Tip:
Highlight text to annotate it
X
>> OKAY, WE'RE GOING TO START
THE TRANSLATIONAL RESEARCH AND
CLINICAL ONCOLOGY COURSE, I'M
TERRY MOODY.
AND WE'VE BEEN
DOING THIS COURSE
FOR TEN YEARS NOW.
THEY MOVED ME TO
SHADY GROVE.
I HAVE AN UNUSUAL PHONE NUMBER
FOR NIH BUT I DO RESEARCH DOWN
HERE IN BUILDING 10.
THE BEST WAY TO GET ME IS SEND
ME AN E-MAIL.
IN TERMS OF ORGANIZING, I WANT
TO THANK JONATHAN WIEST,
DIRECTOR OF THE OFFICE OF
TRAINING AND EDUCATION IN CTR
AND PAYS THE BILLS FOR THIS
CLASS.
AND SO IN TERMS OF THE SCHEDULE,
WE ALWAYS LECTURE ON MONDAY
EXCEPT FOR OCTOBER 13.
THAT DAY IS COLUMBUS DAY HOLIDAY
SORRY WE CHECK TOURING ON
WEDNESDAY THAT PARTICULAR DAY.
TODAY I'M LECTURING, AS WELL AS
JOEL SMITH CLINICAL TRIALS AND
WE GO INTO DIFFERENT TYPES OF
CANCER, LYMPHOMA, OVARIAN CANCER
THE FOLLOWING WEEK AND IMMUNE
CHECKPOINT INHIBITORS, A NEW
AREA IN CLINICAL RESEARCH,
HAVING GREAT SUCCESS, AND
BASICALLY IT'S BEEN KNOWN FOR A
LONG TIME THAT MANY CANCERS
DON'T REALLY RESPOND TO THE
IMMUNE SYSTEM SUCH AS MY
SPECIALTY, LUNG CANCER IT MAKES
SERB LIGANS NEUTRALIZE THE
IMMUNE SYSTEM AND THE CONNER IS
IS MORE RESPONSIVE TO IMMUNE
THERAPY.
AND SMALL KINASE INHIBITORS ARE
USED IN
DIFFERENT TYPES OF
CANCER.
IN OCTOBER WE CONTINUED THE
CLASS AND FOCUSED ON TUMOR
IMAGING, A GOAL IN CANCER IS
ALWAYS DETECT IT EARLY IN STAGE
ONE, AMENABLE TO SURGICAL
REMOVE.
CANCER STEM CELLS ARE RESISTANT
TO THERAPY SUCH AS CHEMOTHERAPY.
END OF NOVEMBER WE GO INTO
SPECIAL TOPICS SUCH AS RNA
INTERFERENCE, microRNA, AND WE
END TALKING ABOUT
NANOTECHNOLOGY.
SO --
>> TERRY?
>> YES?
>> SORRY.
THIS IS FREDERICK.
WE'RE NOT SEEING THE
PRESENTATION RIGHT NOW.
>> OKAY.
WE'LL WORK ON IT.
>> DO YOU HAVE ANY --
>> OKAY.
>> HERE IT COMES.
SO IN TERMS OF REGISTRATION, WE
HAVE 150 REGISTRANTS, IF ANY OF
YOU WANT TO TAKE THE CLASS AND
HAVEN'T REGISTERED SEE ME AFTER
CLASS AND FILL OUT A FORM AND
WE'LL GET YOU REGISTERED.
AND THEN WHEN YOU NEED
COMPONENTS OF THIS CLASS
RELATIVE TO ACADEMIC CLASS WE
HAVE A HANDS-ON SECTION, WHERE
YOU CAN SIGN UP TO VISIT TUMOR
BOARDS WHERE THEY REVIEW PATIENT
CASES, AND THEN YOU CAN VISIT
VARIOUS CORE FACILITIES SUCH AS
PLACES WHERE THEY DO NEXT
GENERATION SEQUENCING.
SO I'LL BE WORKING ON THIS LATER
THIS WEEK, AND I'LL BE SENDING
ALL OF YOU AN E-MAIL TO SEE IF
YOU WANT TO SIGN UP FOR VARIOUS
COMPONENTS, THESE USUALLY OCCUR
IN OCTOBER AS WELL AS NOVEMBER.
AND FINALLY YOU CAN GET A
CERTIFICATE OF PASSING THE
COURSE.
WE HAVE A COMPUTER-BASED
EXAMINATION AT THE END OF THE
COURSE, NOT THAT DIFFICULT.
THERE'S ONE MULTIPLE GUESS
ANSWER FROM EACH LECTURE, AND TO
PASS YOU NEED TO GET 70%
CORRECT.
SO THIS COURSE, ALL THE
LECTURES, WE HAVE PEOPLE IN NCI
FREDERICK THAT WE VIDEO
CONFERENCE TO, TWO DAYS
AFFIDAVIT, AFTER,
IT IS ARCHIVED.
TWO DAYS LATER YOU CAN CALL IT
UP ON YOUR COMPUTER AND SEE IT
THERE.
ARE THERE ANY QUESTIONS ON THE
ORGANIZATION?
OKAY.
WE'LL GET INTO THE MEAT OF THE
LECTURE NOW, AND THAT BEING WE
FIRST GET AN OVERVIEW OF
DIFFERENT TYPES OF CANCERS
IMPORTANT IN THE U.S., AND OF
COURSE LUNG CANCER KILLS ABOUT A
THIRD OF ALL THE PATIENTS THAT
DIE FROM CANCER IN THE U.S.
ANNUALLY WE HAVE AN INCIDENCE OF
170,000, AND ALMOST 160,000 ARE
DYING.
SO THIS MEANS THAT OUR TREATMENT
OF LUNG CANCER NEEDS TO BE
DRAMATICALLY IMPROVED, AND LATER
ON WE'LL BE DISCUSSING KINASE
INHIBITORS COMING INTO PLAY IN
THE PAST DECADE.
IN CONTRAST, COLON, PROSTATE AND
BREAST CANCER IS MORE AMENABLE
TO TREATMENT.
200,000 BEING DIAGNOSED IN
BREAST
WE'RE GETTING QUITE GOOD.
WE'VE DEVELOPED LOTS OF
ANTIBODIES AND KINASE INHIBITORS
AND VARIOUS CHEMOTHERAPEUTIC
DRUGS.
LUNG CANCER IS DIFFICULT TO
TREAT.
TOTAL 1.3 MILLION CASES OF
CANCER DIAGNOSED IN THE U.S.
ANNUALLY, AND ABOUT 550,000
PEOPLE DIE, ANNUALLY FROM THE
DISEASE.
THE TREATMENT GETS BETTER, WE
HAVE MORE AND MORE SURVIVORS,
NOW WE HAVE OVER 12 MILLION
CANCER SURVIVORS IN THE U.S.
SO WE MENTIONED THE BIG FOUR,
LUNG CANCER, COLON CANCER,
BREAST CANCER, PROSTATE CANCER,
OTHER CANCERS THAT KILL 10,000
TO 30,000 ANNUALLY ARE
PANCREATIC, WHICH JOE WILL TALK
ABOUT SHORTLY, VERY DIFFICULT TO
TREAT AS IS OVARIAN CAN KERR,
AND BRAIN CANCER, GLIOBLAST HOME
A, LUNG, PANCREATIC
OVARIAN AND GLIO LLAST ARE
DIFFICULT TO TREAT.
DRINKING EXCESSIVE ALCOHOL IS A
RISK, THIS CAN CONTRIBUTE TO
LIVER CANCER.
ASBESTOS IN THE INSULATION OF
WALLS CAUSES MESOTHELIONA, AND
IN JAPAN THEY EAT PICKELED FOOD,
AND THEY GET A HIGHER INCIDENCE
OF STOMACH CANCER.
THAT'S QUITE RARE REALLY IN THE
U.S.
THERE ARE GENETICS FACTORS SUCH
AS IN BREAST CANCER, WE HAVE THE
BRCA 1 AND BRCA 2 GENES WHICH
WHEN THEY GET MUTATED THE WOMEN
THEN GET THE BREAST CANCER.
VARIOUS HORMONES COME INTO PLAY,
SUCH AS ESTROGEN FOR WOMEN, AND
THAT CAN INDUCE BREAST CANCER.
