENDING ON THE SIZE OF THE
TUMOR, DEPENDING ON HOW
PROGRESSIVE IT IS, IT MAY BE
PORE TANT CERTAIN STAGES OF
TUMOR GROWTH AND MAY BE LESS
EFFECTIVE IN THE METASTATIC
SETTING.
AND IT GOES BACK TO THE FACTORS,
IF YOU TARGET VEGF, VEGF IN
ITSELF IS ALSO REGULATED BY
TUMOR SECRETE VEGF AND THERE'S
ALSO VEGF FROM THE ENDOTHELIAL
CELLS.
SO I THINK THE REASON WHY
THEY'RE, I GUESS IN MY NAIVE
INTERPRETATION OF THE DATA, IS
THAT THE REASON WHY THERE ARE
DIFFERENCES IN TERMS OF THE
EFFICACY, IS THAT ONE NEEDS TO
UNDERSTAND THESE RELATIVE
BALANCES OF HOW MUCH OF IT IS
TUMOR DERIVED, WHICH IS STROMAL
DERIVED, AND THAT'S WHY IN SOME
WAYS, THESE -- I WOULDN'T SAY
THAT THEY WOULD NOT -- WERE NOT
EFFECTIVE, IT'S JUST THAT THE
EFFECTS ARE NOT COMPLETELY
UNDERSTOOD.
AND ARE STILL BEING FLESHED OUT,
ESPECIALLY GIVEN THAT THERE ARE
ORGAN-SPECIFIC REACTIONS WHEN WE
TARGET DIFFERENT ENDOTHELIAL
CELLS.
>> SO WHAT DO YOU THINK,
JONATHAN, IN YOUR REMARKABLE
SETUP THAT YOU DESCRIBE, IS THIS
SOMETHING THAT YOU'RE
INVESTIGATING OR IS WORTHWHILE
INVESTIGATING?
>> I THINK THERE'S A COUPLE OF
PIECES OF DATA THAT SHOULD BE
STATED ABOUT WHY.
I DON'T THINK THIS SORT OF -- IF
YOU'RE GOING TO TRY AND PROHIBIT
MICRO METASTASIS, WE DON'T
REQUIRE THIS BLOOD SUPPLY, WE
DON'T NEED IT, WE DON'T DEPEND
ON IT, SO IT'S NOT NECESSARY.
WE HAVE SOME DATA, PRE-CLINICAL
DATA THAT WOULD SUGGEST THAT
WHEN CELLS GET INTO THE LIVER,
THEY PROBABLY STAY RIGHT AROUND
THE PERIVASCULATURE, THEY
PROBABLY GET PLENTY OF OXYGEN.
THEY DON'T REQUIRE NEW BLOOD
VESSELS UNTIL THEY'VE REACHED A
CERTAIN CELL MASS.
NOW, WE SHOULD TALK ABOUT
THERE'S A DRUG CALLED BEV SIZ
BEVACIZUMAB, SO IT FINDS THE
ACTUAL FACTOR.
THIS IS A VERY POTENT MEDICA
MEDICATION.
IT'S BEEN USED IN COLON CANCER,
IT'S USED IN COMBINATION WITH
OTHER AGENTS FOR STAGE IV
DISEASE, IT'S BEEN TRIED IN
MULTIPLE SCENARIOS TO TRY AND
PREVENT MIC MICRO METASTASES.
WHAT YOU SEE IS THE CURVE
SHIFTS, YOU CAN DELAY THAT
OUTGROWTH, SUGGESTING THAT THOSE
CELLS DO EVENTUALLY REQUIRE
THAT.
BUT THOSE CELLS CIRCUMVENT IT
SUCH THAT EVERYBODY WHO WAS
GOING TO RECUR, RECURRED, SUCH
THAT THE RECURRENCE RATE OR
EQUIVALENT, SURVIVAL OR
EQUIVALENT IS NOT USED IN A
SETTING TO USE MICRO METASTASES
BECAUSE THERE'S PROBABLY
WORK-AROUND CIRCUITS, NUMBER
ONE.
NUMBER TWO, EARLY ON THEY
PROBABLY DON'T NEED NEW
VASCULATURE TO GROW.
AND SO THIS SORT OF CONCEPT HAS
FALLEN OUT OF FAVOR BECAUSE IT
DOESN'T WORK.
>> HERE'S AN INTERESTING
QUESTION.
ARE M METASTASES USUALLY DRUG
RESISTANT EVEN IF THE PRIMARY IS
NOT?
>> YES.
YES.
>> THEY ARE INVARIABLY DRUG
RESISTANT?
I MEAN, YOU KNOW, MOST LIKELY,
SOMETHING?
>> SO YOU KNOW, IT'S FUNNY, YOU
KNOW, BECAUSE YOU TAKE A
PATIENT, LET'S TAKE A GIVEN
PATIENT AND THEY MAY HAVE 10
METASTASES AND WE GIVE THEM
DRUGS AND THEY RESPOND.
OKAY.
10 TUMORS SHRINK A LITTLE BIT.
LET'S SAY YOU GIVE THAT PATIENT
NO TUMORS BUT GIVE THEM MICRO
KRO METASTASES EVERYWHERE.