AND FOR MEN, WE HAVE THE
TESTOSTERONE, WHICH CAN
CONTRIBUTE TO PROSTATE CANCER.
IN TERMS OF OBESITY, A HIGH BODY
MASS INDEX IS ASSOCIATED WITH
INCREASED RISK OF COLON CANCER.
IN TERMS OF RADIATION, IONIC
RADIATION LEADS TO LEUKEMIA,
WHEN WE DROPPED THE ATOMIC BOMB
IN JAPAN MANY PEOPLE DIED FROM
LEUKEMIA.
TOBACCO IS A RISK FOR LUNG
CANCER.
UV RADIATION CAN CAUSE MELANOMA.
ARIZONA, TEXAS, FLORIDA, WE HAVE
A HIGH INCIDENCE OF MELANOMA.
AND THEN VIRUSES CAN CONTRIBUTE
TO VARIOUS CANCERS SUCH AS THE
HEPATITIS VIRUS CAUSES LIVER
CANCER, THIS IS QUITE HIGH, IN
CHINA, AND THEN THE CERVICAL
CANCER, THE HPV CAN LEAD TO
CERVICAL CANCER.
WE HAVE MANY RISK FACTORS
ASSOCIATED WITH CANCER.
MY SPECIALTY IS LUNG CANCER.
WE'LL SORT OF BRIEFLY GIVE AN
INTRODUCTION.
IT KILLS 150,000 ANNUALLY,
SOCIALED WITH CIGARETTE SMOKING,
45 MILLION CURRENT SMOKERS,
45 MILLION EX-SMOKERS, IN THIS
COUNTRY.
BUT OF THESE SMOKERS, ONLY
REALLY 16% WILL DIE FROM LUNG
CANCER.
MANY OF THEM WILL DIE FROM OTHER
THINGS SUCH AS HEART DISEASE.
SO IN TERMS OF THE CARCINOGENS
PRESENT IN CIGARETTE SMOKE
THERE'S MANY THAT HAVE BEEN
IDENTIFIED, SUCH AS HEAVY
METALS, CHROMIUM, BUT THEN WE'LL
FOCUS ON THE POLY AEROMATIC
HYDROCARBONS, HAH'S, AND NNK IS
ASSOCIATED.
THE HYDROCARBONS ARE IN THE
CIGARETTE SMOKE AND HAVE TO BE
ACTIVATED TO BE A CARCINOGEN,
OXIDIZED IN PARTICULAR, AND THEN
THEY FORM ADDUCTS WITH THE DNA
CAUSING MUTATIONS, TWO GENES
FREQUENTLY MUTATED IN LUNG
CANTER ARE
P-53 AND K-RAS.
BENZ-A-PYRENE, AND THE ACTIVE
CARCINOGEN, BPDE, AND THIS BINDS
TO THE DNA, ESPECIALLY GUANINE
NUCLEOTIDES.
AND SO
THE DNA GETS MUTATED,
PHASE 2 ENZYMES WILL TRY TO
CONVERT THEM INTO WATER SOLUBLE
PRODUCTS THAT CAN BE EXCRETED,
BUT DNA GETS MUTATED.
SO WITH LUNG CANCER, THE PROBLEM
IS PEOPLE SMOKE CIGARETTES, AND
AFTER ABOUT 20 YEARS THEN THEY
START GETTING CANCER CELLS IN
THEIR BODY, AND MORE AND MORE
GENES GET MUTATED, REALLY DOZENS
OF GENES GET ALTERED AND LUNG
CANCER.
P-53 IS MUTATED IN ABOUT HALF OF
THE LUNG CANCER PATIENTS, AND
WHAT WE SEE IS P-53 MEDIATES G1
TO S-FACE CHECKPOINT, IF THE DNA
GETS MUTATED, IT TRIES TO INDUCE
PROGRAMMED CELL DEATH, SO THAT'S
A CANCER CELLS THAT WILL DIE.
BUT WHEN P53 GETS MUTATED IT
BECOMES INACTIVE AND CAN'T CAUSE
THE CANCER CELLS TO DIE.
G TO T ADVANCE VERSIONS OCCUR AT
CPG RICH CODONS, AND CERTAIN
CODONS ARE ESPECIALLY MUTATED
SUCH AS 157, 158, 245, 248, 249
AND 274.
SO THE MUTATION IS NOT A RANDOM
PROCESS, IT OCCURS AT SPECIFIC
AREAS.
IN THE CELL CYCLE P-53, G-1 IS
RESTING PHASE, S 1 IS WHERE IT
IS REPLICATED, ADDITIONAL
ENZYMES ARE MADE IN.
G-2 AND IN M-PHASE CHROMOSOMES
ARE SEGREGATE AND PARENT BECOMES
TWO DAUGHTER CELLS AND WE GO
BACK TO THE G-1 PHASE.
IN EPITHELIAL CELLS, THEY CAN
BECOME QUIESCENT.
CANCER CELLS JUST GROW AS FAST
AS THEY POSSIBLY CAN.
WE MENTIONED P-53 MEDIATES, THE
DNA GETS DAMAGED THEN P-53
53
TRIESED TO BE INCREASED, AS WELL
AS P-21 AND NORMALLY P-53 DRIVES
PROGRAMMED CELL DEATH WHERE
APOPTOSIS AFTER DNA DAMAGE, THAT
IF THE GENES ARE MUTATED, THIS
DOES NOT OCCUR.
WE HAVE A SERIES OF ENZYMES
REGULATING, AT THE G-1 PHASE,
CYCLIN IS IMPORTANT.
IN G-1 PHASE, CYCLE INDEPENDENT
KINASES 4 AND 6 ARE IMPORTANT,
AND THE S-PHASE KINASE 2 IS
IMPORTANT AND G-2 AND M-PHASE
KINASE 1 IS IMPORTANT.
AND CYRLIND IS INHABITED BY
P-21, P-27, P-57, 15, 16, 18 AND
19.
SO THERE'S A WHOLE BUNCH OF
CYCLIN DEPENDENED KINASE AND
INHIBITORS.
WE MEASURE TOBACCO SMOKE IN PACK
YEARS, ONE PACK FOR ONE YEAR IS
ONE PACK YEAR.
MOST CHRONIC SMOKERS SMOKE TWO
PACKS EACH DAY FOR A YEAR, AND
THEN AFTER 20 YEARS THAT WOULD
BE 40 PACK YEARS OF CIGARETTE
SMOKE, BUT WE SEE AFTER 10 YEARS
THE LUNG STARTS TO UNDERGO
HYPERPLASIA, AFTER 25 YEARS A
MALIGNANT CANCER CAN FORM.
SO THE CANCER CELLS ARE
CONSTANTLY MUTATING, AND THE
CANCER BECOMES INCREASINGLY
AGGRESSIVE.
WE SEE A CARTOON OF NORMAL THINK
WITH HYPERPLASIA, AND WE SEE
MALIGNANT CANCER CELLS FORMING,
CONFINED TO THE PRIMARY ORGANS
SUCH AS LUNG AT THIS POINT, BUT
THEN WHEN A FULL BLOWN CANCER
DEVELOPS, IT CAN UNDERGO
METASTATSIS TO OTHER ORGANS, THE
LUNG CANCER UNDERGOES METASTASIS
TO THE LIVER, LYMPH NODES, BONE,
AND BRAIN.
SO THIS IS JUST AN H AND E STAIN
OF THE LUNG TISSUE, PINK IS
CYTOPLASM, PURPOSE THE IS
NUCLEUS.
THE LUNG IS HIGHLY ORDERED, ON
THE SURFACE WE SEE LITTLE VILLI.
WE BREATH IN O-2, EXHALE CO-2.
WHEN WE GET TO HYPOPLASIA, WE
SEE MORE AND MORE CELLS, IT'S
NOT AN ORDERLY LAYER, LAYERS
HAVE FIVE OR SIX CELLS IN THEM.
AND THEN WE GET TO DYSPLASIA,
CELLS BECOME DISORDERED, AND WE
SEE THE VILLI NOW STARTING TO
DISAPPEAR AND NUCLEI ARE
BECOMING VERY BIG.
CANCER CELLS HAVE BIG DARK
NUCLEI.
PINK CYTOPLASM.
THIS IS AN ADENOMA OF THE LUNG.