IF THE DRUG KILLS 99 OUT OF 100
OF THOSE MICRO METASTASES BUT
ONE GROWS FOR WHATEVER REASON,
WE WOULD SAY SAID DRUG DOESN'T
WORK.
WE DON'T HAVE A WAY TO SORT OF
GAUGE, YOU KNOW, THE DEGREE OF
WORKING OR NOT.
WE SORT OF HAVE A BLACK AND
WHITE READOUT IN THE END AS DID
THEY RECUR, DID THEY DEVELOP A
MICRO METASTASES?
SO I THINK IT'S POSSIBLE THAT
SOME OF THE STUFF HAS BEEN
DISMISSED AS NOT WORKING WHEN,
IN FACT, MAYBE IT DID REDUCE BY
A LARGE PERCENTAGE THE AMOUNT OF
DISSEMINATED TUMOR CELLS BUT
JUST DIDN'T GET RID OF ALL OF
THEM SUCH THAT SOME OF THEM WERE
TO OUTGROW.
THE PROBLEM IS REALLY QUITE
COMPLICATED AND I THINK HAS TO
BE -- IF YOU'RE GOING TO LOOK AT
THIS FROM A TARGETABLE
PERSPECTIVE, YOU REALLY HAVE TO
UNDERSTAND THE COMPLEXITY OF THE
MICRO ME TAS SEES, DISSEMINATED
TUMOR CELLS THAT MAY NOT ALL BE
ONE THING.
I LIKE TO NOT SAY BECAUSE IT
CREATES AN ALMOST UNSOLVABLE
PROBLEM BUT IT COULD VERY WELL
BE THE CASE.
>> MAY I ADD, SO I THINK THAT IT
MAY NOT BE THAT IS RESISTANCE,
PER SE, BUT IN THAT
MICROENVIRONMENT, HOW THE CELLS
SIGNAL AND RECEIVE QUEUES ARE
DISTINCT FROM WHAT THE PRIMARY
TUMOR ENVIRONMENT IS IN TERMS OF
REGULATED CELL SIGNALING EVENTS,
AND THESE MICROENVIRONMENT TALL
FACTORS MAY RENDER THESE DRUGS
INEFFECTIVE, AND IT HAS NOTHING
TO DO WITH THE SIGNALING THAT'S
BEING TARGETED, IT'S SIMPLY THAT
IT'S BEING BLUNTED BY THE
EFFECTS OF WHAT MICROENVIRONMENT
THAT THESE CELLS SEE.
SO I THINK UNTIL WE UNDERSTAND
HOW DRUGS -- I WOULD SAY HOW
CELLS RESPOND TO DRUGS IN
DIFFERENT MICRO ENVIRONMENTS,
AND THIS COULD BE DONE IN SORT
OF -- SETTINGS, ONLY THEN CAN WE
TRULY ASSESS IF THERE'S
RESISTANCE OR SIMPLY JUST SIMPLY
NOT EFFECTIVE BECAUSE OF OTHER
FACTORS.
>> WE HAVE ANOTHER QUESTION
THAT'S SORT OF TIMELY, IT SEEMS.
DO WE HAVE INFORMATION ABOUT THE
ROLE OF THE MICROBIOME IN THE
ROLE OF THE MICROENVIRONMENT?
>> RIGHT.
SO I THINK THAT IS GREGORIA
CHINCURRI'S WORK, HOW THE
MICROBIOME CAN PLAY A ROLE.
AS FAR AS I KNOW, THEY ARE
RELATED EXPERTS, IN CHAIN CAL
TRIAL BUT THAT'S THE EXTENT THAT
I KNOW.
I DON'T KNOW IF JONATHAN KNOWS
MORE THAN I DO.
>> I DON'T HAVE A COMMENT HERE
OTHER THAN TO SAY I THINK IT'S
INTERESTING, I THINK IT'S BEING
LOOKED AT BUT I'M NOT SURE
WHAT'S GOING TO COME OF IT.
WHAT I KNOW IS THAT THIS IN MICE
LOOKS VERY DIFFERENT THAN IT
DOES IN PEOPLE.
I'VE JUST SEEN SOME DATA IN MICE
DONE IN A NUMBER OF PEOPLE, IT
DOESN'T SEEM TO WORK THAT WAY.
I THINK IT'S SUPER INTERESTING,
I THINK THERE ARE SOME TRIALS
HAPPENING.
BUT AS FAR AS IMPACT UPON MICRO
METASTASES AND DISSEMINATED
TUMOR CELLS AND DORMANCY, I
THINK IT'S VERY HARD TO KNOW.
>> SO I'LL JUST SAY MAYBE TO
DIRECT THAT PERSON, THERE IS
WORK BEING DONE AND THE EXPERTS
ARE HERE AT THE NCI, IN MY
BUILDING ON THE THIRD FLOOR, SO
MAYBE THAT WOULD BE A GOOD WAY
FOR THEM TO FOLLOW UP.
BECAUSE WHAT I'VE SEEN WAS
EXCITING, BUT THEY WERE DONE IN
MOUSE MODELS.
>> SO WE HAVE A SERIES OF
QUESTIONS ABOUT CIRCULATING
TUMOR DNA AND CIRCULATING CANCER
CELLS.
DO YOU THINK -- IS THIS -- ARE
THESE PREDICTIVE?
OR IF YOU CARRY OUT SOME
PROCEDURE, LET'S SAY A SURGICAL
PROCEDURE, AND YOU FOLLOW A
PATIENT, ARE THEY INDICATIVE OF
RECURRENCE?
PEOPLE HAVE ALSO ASKED DO ALL
SOLID CANCERS HAVE TUMOR DNA IN
THE BLOOD?
AND IF SO, DOES THAT INDICATE
METASTASES?
I REALIZE THESE ARE SORT OF
GLOBAL ISSUES, BUT I THINK
EVERYONE WOULD BE INTERESTED IN
YOUR VIEWS ABOUT IT.
JONATHAN, DO YOU WANT TO GO
FIRST?
>> WELL, I HAD A FEELING THIS
QUESTION WAS GOING TO COME UP.
I THINK THE DATA IS SUPER
INTERESTING ABOUT CIRCULATING
TUMOR DNA BEING ABLE TO TELL US
ABOUT WHETHER SOMEBODY MIGHT
RECUR OR NOT.
I THINK THIS IS GOING TO COME
INTO PLAY, AND THERE ARE TRIALS
ONGOING ABOUT THIS, WHERE
SOMEBODY LIKE ME WOULD REMOVE A
PRIMARY TUMOR, AND THIS WOULD BE
A SITUATION WHERE IT WASN'T
REALLY CLEAR THAT CHEMOTHERAPY
OR ADJUVANT THERAPY WAS GOING TO
BE OF GREAT BENEFIT, AND WOULD
YOU THEN USE THAT MEASUREMENT OF
CIRCULATING TUMOR DNA AFTER THE
TUMOR WAS OUT AND IF THAT WAS
PRESENT, THAT WOULD BE
INDICATIVE THAT THE PATIENT
SHOULD, IN FACT, RECEIVE
TREATMENT BECAUSE THEY'RE LIKELY
TO HAVE DISSEMINATED TUMOR CELL.
AGAIN, WE REMOVE THE SOURCE, YET
THEY STILL HAVE THIS CIRCULATING
TUMOR DNA PRESENT.
DOES THAT MEAN THEY HAVE
METASTASES?
I THINK IT'S LIKELY THAT MEANS
THEY HAVE DISSEMINATED TUMOR
CELLS AND THEY'RE MOVING AROUND.
AGAIN, THE DIFFICULT PART IS,
IT'S NOT THE DISSEMINATION THAT
MATTERS, IT'S WHEN THE CELLS
BEGIN TO GROW AND COLONIZE,
THAT'S THE EVENT WE DON'T WANT.
SO I THINK DISSEMINATED TUMOR
DARN, I'M GOING TO USE THIS
SYNONYMOUSLY, MOSTLY THE FIELD
HAS TURNED TO DISSEMINATED TUMOR
DNA, I THINK IT'S GOING TO BE A
PREDICTION TOOL.
THE DATA LOOKS REALLY GOOD, I'D
LIKE TO SEE IT REPLICATED, BUT
THE PUBLICATION FROM JAPAN LOOKS
AMAZINGLY GOOD IN A VERY LARGE
NUMBER OF PATIENTS.
BUT I THINK IT'S GOING TO BE A
STRATIFICATION TOOL.
AND I THINK IT MAY HELP PEOPLE
AVOID CHEMOTHERAPY WHO PROBABLY
DO NOT NEED IT.
BUT ON THE OTHER SIDE OF THAT
TOKEN, LET'S SAY YOU FOUND
SOMEONE YOU THINK SHOULD HAVE
IT, WE HAVE VERY LIMITED TOOLS
TO TREAT THIS DISEASE.
IN TREATING DISEASE YOU CANNOT
SEE, YOU KNOW, IT'S TOUGH.
AND WE DON'T HAVE A LOT OF
TOOLS.
SO I THINK THE BIGGEST BANG FOR
THE BUCK IN THIS SORT OF FIELD
IS GOING TO BE CAN WE UTILIZE
THIS DATA TO AVOID TREATING
PEOPLE -- REMEMBER I SHOWED YOU
THAT CIRCLE UNDER THE CURVE
WHERE A LOT OF THE PEOPLE ARE
NOT GOING TO RECUR.
YOU CERTAINLY WOULDN'T WANT
CHEMOTHERAPY IF YOU DIDN'T NEED
IT.
I THINK WE CAN USE IT IN THAT
WAY, AND THAT'S ULTIMATELY HOW I
SEE THIS PLAYING OUT, WHERE WE
WILL USE THAT TO SORT OF AVOID
TREATING PEOPLE WHO DON'T NEED
IT.
SUBJECTING THEM TO ALL OF THE
RISKS BUT THEY HAVE NO REAL WAY
OF BENEFITING FROM IT BECAUSE
THEY DON'T NEED IT.
>> SO I THINK THAT IF YOU WANT
TO GO BACK TO SOME OF THE
EARLIER WORK LIKE FIDDLER WHO
WAS AT THE NCI WHO STUDIED THAT
FOR EVERY GRAM OF TUMOR, THERE'S
A MILLION CELLS THAT IS
DISSEMINATED AND ABOUT 0.01% OF
THESE CELLS CAN FORM TUMORS.