IN THIS CASE, THESE ARE SORT
OF -- THIS IS LIKE A CARCINOMA
IN SITU, AND THEN WITH FURTHER
PROGRESSION, WE CAN GET A FULL
BLOWN ADENOMA, AND THIS SECRETES
MUCUS, AND THESE CELLS CAN
UNDERGO METASTASIS TO DISTANT
ORGANS.
SO THE PROCESS OF CARCINOGENESIS
WE SEE LESS PINK.
HERE IS ANOTHER CARTOON SHOWING
WE HAVE THE CARCINOGEN, BENZATE
PYRENE, AND ALTERED CELLS GROW,
YOU GET A CARCINOMA IN SITU,
THAT CAN UNDERGO METASTATSIS.
WE HAVE A CARCINOMA INITIALLY, A
CLUSTER OF TUMOR CELLS.
BUT THEN AS THE TUMOR GETS BIG,
WHAT HAPPENS IS IT NEEDS ANGIO
GENESIS, WHEREBY BLOOD VESSELS
FROM THE HOST WILL GROW INTO THE
TUMOR PROVIDING OXYGEN AND
NUTRIENTS FOR THE TUMOR FOR
FURTHER GROWTH.
IF THIS DOES NOT OCCUR TUMOR
CELLS IN THE INTERIOR WILL DIE,
THEY WILL STARVE, THEY WON'T
HAVE OXYGEN, WON'T HAVE
NUTRIENTS.
THE HOST ACTUALLY SENDS ITS
BLOOD VESSELS INTO THE TUMOR AND
THE TUMOR FURTHER GROWS AND CAN
UNDERGO MIGRATION, INVASION, AND
METASTASIS.
AND WE WILL TALK LATER ON IN THE
COURSE ABOUT ANGIO GENESIS.
AND GENETIC ABNORMALITIES, WE
CAN GET MUTATION OF TUMOR
SUPPRESSOR GENES SUCH AS P53, WE
DON'T ALWAYS NEED THE GENES TO
BE MUTATED THOUGH.
WE CAN SILENCE THE GENES THROUGH
EPIGENETIC PHENOMENON AND DR.
BURMA WILL TALK ABOUT THIS.
AND YOU CAN GET CYCLIN D1, EGF
RECEPTOR AND ERBB-2.
THESE ARE BIG PROTEINS WITH AN
EXTERIOR, OUTSIDE THE PLASMA
MEMBRANE WHERE THEY BIND THE
VARIOUS GROWTH FACTORS.
THEN ON THE INSIDE WE HAVE A
LARGE TYROSINE KINASE DOMAIN.
THIS WILL FIND TYROSINE
SUBSTRATES IN THE TYROSINE
KINASE RECEPTOR OR IN OTHER
PROTEINS, AND IT WILL CAUSE
TYROSINE PHOSPHORYLATION OF THE
PROTEINS.
THEN THE PROTEINS WILL BECOME
ACTIVE, AND ALTER SECOND
MESSENGER PRODUCTION.
SO WE NOT ONLY HAVE THE AGF
RECEPTOR, ANOTHER ONE IS THE
IGF-1, INSULIN GROWTH ONE,
FIBROBLAST GROWTH FACTOR
RECEPTOR IS IMPORTANT.
AND THE VEG-F IS IMPORTANT IN
ENDOTHELIAL CELL.
CANCER CELLS MAKE VEG-F AND
STIMULATES ENDOTHELIAL CELLS TO
GROW INTO THE TUMOR AND CAUSE
ANGIO GENESIS.
AND SO WE'LL BE FOCUSING HERE ON
THE EGF RECEPTOR,
WHICH HAS MANY
LIGANDS THAT CAN BIND.
I WOULD HAVE SEVERAL NAMES FOR
IT.
THE EGF RECEPTOR IS IMPORTANT IN
LUNG CANCER, BREAST CANCER THE
ERB-2 IS IMPORTANT.
AND THEN OTHER MEMBERS OF THE
FAMILY INCLUDE THE.
RB3 AND 4, WHICH BINDS NRG-2
AND NRG-3.
ONCE THEY BIND THE LIGANDS, THEY
CAN DIMERIZE, WITH ITSELF OR
FORM A HETERODIMER, AND YOU'LL
GET TYROSINE PHOSPHORATED WELL.
621 AMINO ACIDS IN THE
EXTRACELLULAR DOMAIN THAT BINDS
EGF OR ALPHA.
THERE'S 541 AMINO ACIDS IN THE
INTRACELLULAR DOMAIN, AND LYSINE
721 BINDS ATP AND WILL TRANSFER
THE PHOSPATE TO A TYROSINE AMINO
ACID AND VARIOUS PROTEINS CAN BE
TYROSINE PHOSPHORYLATED.
AND HERE WE SEE THE EGF RECEPTOR
BINDS WITH HIGH ACIDITY, TGF
ALPHA, THE GROWTH ACTOR, TOXIN
38 CONJUGATE, CYTOTOXIC FOR
CANCER CELL.
AND HERE WE SEE THE EGF RECEPTOR
GETTING TYROSINE PHOSPHORYLATED,
A DARK BAND.
THESE PARTICIPATE IN SECOND
MESSENGER PRODUCTION.
FOR THE EGF RECEPTOR, WHAT'S
UNIQUE ABOUT LUNG CANCER, IT
GETS MUTATED.
TWO AREAS COMMONLY MUTATED ARE
L858R AND G719S.
THEY BIND TYROSINE KINASE
INHIBITORS WITH HIGH AFFINITY
AND TYROSINE KINASE INHIBITORS
USED IN EUROPE AND THE UNITED
STATES, THESE ARE APPROVED BY
THE FDA IN THE U.S. FOR
TREATMENT OF LUNG CANCER
PATIENTS WHO FAIL CHEMOTHERAPY.
IN HERE WE GET ANOTHER LOOK AT
THE DOMAIN OF THE EGF RECEPTOR
AND MUTATIONS, G719C AND L858R.
THERE'S ALSO SOME DELETION
MUTATION.
THESE MAKE THE EGF RECEPTORS
SENSITIVE TO TYROSINE KINASE
INHIBITORS.
WE'RE AT THE AGE OF MOLECULAR
MEDICINE, WHAT TO DO NOW IN NCI
PROTOCOL IS THE LUNG PATIENT
COMES IN, THEY WILL DO A
MOLECULAR ANALYSIS, TO SEE IF
THE EGF RECEPTORS MUTATED, IF IT
IS THEY KNOW THEY CAN USE
TYROSINE KINASE INHIBITORS ON
THE PATIENT.
IN TERMS OF SECOND MESSENGER
PRODUCTION THEN, WHEN THE EGF
RECEPTOR GETS ACTIVATED, IT CAN
INDUCE PROLIFERATION OF THE
CANCER CELLS THROUGH THIS
PATHWAY CALLED THE RAS, RAF, MEK
AND ERK PATHWAY.
K-RAS, ONE OF THE INITIAL STEPS,
IT'S MUTATED IN ABOUT 20% OF THE
LUNG CANCER PATIENTS.
AND WHEN IT GETS MUTATED THEN,
NORMALLY RAS WILL BIND GTP BUT
GET HYDROLIZED TO GPS WHICH IS
BIOLOGYICALLY INACTIVE.
BUT WHEN IT'S MUTATED, GTP
REMAINS BOUND, G TO T CODON 12,
THE FREDERICK NATIONAL LAB IS
DOING A BIG PROJECT WITH RAS TO
COME UP WITH NEW MODES OF
THERAPY FOR PATIENTS WHO HAVE
MUTATED RAS.
RAF IS DOWNSTREAM FROM RAS, ONCE
RAS GETS ACTIVATED, RAF CAN GET
PHOSPHORYLATED, AND THEN IT
BECOMES BIOLOGICALLY ACTIVE.
AND WITH RAF, IT'S ACTUALLY
MUTATED IN MELANOMA, SO WE HAVE
THE MUTATIONS OF V600E AND WHEN
THIS OCCURS YOU CAN USE THIS
TYROSINE KINASE INHIBITOR, THE
PLX4032, AND THIS IS VERY
EFFECTIVE ON THE PATIENTS
INITIALLY.
SO BOTH RAS AND B-RAF WHEN
MUTATED ARE DRIVER MUTATIONS IN
THE CANCER.