SO IT'S AN INEFFICIENT PROCESS.
SO INSTEAD, I THINK -- THE
DIRECTION THE FIELD IS GOING, MY
COLLEAGUE, SEE MORE AGARWAL,
WHAT SHE'S DOING, YOU DO HAVE
ACCESS TO BLOOD SAMPLES AND YOU
CAN SERIALLY OR LONGITUDINALLY
SAMPLE BLOOD, IT'S EASY TO GET
BLOOD FROM PATIENTS, AS OPPOSED
TO HAVING TO GO DO TUMOR
BIOPSIES.
THE QUESTION THEN IS HOW DO YOU
EXPAND AND KEEP THESE
CIRCULATING TUMOR CELLS IN
CULTURE LONG ENOUGH AND COULD
YOU THEN USE THESE TO SORT OF DO
DRUG SCREENS AND SHE HAS
SUCCESSFULLY DONE THESE
XENOGRAPH MODELS FROM THESE
CIRCULATING TUMOR CELLS AND THEN
CAN BE USED TO BE ABLE TO SEE
WHICH OF THESE DRUGS ARE
EFFECTIVE, GOING BACK TO USING
THAT AS SCREENING PROCESS.
SO FROM THE BASIC CLINICAL SIDE,
THIS IS WHERE PEOPLE ARE GOING,
AND THE FACT THAT YOU COULD GET
THESE CELLS EXPANDED AND SURVIVE
AND IN CULTURE WITHOUT CHANGING
ANY PHENOTYPES FROM THE ORIGINAL
STRUCTURES, I THINK IS
PROMISING.
>> WE ALSO HAD SOME INQUIRY, OF
COURSE I HAD MENTIONED IT IN THE
BEGINNING, JONATHAN, ABOUT YOUR
WORK WITH EXTRACELLULAR
VESICLES.
THIS IS ANOTHER SORT OF
EXPANDING AREA OF GREAT INTEREST
FROM MANY DIFFERENT
PERSPECTIVES, BUT FROM THE
STANDPOINT OF CAN SE YOU WANT TU
WANT TO TELL US, ARE THE
EXTRACELLULAR VESICLES CREATED
BY CANCER CELLS, DO THEY HAVE
DIAGNOSTIC OR PROGNOSTIC VALUE?
WHAT'S THE STATE OF THAT FIELD?
>> YOU KNOW, BEFORE I CAME TO
THE NCI, I WORKED WITH DAVID
LYDON IN NEW YORK EXTENSIVELY,
AND DAVID AND HIS GROUP, WE
WORKED TOGETHER ON A LARGE
NUMBER OF PAPERS ABOUT HOW
PREMETASTATIC -- EDUCATION AND
HOW YOU CAN USE EXTRACELLULAR
VESICLES REFERRED TO AS EXOSOMES
TO SORT OF -- THESE WOULD
DICTATE WHERE THE SEED IN SOIL
TYPE THING WAS HAPPENING.
I THINK THE ISOLATION OF
EXOSOMES IS NOT -- IT TAKES SOME
TIME AND EFFORT AND I THINK IF
YOU'RE LOOKING AT IT FROM A
PREDICTION PERSPECTIVE ALONE, I
THINK THE CIRCULATING TUMOR DNA
FIELD, JUST BECAUSE OF THE EASE
OF A BLOOD DRAW AND NOT
REQUIRING HAVING TO ISOLATE
EXTRACELLULAR PARTICLES WILL
PROBABLY TAKE THE LEAD INSOFAR
AS PREDICTION AS FAR AS A
CLINICALLY RELEVANT TEST.
I DO THINK EXTRACELLULAR
VESICLES AND EXOSOMES ARE SUPER
INTERESTING, BECAUSE THEY HAVE
THE ABILITY AND DATA HAS SHOWN
THIS, WE'VE SHOWN IT ON MULTIPLE
LEVELS, TO ALTER THE PHENOTYPE
OF RECIPIENT CELLS, AND THAT'S
WHY INTRODUCTION OF PROTEINS
THROUGH THOSE EXOSOMES AND OTHER
THINGS.
SO I THINK THE FIELD ABOUT
UNDERSTANDING CANCER BIOLOGY IS
CERTAINLY GOING TO LIE WITH THE
EXTRACELLULAR VESICLES AND
PARTICLES, BUT IF YOU ASK ME, I
THINK THE PREDICTION ABOUT WHO'S
GOING TO RECUR ON A CLINICALLY
VALUABLE TEST AND YOU THINK
ABOUT A TEST HAS TO BE DONE IN
SO MANY PATIENTS, IT HAS TO BE
EASY, IT HAS TO BE DONE IN
MULTIPLE LABORATORIES.
I THINK THE CIRCULATING TUMOR
DNA FIELD IS GOING TO SORT OF
LIVE IN THAT SPACE.
BUT THE EXOSOMES ARE REALLY
INTERESTING AS FAR AS CANCER
BIOLOGY GOES, EDUCATING ON
PREMETASTATIC NICHE, THESE
AREAS, AND CHANGING BIOLOGY OF
NEIGHBORING CELLS, THESE THINGS
ARE POSSIBLE WITH EXOSOMES.
SO I LOOK AT THIS IN SORT OF
THAT WAY.
>> SO KANDICE, GRANTED YOU'RE YR
REALLY EXCITING, BRILLIANT WORK
WITH ZEBRAFISH AND BIOPHYSICAL
PLESHMENTS ASSOCIATED WITH THE
MOVEMENT OF TUMOR CELLS AN.
IF THE HYPOTHESIS THAT THE ANG
LAAANGULARITY AND ASSOCIATED
FACTORS IS IMPORTANT IN WHERE
TUMORS GO, IT'S ALL RATHER
MYSTERIOUS TO ME WHY METASTATIC
TUMORS VERY RARELY GO TO THE
KIDNEY, FOR EXAMPLE.
WHICH HAS AN ENORMOUS BLOOD
SUPPLY AND MANY CURVED AND
BRANCHED AND IT'S A WHOLE -- THE
WHOLE NETWORK, GRANTED, YOU
KNOW, YOU'RE WORKING WITH A
MODEL AND THE MODEL IS
EXCEPTIONAL FOR UNDERSTANDING
BASIC MECHANISMS, BUT IT IS A
CURIOUS PHENOMENA, AND I THINK
THAT'S CORRECT, AM I WRONG,
JONATHAN, THAT RARELY METASTASES
GO TO THE KIDNEY?
>> YOU KNOW, I THINK THE EXAMPLE
YOU CITED SUCH THAT THE TUMOR
CELLS ARE IN THE KIDNEY BUT WHEN
THE ORGAN GETS TRANSLATED TO
IMMUNOSUPPRESSED PATIENT THEN
YOU GET OUTGROWTH.
THAT WAS ONE OF THE EARLIEST
EXAMPLES OF THESE DISSEMINATED
CELLS BEING DORMANT FOR VERY
LONG PERIODS OF TIME.
IT'S A VERY CURIOUS THING, WHY
DOESN'T THE KIDNEY GET
METASTASES?
I TALK ABOUT THIS ALL THE TIME.
OH, THAT'S NOT A METASTASIS.
THAT'S JUST A CYST.
WE NEVER SEE KIDNEY METASTASES,
AT LEAST WITH THE CANCERS I SEE.
I DON'T THINK THAT MEANS THE
CELLS DON'T GET THERE, THE CELLS
DON'T PERSIST, PERHAPS.
I THINK IT MEANS THEY CAN'T
OUTGROW WHICH GETS TO THE WHOLE
POINT THAT THE COLONIZATION PART
OF THIS IS THE REALLY IMPORTANT
PART.
IF THEY GET THERE AND THEY NEVER
DO ANYTHING AND THEY JUST
PERSIST FOREVER, THE PATIENT HAS
NO PROBLEMS, THEY GO ON TO LIVE
THEIR NATURAL LIFE.
THE ISSUES BECOME WHEN THEY CAN
START TO GROW AND TAKE OVER AN
ORGAN.
I DON'T THINK THEY CAN DO THAT
IN THE KIDNEY.
BY AND LARGE.
WHY THAT IS, SUPER INTERESTING
QUESTION.
I DO NOT HAVE THE ANSWER.
>> SO APROPOS, KANDICE, OF YOUR
STUDIES INVOLVING BONE MARROW
CELLS GOING - TO THE BONE MARRO,
AMONGST THE BIOMARKERS THAT ARE
CURRENTLY WRITTEN ABOUT, SORT OF
LIQUID BIOPSIES LOOKING AT
CIRCULATING DNA AND TUMOR DNA,
AND THEN APPARENTLY AS AN EARLY
INDICATION, I GATHER FOLKS ARE
DOING BONE MARROW BIOPSIES OR
ASPIRATIONS IN PATIENTS WITH
BREAST CANCER, AS PART OF THE
INITIAL SCREENING LOOKING FOR
METASTASIS.
AND I WAS THINKING OF YOUR
PRESENTATION, DO YOU SEE ANY
RELATIONSHIP BETWEEN THAT, WHY
WOULD BREAST CANCER CELLS
PARTICULARLY GO TO THE BONE
MARROW?
>> WELL, I FEEL LIKE THE
CROSSTALK BETWEEN WHAT DIFFERENT
RECEPTORS ARE FOUND IN BREAST
CANCER CELLS AND THOSE FOUND
EITHER -- THE LIGANDS SECRETED
BY THE OSTEOCLASTS PRESENT IN
THE BONE MARROW NICHE, THERE'S
SOME EVIDENCE IN TERMS OF THESE
RECEPTOR COMPATIBILITY.
NOW, ONE OF THE PROVOCATIVE
IDEAS IS THAT THE BONE MARROW
NICHE IS ALSO SORT OF LIKE A
RESIDENT FOR IMMUNE CELLS AND
MAYBE IN THAT CASE, THEY COULD
ALSO RECRUIT THESE IMMUNE CELLS
TO SORT OF ACTIVATE THE CELLS'
ABILITY TO FORM LESIONS THERE.