SO WE STATED THAT IN LUNG CANCER
YOU HAVE DOZENS OF MUTATIONS,
BUT NOT ALL OF THEM ARE WHAT'S
DRIVING THE CANCER.
IF YOU HAVE RAS GETTING MUTATED,
HOWEVER, OR B-RAF, THAT'S A VERY
SERIOUS EVENT AND THEN YOU CAN
TARGET THAT IN YOUR THERAPY.
SO ONCE RAF GETS PHOSPHORYLATED,
IT WILL PHOSPHORYLATE MEK 1 AND
2, AND THEY HAVE INHIBITORS, AND
THIS IS BEING INVESTIGATED IN
THERAPY WITH THE DOCETAXEL.
AND DOWNSTREAM FROM MEK IS ERK.
WHEN THAT GETS TYROSINE
PHOSPHORYLATED, IT ALTERS.
SO THE FIRST PATHWAY IS VERY
IMPORTANT IN TERMS OF
PROLIFERATION, AND HERE WE SEE
THE EGF RECEPTOR DIMERIZING, AND
THEN WHEN IT DIMERIZES, IT
CAUSES GTP TO BE BOUND TO THE
K-RAS WHICH WILL ACTIVATE THE
RAF WHICH WILL POSITIVE FOR LATE
THE MEK, WHICH PHOSPHORYLATES
ERK AND GOES INTO THE NUCLEUS
AND ALTERS THE EXPRESSION OF
TRANSCRIPTION FACTORS.
SO WHAT WE DO IS WE GET SIGNAL
AMPLIFICATION, ACTIVATING ONE
EGF RECEPTOR, YOU'LL GET
THOUSANDS OF PHOSPHORYLATED ERK.
AND THIS PROCESS OCCURS VERY
RAPIDLY.
IN THE LAB, I CAN ADD EGF, AND
WITHIN ONE MINUTE I CAN SEE
PHOSPHO-ERK.
IT'S A VERY RAPID PROCESS.
AND HERE IS A CARTOON SHOWING
EGF RECEPTOR, HERE WE SEE ON
MONOMER.
ONCE IT BINDS IT STARTS TO
DIMERIZE AND UNDERGOES
CONFIRMATION CHANGE, AND TURNS
ON THE TYROSINE KINASE ACTIVITY.
A SECOND BIG PATHWAY FOR THE
TYROSINE KINASE RECEPTORS, THIS
CAUSES SURVIVAL OF THE CANCER
CELL.
SO THE ERK PATHWAY CAUSES
PROLIFERATION, HERE WE MINIMIZE
THE APOPTOSIS OF CANCER CELLS.
AND SO WHAT HAPPENS IS WHEN THE
EGF RECEPTOR DIMERIZES, THEN WE
GET PI-3 KINASE, AND IT PRODUCES
THE PHOSPATE METABOLITES, WHICH
THEN IN TURN STIMULATE THE
PHOSPHORYLATION OF AKT CAUSING
PHOSPHORYLATION OF MTOR.
SO THE PI-3 KINASE, THE 100
UNITS IS INVOLVED, THE
METABOLISM, AND THEN THE PI3
KINASE CAN BE MUTATED IN BREAST
CANCER, ABOUT 25% OF THE
PATIENTS, GLIOBLASTOMA 25 MRS.,
COLON 30 PER CENT, STOMACH
CANCER 25%.
WHEN MUTATED IT'S TURNED ON.
YOU GET MORE METABOLITES.
P-10 IS AN ENZYME WHICH TRIES TO
METABOLIZE, BUT IT'S MUTATED IN
ABOUT 13% OF THE BREAST CANCER
PATIENTS.
SO WHEN PTEN IS MUTATED, THE
METABOLITE IS FILLED UP.
AKT SPOTS PHOSPHORYLATES,
PRESENTING APOPTOSIS, AKT IS
MUTATED IN 5% OF BREAST CANCER,
6% OF THE COLON CANCER PATIENTS.
AND FINALLY WE GET TO MTOR, AND
MTOR, ONE OF THE KEY THINGS IT
DOES IS IT CAUSES AUTOPHAGE AND
IF NOT ACTIVE, THEN THERE'S
DECREASE AUTOPHAGE, A CLINICAL
PROTOCOL THAT'S BEING DONE AT
THE NCI, AND SO THIS IS FOR LUNG
CANCER PATIENTS.
THEY INITIALLY DO A BIOPSY OF
THE TUMOR TO SEE WHAT GENES GET
MUTATED.
IF THE AGF RECEPTOR IS MUTATED,
THE PATIENT IS TREATED.
IF THESE GET MUTATED, THE
PATIENT IS TREAT THE WITH THE
MEK INHIBITOR, ACD-44.
IF THAT'S NOT MUTATED THEY LOOK
FOR PTEN, AND THEY TREAT WITH
THE PI3 KINASE INHIBITORS,
MK2206 AND LOOK AT ERB2 AND
TREAT THE PATIENT.
THEY LOOK FOR PEGF MUTATION,
RECEPTOR A, AND TREAT.
AND IF THAT DOESN'T WORK, THEY
TRY TO FIGURE OUT SOMETHING
ELSE.
BUT THEN THE KEY THING IS WITH
THESE TYROSINE KINASE
INHIBITORS, THEY FIND IF THEY
GIVE THEM TO PATIENTS, THE
PATIENTS CAN BECOME RESISTANT TO
THE DRUG.
SO AT THE END OF THE STUDY THEN,
IF THEY SEE RESISTANCE THEY DO
ANOTHER BIOPSY SPECIMEN AND SEE
IF THE TYROSINE KINASE ENZYME
HAS BEEN FURTHER MUTATED.
SO THIS IS THE AGE OF MOLECULAR
MEDICINE, AND SO WE DO ALL OF
THESE ANALYSES AND WHAT WE SEE
THEN, BASED ON THE MUTATIONS,
DICTATES THE THERAPY.
WE MENTIONED THAT IN ABOUT 50%
OF THE PATIENTS, THEY DEVELOP
RESISTANCE AFTER A YEAR, AND
PRIMARILY THIS IS A SECONDARY
MUTATION OF THE EGF RESENTER,
T790M.
SO ANOTHER DRUG THAT'S BEEN USED
IN CHRONIC MYELOGENOUS, IN THE
EARLY 2000'S, IT STARTED THE
CRAZE.
THEY HAVE AN ALTERATION OF
CHROMOSOME 22, THE PHILADELPHIA
CHROMOSOME, SEGMENTS OF
CHROMOSOME 9 AND 22 GET FUSED,
RESULTING IN AN ENZYME THAT'S
CONSTITUITIVELY ACTIVE.
HERE WE SEE ON CHROMOSOME 22,
AND CHROMOSOME 9 THERE'S A
TRANSLOCATION, LEADING TO THE
FUSED BCR-ABL GENE.
HERE YOU CAN SEE ON THE
CHROMOSOME FOR CHROMOSOME 9, IT
BECOMES LARGER, THE MUTATED
CHROMOSOME 22 THE MUTATION
BECOMES SMALLER, ILLUSTRATED
HERE.
THE BCH-ABL IS ACTIVE AND THESE
PATIENTS RESPOND TO GLEEVEK.
THERE'S ALWAYS SOME TOXICITY,
ESPECIALLY RASH, USING THE
TYROSINE KINASE INHIBITORS.
AFTER A YEAR ON GLEEVEC 53 OUT
OF 54 RESPONDED, 51 WERE DOING
WELL AFTER A YEAR, AFTER FIVE
YEARS 89% STILL RESPONDED BUT
SOME DEVELOPED RESISTANCE TO THE
DRUG.
GLEEVEC IS A TYROSINE KINASE
INHIBITOR IN PURPLE, BINDS TO
THE ENZYME, ATP CAN'T GET IN AND
PHOSPHORYLATE SUBSTRATE.
SO WE MENTIONED THEN WITH THE
GLEEVEC RESISTANCE, IT'S BECAUSE
OF A T315I MUTATION, NOW
DEVELOPING NEW DRUGS FOR THIS
MUTATION SUCH AS PONATINIB.
CANCER IS NOT STATIC.
IT'S A MOVING TARGET.
YOU CAN FIND A DRUG THAT WORKS,
AND THEN A YEAR LATER THAT SAME
DRUG DOESN'T WORK, BECAUSE THE
CANCER MIGRATED, OR MUTATED INTO
SOMETHING ELSE.