NOW GOING BACK TO OUR SYSTEM, WE
HAVE TO BE VERY CLEAR ABOUT WHAT
WE'RE ABLE TO RECAPITULATE.
WE'RE LOOKING AT THE ENDOTHELIAL
INTERFACE, BUT THERE IS NO
SKELETAL BONE THAT'S PRESENT AT
THE TIME THAT WE'RE LOOKING AT.
INSTEAD, WE'RE LOOKING AT
COMPONENTS THAT ARE REMINISCENT
OF THE FACTORS THAT CONTRIBUTE
TO THE MYELOID LINEAGE
DERIVATIONS, SO THIS SYSTEM
ALLOWS YOU TO TEASE OUT THOSE
CONTRIBUTIONS.
BUT IF ONE WERE TO SAY THAT IS
REMINISCENT OF WHAT YOU WOULD
SEE IN A -- WHERE YOU HAVE THE
SKELETAL TISSUE AS WELL AS THESE
MYELOID DERIVED CELLS OR I WOULD
SAY EMBRYONIC LINEAGES, THEN
THAT IS NOT THE CASE.
SO TO ANSWER THE QUESTION THAT
YOU JUST PROPOSED, INSTEAD WE
WOULD HAVE TO LOOK AT THE ADULT
FISH IN THAT SKELETAL METASTASIS
MODEL WHERE WE HAVE ALL OF THE
POPULATIONS OF THE CELLS THAT
RECAPITULATE A BONE NICHE AND
ONLY THEN COULD I GIVE YOU AN
ANSWER.
>> SO HERE'S AN INTERESTING
QUESTION THAT CAME IN.
OUR METASTASES ALWAYS DERIVED
FROM THE PRIMARY TUMOR.
DOES METASTASIS GIVE RISE TO A
SECOND METASTASIS?
>> THIS IS A FUN QUESTION.
I LIKE THINKING ABOUT THIS
QUESTION, AND WE'VE TOSSED THIS
AROUND A LOT.
I THINK IT WOULD BE ALMOST
NONSENSICAL TO THINK THAT A CELL
THAT WAS ABLE TO ESCAPE TO A NEW
SITE COULD NOT THEN DO IT AGAIN.
DO WE HAVE GOOD EVIDENCE THAT
THIS HAPPENS?
NOT TO MY KNOWLEDGE.
IT'S CERTAINLY A QUESTION I
THINK ABOUT, AND THE OTHER
QUESTION I THINK ABOUT IS, COULD
A PRIMARY TUMOR SEND OFF NEW
METASTASES AND DO THEY END UP
GUGOING TO METASTATIC SITES SUCH
THAT THAT WOULD CONTRIBUTE TO
THE HETEROGENEITY AS WELL?
I USE THE ANALOGY, YOU WALK INTO
A BAR AND YOU DON'T KNOW ANYBODY
AND YOU SEE A TABLE OF YOUR
FRIENDS, YOU'RE PROBABLY GOING
TO GO SIT NEXT TO YOUR FRIENDS.
THERE'S THE SAME SORT OF THING
THAT CONTRIBUTES.
I THINK THERE'S A WHOLE DYNAMIC
HAPPENING BELOW THE LEVEL OF
VISIBILITY THAT'S SUPER
FASCINATING THAT I DON'T THINK I
HAVE ANY REAL UNDERSTANDING OF,
BUT IT IS A VERY BIG QUESTION.
I WOULD SAY IT WOULD BE
NONSENSICAL TO THINK THAT A
METASTASES COULD NOT IN TURN
METASTASIZE, BUT DO I HAVE PROOF
THAT THAT HAPPENS?
I DO NOT.
>> GOING BACK TO THE
PRE-CLINICAL MODELS, THERE ARE
SOME -- THERE IS SOME DATA THAT
SUGGESTS IN A MOUSE MODEL THAT
THERE ARE SOME SITES OF
METASTASES THAT SEED OTHER
SITES.
AND THIS IS ONLY IN VERY
AGGRESSIVE ADVANCED STAGES OF
CANCERS, AND PEOPLE HAVE DERIVED
THIS BY LOOKING AT LINEAGES
BEING ABLE TO SEE WHERE THESE
CELLS ORIGINATED FROM AND IF
THEY CAME FROM YOUR PRIMARY
TUMOR OR IF THEY CAME FROM
ANOTHER METASTATIC LESION.
AGAIN THESE ARE MOUSE MODEL, AND
I DON'T KNOW IF ANYONE HAS DONE
THIS IN HUMAN STUDIES, BUT I
ARGUE IF IT HAPPENS IN A MOUSE,
IT COULD HAPPEN IN A HUMAN.
BUT AGAIN, YOU'RE TALKING TO A
VERY NAIVE BASIC SCIENTIST HERE.
>> WE'RE ALL NAIVE.
>> I WOULD AGREE WHOLEHEARTEDLY
WITH THAT.
>> WE'VE GOT TIME FOR A FEW MORE
HERE.
HERE'S ANOTHER ONE.