SO WE SEE HERE THEN FOR CML,
D.C.R-ABL, AND THE ANTIBODY
HERCEPTIN IS USED FOR MELANOMA.
AND FOR THE LUNG CANCER,
MUTATIONS IN THE EGF
RESEPTEMBERROR, GEFITINIB AND
ERLOTINIB ARE BIOLOGICAL ACTIVE.
WE'RE GOING TO CONCLUDE THIS
LECTURE.
CHECK YOUR HOUSE FOR RADON.
WHEN I MOVED TO MARYLAND I LIVED
IN A HOUSE IN THE COUNTRY, AND
WHEN I WENT TO SELL THIS HOUSE,
I WAS TOLD IT HAD RADON IN THE
BASEMENT.
SO TO SELL THE HOUSE, WHAT I HAD
TO DO WAS INSTALL AN AIR PUMP
THAT PUMPED AIR OUT OF THE
BASEMENT, INTO THE OUTSIDE
ATMOSPHERE.
AND SO IN MARYLAND, A LOT OF THE
HOUSES ON HILLS ESPECIALLY HAVE
ROCK, AND THE ROCK HAS THE RADON
GAS IN IT.
SO THE BASEMENTS CAN GET
CONTAMINATED, AND I WAS HOLD IF
ANYONE HAD LIVED DOWN THERE, IT
WAS THE EQUIVALENT OF SMOKING
TWO PACKS OF CIGARETTES A DAY.
SO YOU CAN GET LUNG CANCER FROM
RADON.
A SECOND THING, CHECK YOUR HOUSE
FOR ASBESTOS SUCH AS THE WALLS
HAVE A LOT OF INSULATION IN
THEM, AND THE OLD INSULATION HAD
ASBESTOS IN IT.
AS LONG AS IT STAYS IN THE WALL,
IT'S FINE.
BUT IF YOU START GOING INTO THAT
WALL, THE FIBERS WILL GET INTO
THE AIR, YOU CAN BREATHE THEM
INTO YOUR LUNGS AND YOU CAN GET
MESOTHELOMIA OF THE LUNGS.
TAKE PRECAUTIONS IN YOUR
WORKPLACE.
MY OLD OFFICE WAS IN BUILDING
31, AND ON THE WALLS THEY HAD A
LITTLE SIGN, BEWARE OF ASBESTOS.
BECAUSE THIS BUILDING WAS BUILT
30 YEARS AGO, AND THAT'S WHEN
THEY USED ALL INSULATION WITH
ASBESTOS.
IT STILL HASN'T BEEN REPLACED IN
ALL OF NIH.
CHECK YOUR COMMUNITY WATER
SYSTEM.
YOU WANT TO BE DRINKING GOOD
WATER, NOT WATER THAT HAS
CARCINOGENS IN IT.
AVOID BREATHING POLLUTED AIR.
WHEN I WAS A GRADUATE STUDENT, I
LIVED IN LOS ANGELES.
AND EVERY DAY AROUND 2:00 THE
OZONE WOULD ROLL IN FROM WESTERN
L.A., AND PASADENA, YOU WOULD
JUST START CHOKING.
YOUR LUNGS WOULD START BURNING,
AND THEN 5:00 IT WOULD BLOW EAST
TO RIVERSIDE, AND THEY WOULD GET
IT.
SO MORE AND MORE PLACES NOW ARE
HAVING POLLUTED AIR.
PROTECT YOUR SKIN.
WE MENTIONED ABOUT THE MELANOMA,
AND IT'S EVER-INCREASING IN
ARIZONA, AS WELL AS TEXAS AND
FLORIDA.
ONE OF THE PRIMARY REASONS FOR
THIS IS WE NORMALLY HAVE OZONE
IN THE UPPER ATMOSPHERE.
THAT PROTECTS US FROM THE UV
RAYS OF THE SUN BUT THE
AUTOMOBILE EXHAUST DEPLETES
OZONE SO WE'RE AT GREATER RISK
THAN WE USED TO BE.
DON'T BREATHE SMOKE.
INITIALLY THEY FOUND LUNG CANCER
IN CHIMNEY SWEEPS IN IT ENGLAND.
PEOPLE WHO WOULD GO UP AND CLEAN
OFF THE SOOT.
EXERCISE DAILY.
OBESITY LEADS TO COLON CANCER.
I MYSELF AM A AM BICYCLIST, IN A
COUPLE WEEKS I'LL DO A 100-MILE
BICYCLE RIDE.
AVOID PESTICIDES.
PESTICIDES CAN LEAD TO PROSTATE
CANCER.
EAT FRUITS AND VEGETABLES, THESE
HAVE LOTS OF ANTIOXIDANTS AND
REDUCING AGENTS IN THEM, AND
THIS PREVENTS OXIDATION OF
POTENTIAL CARCINOGENS.
REDUCE RED MEAT CONSUMPTION.
THAT'S GOT QUITE A BIT OF FAT IN
IT.
EAT FISH WITH OMEGA FATTY ACIDS.
MINIMIZE FRIED FOODS, YOU DON'T
WANT TO EAT TOO MUCH OF THAT
BARBECUE AND EAT A LOT OF THAT
SOOT.
DRINK ALCOHOL IN MODERATION, TOO
MUCH ALCOHOL CAN LEAD TO LIVER
CANCER.
AVOID UNNECESSARY X-RAYS.
AND REDUCE INFECTIONS.
INFECTIONS CAN LEAD TO
INFLAMMATION, IT'S THOUGHT THAT
THE 18% OF CANCERS RESULT FROM
INFLAMMATION.
WHAT HAPPENS IS THE ANTIBODIES
COME IN AND THEY RELEASE ALL OF
THESE CYTOKINES USED BY CANCER
CELLS TO GROW.
AND FINALLY, WE HAVE A FEW
REFERENCES FOR YOU.
SO THAT CONCLUDES THE
INTRODUCTION.
I'D BE HAPPY TO ANSWER ANY
QUESTIONS.
(INAUDIBLE QUESTION)
>> WELL, WITH CANCERS YOU HAVE
TO RECOGNIZE, FIRST, A TUMOR,
IT'S A MIXTURE OF CELLS.
LUNG CANCER IN THE '80s, WE
DEVELOPED ALL OF THESE CULTURES
FROM BIOPSY SPECIMENS, BASICALLY
YOU GET THE SPECIMEN FROM THE
PATIENT.
YOU DISSOLVE IT IN, PUT IT IN A
SERUM-FREE MEDIUM SO CANCER
CELLS DIE.
IN 1% OF THE CANCER CELLS, THEY
ARE THOUGHT TO BE STEM CELLS.
SO WHAT HAPPENS IN LUNG CANCER,
ESPECIALLY, WE HAVE WHAT'S
CALLED THIS FIELD EFFECT.
ONE CLONE GROWS OUT AND THEN YOU
MAY STOP THIS CLONE, BUT THEN A
DIFFERENT CLONE GROWS OUT.
THE FIRST CLONE MAY BE
RESISTANT, SENSITIVE TO
CHEMOTHERAPY, THE SECOND CLONE
ISN'T.
SO THEN YOU LOOK FOR YOUR
MUTATION, SUCH AS THE EGF
RECEPTOR, IF YOU SEE THIS SECOND
CLONE HAS THE EGF RECEPTOR
MUTATIONS, YOU CAN USE THE
TYROSINE KINASE INHIBITOR,
ERLOTINIB.
BUT IT'S A PECULIAR THING.
THEY FOUND USING THESE TYROSINE
KINASE INHIBITORS, CANCER CELLS
WERE SMART BECAUSE AFTER A
LIMITED PERIOD OF TIME THEY
COULD FIGURE OUT WAYS AROUND IT
BY CAUSING FURTHER MUTATIONS.
SO NOW THE SCIENTISTS ARE TRYING
TO BECOME SMARTER.
THEY ARE DEVELOPING A SECOND
GENERATION, A THIRD GENERATION
OF TYROSINE KINASE INHIBITORS.
CANCER, YOU KNOW, IT'S VERY
CLEVER.
IT'S ALWAYS MUTATING, AND SO
IT'S VERY DIFFICULT TO FIGHT.
ONE OF THE THINGS THAT WE REALLY
HAVE NOTHING FOR RIGHT NOW IS IF
IT UNDERGOES A K-RAS MUTATION
AND THEY HAVE A NEW PROJECT IN
FREDERICK WHERE THEY ARE TRYING
TO FIGURE OUT SOMETHING TO TREAT
PATIENTS WITH K-RAS MUTATIONS.
SO IT'S A MULTITUDE OF THINGS.
YOU NOT ONLY HAVE THE MUTATIONS,
THERE CAN BE SILENCING OF TUMOR
SUPPRESSOR GENES, AND THIS SORT
OF CAN BE SWITCHED ON AND OFF,
WHEREAS THE MUTATIONS, IT'S AN
EVENT THAT CAN'T BE CHANGED,
ONCE YOU GET MUTATIONS.
YOU HAVE THE EPIGENETIC
PHENOMENON ALSO CONTRIBUTING,
AND SO IT'S A VERY COMPLEX
PROBLEM AND THAT'S WHY WE'RE SO
MUCH INTO THE GENETIC ANALYSIS
OF THE TUMORS HERE AT NCI.
(INAUDIBLE QUESTION).
>> YES, IN LUNG CANCER WHEN THEY
FIND THE RESISTANCE TO THE
TYROSINE KINASE INHIBITORS, 50%
OF THE TIME IT'S BECAUSE THE AGF
RECEPTOR HAS BECOME MUTATED.
20% OF THE TIME THE K-RSA BECAME
MUTATED.
AND 15% OF THE TIME, IT'S
BECAUSE OF MET MUTATIONS, AND
THEN THERE'S ABOUT 15% WHERE
THEY HAVE ABSOLUTELY NO IDEA.
SO THOSE ARE HARD NUMBERS FOR
LUNG CANCER, AND 15% WE JUST
DON'T KNOW.
BUT THE GOOD NEWS IS NOW WE HAVE
THE IMMUNE CHECKPOINT
INHIBITORS, THEY ARE STARTING TO
WORK ON SOME OF THE LUNG CANCER
PATIENTS.
SO WE HAVE A LOT OF HOPE FOR
THAT NOW.
SO TEN YEARS AGO, ALL WE HAD FOR
LUNG CANCER WAS CHEMOTHERAPY,
AND A LITTLE BIT OF RADIATION
THERAPY.
NOW WE'VE GOT TYROSINE KINASE
INHIBITORS AND IMMUNE CHECKPOINT
INHIBITORS AND WE'RE QUITE
EXCITED.
LUNG CANCER DEATHS HAVE LEVELED
OFF.
THEY ARE NO LONGER GOING UP IN
THE U.S.
WE WOULD LIKE TO GET IT TO THE
POINT OF THE BREAST CANCER,
WHERE THE DEATHS START GOING
DOWN.
YES?
(INAUDIBLE QUESTION)
>> RIGHT.
WELL, THE EGF RECEPTOR IS
MUTATED IN ABOUT 13% OF THE LUNG
CANCER PATIENTS.
THEY FIGURED OUT IT WAS MUTATED,
THEY STARTED USING THE ERLOTINIB
IN THE U.S. AND IT DID IT WORK
VERY GOOD IN U.S. PATIENTS AND
THEY TRIED IT IN JAPAN AND IT
WORKED QUITE GOOD.
AND THEN THEY FOUND OUT THAT IN
THE JAPANESE WOMEN, ABOUT 30% OF
THEM HAD EGF RECEPTOR MUTATIONS,
AND MOST OF THESE WERE
NONSMOKERS.
SO THEN THEY FOUND OUT IN THE
U.S., WELL, THIS IS ONLY GOING
TO WORK IF, YOU KNOW, THE
PATIENT HAS EGF RECEPTOR
MUTATIONS, AND SO IN THE U.S. WE
HAVE ABOUT 10%, BUT IN SOME OF
THE ASIAN COUNTRIES 30% HAVE
MUTATED EGF RECEPTORS.
THOSE THINGS ARE IN VOGUE THERE.
WE WORRY ABOUT CANCER STEM
CELLS.
WE DON'T REALLY KNOW WHAT THEY
ARE DOING.
THEY ARE IN ALL OF OUR CULTURES,
AND IN LUNG CANCER IT'S ABOUT 1%
OF THE CELLS ON THE AVERAGE ARE
STEM CELLS AND WE DON'T KNOW
WHAT THEY ARE DOING BECAUSE, YOU
KNOW, ALL THE OTHER CELLS HAVE
THE EGF RECEPTORS, WE'RE NOT
CERTAIN OF THE PROPERTIES OF THE
STEM CELLS, BUT THE NOTCH
PATHWAY SEEMS TO BE INVOLVED
THERE.
OKAY.
WE'LL MOVE ON THEN TO OUR NEXT
SPEAKER, JILL SMITH FROM
GEORGETOWN UNIVERSITY, AND SHE'S
GOING TO TALK ABOUT
TRANSLATIONAL RESEARCH, BENCH TO
BEDSIDE, CLINICAL TRIALS.
>> GOOD AFTERNOON.
HOW MANY OF YOU IN THE AUDIENCE
ARE EITHER Ph.D.'S OR Ph.D.
CANDIDATES?
OH, OKAY.
HOW MANY OF YOU ARE M.D. OR M.D.
CANDIDATES?
OKAY, GOOD.
ANYBODY BOTH?
GOOD!
ALL RIGHT!
ALL RIGHT!
WELL, THANK YOU, DR. MOODY, FOR
INVITING ME.
THIS IS MY NEW HOME AT
GEORGETOWN.
LAST YEAR I WAS HERE AT NIH.
SO THIS IS MY NEW PLACE.
AND I HAVEN'T QUITE FIGURED OUT
IN THIS PICTURE, MY LAB IS NEXT
TO THE MEDICAL-DENTAL BUILDING,
IT'S CALLED BUILDING D BECAUSE I
UNDERSTAND THEY HAVEN'T GOTTEN A
DONOR YET FOR IT.
I DO HAVE A FEW DISCLOSURES.
I'M A CO-INVENTOR ON A FEW
PATENTS AND SOME OF THEM I MAY
MENTION SOME OF THE SCIENCE FROM
THE PATENTS HERE THAT HAVE TO DO
WITH PANCREATIC CANCER, AND I'M
ALSO THE DIRECTOR OF CONSULTING
COMPANY THAT HELPS WITH SOME
BIOTECH DEVELOPMENTS.
AS FAR AS WHAT WE'RE GOING TO
TALK ABOUT IN THE NEXT LESS THAN
HOUR, I HOPE, IS HOW TO
UNDERSTAND HOW AN IDEA IS
ACTUALLY TAKEN FROM THE RESEARCH
LAB TO PATIENT CARE.
AND LEARN ABOUT THE STEMS OF
CONDUCTING CLINICAL RESEARCH,
AND TO UNDERSTAND SOME OF THE
OBSTACLES THAT YOU HAVE TO
OVERCOME FOR DRUG DEVELOPMENT.
AND SOME EXAMPLES I'LL GIVE YOU
FROM MY EXPERIENCE WITH
TRANSLATIONAL PROJECTS, WE'LL
TALK A LITTLE BIT ABOUT THE
PITFALLS AND ALSO THE PRIZES.
SO, FIRST OF ALL, YOU GUYS ARE
ALL HERE BECAUSE YOU HAVE DREAMS
AND AMBITIONS AND WE ALL DO, AND
YOU WANT TO, YOU KNOW, DISCOVER
THAT CURE FOR CANCER.
WELL, I HAVE DREAMS TOO.
MY DREAM IS THAT I'M GOING TO
GET THE NOBEL PRIZE SOMEDAY, I
HAVEN'T GIVEN UP, I LOPE YOU ALL
HAVE DREAMS AND AMBITIONS ALSO.
THERE'S A FEW PEOPLE I ADMIRE.
ONE OF THEM IS NELSON MANDELA.
AND HE SAID THERE IS NO EASY
WALK TO FREEDOM ANYWHERE, AND
MANY OF US WILL HAVE TO PASS
THROUGH THE VALLEY OF THE SHADOW
OF DEATH AGAIN AND AGAIN BEFORE
WE REACH THE MOUNTAINTOP OF OUR
DESIRES.
AND THEN THERE'S EDMOND HILARY,
ALSO ANOTHER PERSON I ADMIRE,
HE'S THE FIRST PERSON WHO
SUMMITED MT. EVEREST.