IN A SERIES OF ARTICLES OVER THE
PAST I DON'T KNOW COUPLE YEARS
ABOUT INTRACANCER BACTERIA, AND
THOSE WHO HAVE WRITTEN THESE
ARTICLES ASCRIBE SOME MEANING TO
IT, THEY DON'T KNOW EXACTLY WHAT
ALL THE MEANING IS, BUT EVEN ONE
HAS SUGGESTED AS A ROLE IN
METASTASIS.
DO YOU HAVE ANY EXPERIENCE OR
WHAT'S YOUR OPINION ABOUT THAT?
THE ROLE OF INTRACELLULAR
BACTERIA IN CANCER.
>> I WOULD SAY WE DO HAVE
EXPERIENCE IN THIS.
THIS SORT OF CAME ABOUT IN A WAY
WHERE WE WERE KEEPING THESE
TISSUES VIABLE OUTSIDE OF
PATIENTS AND THIS CAN BE DONE IN
A COUPLE OF WAYS.
I'VE SHOWED YOU ONE, BUT ONE
CONCERN WE HAD WAS ABOUT
CONTAMINATION, WOULD WE GET
INFECTION, SO -- AND THIS CAME
ABOUT BECAUSE WE DID A BUNCH OF
SEQUENCING ON SOME OF THESE
TUMORS, AND THEN THERE WOULD BE
BACTERIAL SEQUENCE OF PART OF
THE TUMOR SEQUENCING.
WE LOOKED AT IT -- YOU KNOW, I
GOT VERY CONCERNED THAT WE
POTENTIALLY HAD INFECTION WHICH
COULD BE SKEWING RESULTS IN
THESE SORT OF THINGS AND THEN
YOU SORT OF REALIZE THERE ARE
BACTERIA PRESENT INSIDE TUMOR
CELLS.
THERE ARE IDENTIFIABLE AND THERE
ARE BACTERIA THAT -- THERE'S
SORT OF THIS RELATIONSHIP THAT
EXISTS.
THE MORE INTERESTING QUESTION, I
THINK, IS WHAT'S THE NATURE OF
THE RELATIONSHIP AND WHAT IF YOU
PERTURBED IT, WHAT WOULD IT
MEAN?
I DON'T KNOW THE ANSWER TO THAT.
IT'S SUPER INTERESTING TO THINK
ABOUT, PARTICULARLY THE INTRA --
BACTERIA INSIDE THESE TUMOR
CELLS.
MITOCHONDRIA CAME FROM A FOREIGN
BACTERIA MANY EE YONS AGO, BUT
IS THIS A RELATIONSHIP WE COULD
BE LEVERAGING FOR THERAPEUTIC
GAIN?
IT'S FASCINATING, I DON'T HAVE
AN ANSWER.
>> WELL, WE HAVE A WHOLE BUNCH
OF OTHER QUESTIONS, BUT I THINK
WHAT THEY ALL INDICATE IS THAT
THIS IS AN EXTREMELY CHALLENGING
COMPLEX AREA OF SCIENCE FROM ALL
DIFFERENT DISCIPLINES.
AND PERHAPS OUT OF BRIDGING MANY
OF THESE DISCIPLINES, NEW IDEAS
AND CONCEPTS WILL EMERGE.
BECAUSE METASTASIS IS WHAT KILLS
PEOPLE, AND WE HAVE A WAYS TO
GO.
SO THE LAST QUESTION IS ONE I'D
LIKE TO ASK BOTH OF YOU, IF YOU
WOULD BRIEFLY DARE TO GIVE A FEW
PREDICTIONS.
WHAT DO YOU THINK IS THE AREA OR
THE AREAS OF ONGOING AND FUTURE
RESEARCH THAT SEEM TO YOU TO BE
MOST EXCITING AND POTENTIAL IN
TERMS OF ACHIEVING THEIR
OBJECTIVE?
JONATHAN, YOU WANT TO GO FIRST?
>> SURE.
SO I WOULD SAY THE OPPORTUNITY
TO KEEP DISSEMINATED TUMOR CELLS
QUIESCENT OR DORMANT WOULD
CREATE WHAT WOULD OTHERWISE BE
CONSIDERED A CHRONIC CONDITION
FOR CANCER.
YOU NE, I USE THE ANALOGY ALL
THE TIME, I CANNOT STOP TAKING A
PROTON PUMP INHIBITOR BECAUSE I
HAVE ACID REFLUX.
I'M FINE AS LONG AS I TAKE THE
REFLUX MEDICINE BUT IF MY REFLUX
DOESN'T GO AWAY, IT'S JUST
CONTROLLED BY THE ACID
MEDICATION.
THE SAME THING WE SAID OF BLOOD
PRESSURE.
PEOPLE WHO TAKE BLOOD PRESSURE
MEDICINE, THEIR BLOOD PRESSURE
IS STILL HIGH.
THEY JUST TAKE A MEDICINE TO
TREAT IT.
IF YOU CAN TURN CANCER INTO THIS
SAME THING BY KEEPING THOSE
QUIESCENT, THOSE DORMANT CELLS
QUIET, AND SOMEONE LIKE ME COULD
COME ALONG AND CHOP OUT ALL YOUR
TUMOR AND THEN YOU WOULD SIMPLY
HAVE THIS MAINTENANCE SORT OF
THING WHERE YOU KEPT EVERYTHING
AT BAY AND YOU COULD GO ON WITH
YOUR NORMAL LIFE, THAT, I THINK
IS HOW THIS IS GOING TO PLAY
OUT.