BUT, YOU KNOW, HE DIDN'T MAKE IT
THE FIRST TIME.
THE FIRST TIME HE TRIED TO
SUMMIT MT. EVEREST, ACTUALLY THE
MAJORITY OF HIS CREW, INCLUDING
HIS BEST FRIEND, DIED.
AND WHEN HE WAS TALKING TO THE
PARLIAMENT IN ENGLAND, THERE WAS
A BIG PICTURE OF MT. EVEREST
BEHIND HIM.
HE TURNED AROUND AND HE LOOKED
AT THIS POSTER AND HE SAID, YOU
KNOW, MT. EVEREST, YOU HAVE
DEFEATED ME, BUT I WILL RETURN,
AND I WILL DEFEAT YOU.
BECAUSE YOU CAN'T GET ANY
BIGGER, BUT I CAN.
I'M BUILDING UP TO ENCOURAGE YOU
GUYS NOT TO GET DISCOURAGED WHEN
YOUR RESEARCH DOESN'T WORK OUT
THE FIRST TIME.
SO AND THEN OF COURSE THERE'S
MARTIN LUTHER KING JR. WHO DID
HAVE A BIG DREAM, AND HE DREAMED
THAT ONE DAY THIS NATION WOULD
RISE UP AND LIVE OUT THE TRUE
MEANING OF LIFE'S CREED, AND
HOLD ALL THESE TRUTH TO BE SELF
EVIDENT, THAT ALL MEN ARE
CREATED EQUAL.
WE ALL HAVE DREAMS AND DESIRES
AND WE ARE HERE BECAUSE WE WANT
TO SEE WHAT YOU'RE WORKING ON IN
THE LAB, YOUR DISCOVERY TO HAVE
MEANING IN LIFE AND TO HELP
PEOPLE.
THERE'S A PROBLEM THOUGH.
I MEAN, MANY OF US ARE INVOLVED
WITH RESEARCH AND THERE'S A LOT
OF DRUGS BEING TESTED, A LOT OF
IDEAS THAT ARE BEING TESTED, BUT
UNFORTUNATELY, THERE'S THIS
BOTTLENECK, AND OF ALL OF THE
IDEAS AND GREAT THINGS THAT
WE'RE WORKING ON IN THE LAB,
ONLY A CERTAIN PERCENTAGE OF
THEM ACTUALLY GET THROUGH TO
CLINICAL TRIALS, AND ONLY A
CERTAIN PERCENTAGE OF THOSE MAKE
IT AND GET APPROVED BY THE FDA
FOR TREATMENT.
SO WHAT'S THE BOTTLENECK?
THIS IS 495 ABOUT NOW, CLOSE TO
THE 5:00 RUSH HOUR TRAFFIC.
AND IS THE BOTTLENECK BECAUSE
THESE IDEAS ARE CRAZY OR THERE'S
A LOT OF POLITICS INVOLVED WITH
THIS, AND YOU GOT TO GET FDA
APPROVAL AND YOU'VE GOT TO
PLEASE EVERYBODY AND THE
CONGRESSMEN HAVE TO AGREE, AND
WHATEVER.
SO THERE ARE SOME BOTTLENECKS
THAT ARE POLITICAL TOO.
SO SEVERAL YEARS AGO, NIH
ACTUALLY SET UP THE N-CAST WITH
IDEAS ABOUT IMPROVING
TRANSLATIONAL SCIENCE, AND SOME
ARE SHOWN UP HERE ON THIS
SLIDE, AND THEY WANTED TO FOCUS
ON SIX AREAS TO TAKE THE IDEAS
FROM THE LAB TO PATIENT CARE.
WHERE DO YOU START?
YOU'RE THE BRILLIANT GRAD
STUDENT OR POSTDOC IN THE LAB.
YOU GET A WONDERFUL, BRILLIANT
IDEA.
AND THEN, YOU KNOW, OF COURSE
YOU HAVE TO THINK ABOUT THIS
IDEA AND THIS IS THE IDEA
DOWNLOADING, SO YOU'VE GOT TO
COME UP WITH AN IDEA, AND THEN
ONCE YOU HAVE THE IDEA, YOU HAVE
TO HAVE A HYPOTHESIS.
SO WHAT IS THIS IDEA THAT YOU
HAVE, AND WHAT'S THE HYPOTHESIS
THAT YOU'VE PLANNED TO TEST?
WELL, THERE'S DIFFERENT PHASES
OF CLINICAL TRIALS, AND MOST OF
THE TRIALS INVOLVE NEW DRUGS AND
THEY GO THROUGH A SERIES OF
STEPS.
MANY OF YOU ARE WORKING AT THIS
STAGE WHERE YOU'RE IN THE
LABORATORY, YOU MAY BE WORKING
WITH CELLS IN VITRO, OR CANCER
CELLS, OR WITH ANIMALS TESTING A
DRUG OR TREATMENT ON TUMOR OR
KNOCKOUT ANIMAL.
ONCE IT'S DEEMED SAFE IN ANIMALS
YOU GO THROUGH DIFFERENT PHASES,
PHASE ONE THROUGH FOUR THAT'S
TESTING IT IN HUMANS BEFORE IT
THEN WILL BE APPROVED BY THE
F.D.A.
THERE'S ALSO SEVERAL DIFFERENT
TYPES OF CLINICAL TRIALS,
THERE'S THE TREATMENT TRIALS,
PREVENTION TRIALS,
EARLY-DETECTION LIKE BIOMARKER
TRIALS, SCREENING TRIALS,
DIAGNOSTIC TRIALS, QUALITY OF
LIFE TRIALS, IF YOU'RE INTO
PSYCHOLOGY, CLINICAL BENEFIT.
AND TODAY AS DR. MOODY TALKED
ABOUT THERE'S A LOT OF GENETIC
TRIALS GOING ON, BASED UPON WHAT
WE KNOW ABOUT THE NEW GENOME.
ALSO IT CAN BE PHASE ONE THROUGH
FOUR, IT CAN BE RANDOMIZED, OR
IT CAN BE NONRANDOMMIZED,
BLINDED OR OPEN, IT CAN HAVE A
PLACEBO CONTROL OR MAYBE NOT.
AND IT CAN BE A PILOT TRIAL OR
MAYBE NOT A PILOT TRIAL.
SO JUST TO REVIEW FOR YOU WHAT
SOME OF THESE DIFFERENT PHASES
ARE, WE'LL START WITH PHASE 1
TRIAL, AND PHASE 1 IS WHEN YOU
HAVE -- YOU TEST IT IN A SMALL
NUMBER OF PEOPLE, AND THE WHOLE
PURPOSE IS TO DETERMINE WHETHER
YOUR TREATMENT IS SAFE.
PHASE 1 IS PRIMARILY FOR SAFETY
AND TOXICITY.
YOU WANT TO ALSO DECIDE HOW THE
TREATMENT SHOULD BE GIVEN.
SOME PHASE 1 IS YOU'RE TRYING TO
DECIDE IF BETTER TO GIVE IT
SUBCUTANEOUSLY, CAN YOU GIVE IT
ORALLY, WHAT IS THE
BIOAVAILABILITY, AND THEREFORE
YOU DO A LOT OF PHARMACO
KINETICS TO EVALUATE HOW THIS
DRUG IS METABOLIZED IN HUMAN
SUBJECTS AND WHAT WILL SIDE
EFFECTS BE SO MAINLY SAFETY AND
TOXICITY BUT IT DOESN'T TELL YOU
ANYTHING ABOUT HOW WELL IT'S
GOING TO WORK.
YOU MAY BE DOING PHASE 1 IN
NORMAL PEOPLE, NOT WITH CANCER
DRUGS BUT SOME OF THE DRUGS WE
DO.
THEN PHASE 2 IS WHEN YOU GET
INTO THE EFFICACY, AND YOU WANT
TO KNOW, OKAY, WE KNOW IT'S SAFE
IN HUMANS, DOES IT REALLY WORK?
AND SO THE NUMBER OF PEOPLE THAT
ARE TESTED IN A PHASE 2 TRIAL
ARE A LITTLE BIT GREATER.
USUALLY PHASE 2 TRIALS ARE
BLINDED, RANDOMIZED WITH A
PLACEBO.