I THINK THAT'S THE BEST CASE
SCENARIO HOW THIS PLAYS OUT.
I AGREE WITH EVERYTHING YOU SAID
ABOUT THIS BEING INCREDIBLY
COMPLEX, LOTS OF FIELDS HAVE TO
BE INVOLVED, BUT I THINK THE
QUINTESSENTIAL THING IS, CAN WE
KEEP THOSE DORMANT OR QUIESCENT
OR MICRO METASTATIC CELLS FROM
OUTGROWING.
IF THAT'S TRUE, I THINK YOU CAN
CHANGE THE FIELD.
>> KANDICE?
>> SO I'LL SAY THERE ARE THREE
FACTORS I THINK ARE GOING TO BE
REVOLUTIONARY.
ONE IS THAT FOCUSING ON THE IDEA
THAT THE INCLUSION OF PATIENTS
WITH METASTATIC DISEASE IN
CLINICAL TRIALS IS GOING TO BE
GAME CHANGING.
IN TERMS OF BEING ABLE TO
UNDERSTAND HOW DRUGS WORK IN A
MORE ADVANCED DISEASE SETTING
VERSUS THOSE THAT MAY PRESENT
WITH EARLIER STAGES OF CANCER.
AND I THINK THAT REVOLUTION
WOULD THEN REALLY DELINEATE WHAT
DRUGS REALLY WORK AT EARLIER
STAGES THAN WE CURRENTLY KNOW.
THE SECOND IS THE BRIDGING OF
THESE PRE-CLINICAL MODELS WHICH
BEING MORE REALISTIC IN TERMS
OF -- I WOULD SAY EMBRACING THE
COMPLEXITY INSTEAD OF TRYING TO
HAVE THESE MORE SIMPLIFIED
SYSTEMS BECAUSE THEY SIMPLY ARE
NOT BEING PREDICTIVE IN TERMS OF
HOW DRUGS ARE TESTED IN THE
PRE-CLINICAL SETTING AND WHY
THEY FAIL IN THE CLINICAL
SETTING.
AND LARGE LEGAL THIS EMERGENCE
OF TECHNOLOGIES THAT IF WE COULD
GO WITH IMAGE BASED APPROACHES
BECAUSE ULTIMATELY, WHAT A
SURGEON OR ONCOLOGIST HAS
INFORMATION ABOUT IS WHAT THEY
CAN SEE, WITH THE CURRENT
IMAGING MODALITIES, AND THEN
TRYING TO UNDERSTAND WHAT OF
THESE ASPECTS IS PREDICTABLE OF
HOW THIS DISEASE MAY EMERGE, AND
I THINK ARTIFICIAL INTELLIGENCE
IS INDEED GOING TO PLAY A ROLE
AT LEAST FROM THE EXISTING
METHODOLOGIES.
NOW FROM THE BASIC SCIENCE
PERSPECTIVE, AS MUCH AS WE CLOSE
THE GAP BETWEEN WHAT OUR MODEL
SYSTEMS ARE DOING VERSUS WHAT
WE'RE SEEING IN THE HUMAN
RELEVANT DISEASES, I THINK THAT
ALSO WOULD GO A LONG WAY,
ESPECIALLY WITH THESE AI-BASED
TECHNIQUES IN TERMS OF BEING
MUCH MORE PREDICTIVE WITH THE
INFORMATION AT HAND.
SO THOSE ARE MY BIASED FEELINGS.
>> YOU WOULDN'T HELP BUT BELIEVE
IN READING SOME OF THE
LITERATURE, PARTICULARLY THE
REVIEW THAT I MENTIONED, THAT
THIS IS REALLY A BRAVE NEW WORLD
AND MANY EXCITING THINGS ARE
GOING TO HAPPEN WHICH AT THE
MOMENT WE CAN'T FULLY PREDICT
BUT WE CAN HOPE FOR.
SO I WANT TO THANK YOU VERY MUCH
SHARING HER PERSONAL EXPERIENCE.
MOST OF THE PEOPLE WATCHING THIS
AROUND THE WORLD ARE NOT
PHYSICIANS.
THEY'RE YOUNG STUDENTS, GRADUATE
STUDENTS, PH.D.s AND SO FORTH.
AND SO THEY DON'T HAVE THAT
CONTACT WITH PATIENTS AND THE
HUMAN EXPERIENCE IS REALLY
DIRECTED TO.
SO HAVING SHARE YOUR EXPERIENCE
WITH US IS EXTREMELY VALUABLE,
AND WE APPRECIATE IT VERY MUCH.
SO LAST THING I MENTIONED IS
JUST TO MENTION THAT NEXT WEEK,
WE HAVE ANOTHER CHALLENGING
SESSION, AND THAT'S ON MESSENGER
RNA, WILL IT DELIVER US FROM
ILLNESS?
THE CME CREDIT 45392, THE
TELEPHONE NUMBER 443-541-5052.
SO THANK YOU ALL VERY MUCH,
AGAIN, AND WE'RE ALL GRATEFULLY
APPRECIATIVE.
THANK YOU.