YOU WANT TO KNOW DOES IT WORK,
AND IS YOUR TREATMENT BETTER
THAN THE PLACEBO, BUT IN THE
PHASE 2 YOU USUALLY DON'T
COMPARE IT TO OTHER TREATMENTS
AT THAT POINT.
HOWEVER, I WILL SAY THAT IN
CANCER TREATMENT, SOMETIMES WE
COMPARE IT TO THE STANDARD OF
CARE, AND WHEN WE DO THAT, WE
LOOK AT EITHER AN EQUIVALENCY
TRIAL, RATHER THAN -- OR A
SUPERIORITY TRIAL BUT A LOT OF
DRUGS ARE APPROVED BECAUSE THEY
ARE SHOWN TO BE EQUIVALENT TO
ANOTHER FDA-APPROVED DRUG, BUT
THEY MAY HAVE A BETTER SAFETY
PROFILE.
AND THEN PHASE 3 TRIAL IS WHEN
IT TAKES A LOT OF PEOPLE TO DO A
PHASE 3 TRIAL, AND THERE'S EQUAL
CHANCE TO BE ASSIGNED TO ONE OF
THE TWO GROUPS, AND IT LOOKS AS
HOW THE NEW TREATMENT THEN
COMPARES TO THE STANDARD
TREATMENT.
OR YOU CAN ALSO COMPARE IT TO A
PLACEBO, BUT IT'S A LOT LARGER
STUDY.
PHASE 4 IS USUALLY AFTER THE
DRUG HAS BEEN RELEASED, IT'S OUT
IN THE MARKET.
IT'S USUALLY A POST-MARKETING
TRIAL.
AND IT INVOLVES THOUSANDS OF
PATIENTS.
FOR EXAMPLE, THEY WANT TO KNOW
NOW THAT THEY HAVE THIS
VACCINATION APPROVED, HOW IS IT
GOING TO DECREASE THE INCIDENCE
OF, SAY, HEPATITIS B THROUGHOUT
THE WORLD, OR WHATEVER.
SO THEY DO POST-MARKETING
TRIALS.
SO THIS KIND OF SUMMARIZES THE
DIFFERENT PHASES OF THE TRIAL,
HOW LONG THEY TAKE, WHAT THE
PURPOSE OF THE TRIAL IS, AND THE
NUMBER OF DRUGS THAT ACTUALLY
GET TO THAT POINT.
YOU CAN SEE THAT ONCE YOU GET UP
TO PHASE 3, THE NUMBER OF DRUGS
ACTUALLY STARTS TO DROP OFF.
SO A LOT OF DRUGS ONCE THEY GET
INTO PHASE 1, THEY FIND OUT THEY
ARE NOT SAFE AND THEY CAN'T GO
ANY FARTHER.
OR YOU GO TO PHASE 2, AND
THERE'S NO DIFFERENCE THAN A
PLACEBO.
SO THEY DON'T MOVE ON ANY
FURTHER.
SO THOSE ARE A LOT OF THE
BOTTLENECK AND WEEDING OUT OF
THE DRUGS TO FIND OUT WHICH ONES
ACTUALLY WORK.
WITH THE RANDOMIZED TRIALS,
THERE'S AN EQUAL CHANCE TO BE
ASSIGNED TO ONE GROUP OR THE
OTHER, ONE GETS THE MOST WIDELY
ACCEPTED TREATMENT, AND LIKE THE
STANDARD TREATMENT, THE OTHER
GETS A PLACEBO.
THE OTHER ONE MAY GET A STANDARD
OF CARE, AND THEN THE GROUPS
NEED TO BE FAIRLY WELL BALANCED.
YOU CAN'T HAVE ALL WOMEN IN ONE
GROUP, AND MEN IN THE OTHER
GROUP.
SO IF -- YOU TRY TO BALANCE THE
TWO GROUPS.
WITH RANDOMIZATION YOU HAVE A
CONTROL AND TREATMENT GROUP.
AS I MENTIONED, THIS GROUP CAN
EITHER BE PLACEBO OR THE
STANDARD OF CARE.
BECAUSE WE USUALLY DON'T LIKE TO
TEST OUR NEW CANCER DRUGS IN
NORMAL PEOPLE AND YOU DON'T ALSO
LIKE TO WITHHOLD THERAPY FROM
PATIENTS BY GIVING THEM A
PLACEBO IF THEY HAVE KNOWN
CANCER.
SO OFTEN WE WILL -- WHEN WE
RANDOMIZED THEY WILL GET
STANDARD OF CARE VERSUS THE NEW
DRUG.
SO WHAT'S A PILOT TRIAL AND WHEN
WOULD YOU WANT TO DO A PILOT
TRIAL?
I'M WORKING ON ONE OF THEM RIGHT
NOW.
USUALLY IT'S A SMALL STUDY, AND
IT'S YOUR FIRST VENTURE INTO AN
AREA, AND IT HELPS YOU KIND OF
IRON OUT THE DIFFICULTIES
INVOLVED WITH DOING A BIGGER
TRIAL.
AND THE OTHER IMPORTANT PART
ABOUT DOING A PILOT TRIAL IS IT
GIVES YOU SOME IDEA OF HOW
PATIENTS MIGHT RESPOND TO THE
TREATMENT, AND THEN YOU CAN HAVE
YOUR STATISTICIAN USE THAT
INFORMATION TO CALCULATE THE
SAMPLE SIZE THAT YOU NEED TO DO
THE LARGER PHASE 2 TRIAL.
SO OFTEN A PILOT TRIAL IS AN
OPEN LABELED STUDY WHERE YOU'RE
TREATING EVERYONE AND YOU WANT
TO KNOW HOW MANY OF THEM
RESPOND.
AND THEN YOU USE THAT
INFORMATION FOR THE PHASE 2
TRIAL.
SO AGAIN THESE ARE TREATMENT
TRIALS AND IT'S TO DETERMINE THE
MOST EFFECTIVE TREATMENT FOR
PATIENTS WHO HAVE CANCER, TEST
THE SAFETY AND EFFICACY OF NEW
DRUGS AND INTERVENTIONS FOR
CANCER DRUGS.
AND I'M NOT GOING TO SPEND TIME
ON ALL THE TREATMENT TRIALS AND
WHATEVER.
BUT THE EARLY DETECTION TRIALS,
THERE'S A LOT GOING ON NOW,
LOOKING FOR DIFFERENT
BIOMARKERS, THEY CALL THEM THE
LIQUID BIOPSIES.
IF YOU CAN TAKE A BLOOD SAMPLE
FROM SOMEBODY AND TRY TO MAKE A
DIAGNOSIS, OF CANCER, SO THE
EARLY DETECTION TRIALS ARE
REALLY IMPORTANT RIGHT NOW, AND
IF YOU CAN ACTUALLY INTERVENE AT
AN EARLIER PHASE, AND MAYBE
PREVENT CANCER, OR PREVENT THE
BAD OUTCOMES WE HAVE FROM SOME
OF THE CANCERS.
SO THEN THERE ARE SOME OTHER
STUDIES LIKE QUALITY OF LIFE
STUDIES, THAT WE DO SUPPORTIVE
CARE STUDIES, AND THEN THERE'S
THE GENETIC TRIALS, WITH THE
GENETIC TRIALS AND A LOT OF GWA
STUDIES IT'S IMPORTANT THAT WE
REALIZE THERE ARE ETHICAL
CONSIDERATIONS, AND THERE'S A
LOT OF THESE HUGE TUMOR BANKS
WHERE BLOOD SAMPLES HAVE BEEN
BANKED AWAY, NOW WE KNOW THAT
THE IRB REQUIRES IF YOU'RE DOING
A NEW STUDY YOU HAVE TO HAVE
SPECIAL LANGUAGE IN THERE THAT
TALKS ABOUT THAT YOU'RE GOING TO
BE TESTING THE PERSON'S BLOOD OR
TISSUE FOR GENETICS, SO JUST
KEEP THAT IN MIND IF YOU'RE
DOING ANY OF THESE MUTATION
STUDIES BECAUSE THAT'S NOW
REQUIRED.
AND HOW ARE THE PATIENTS' RIGHTS
PROTECTED?
WELL, OF COURSE, THERE'S ETHICAL
AND LEGAL CODES THAT GOVERN THE
MEDICAL PRACTICE, AND THERE ARE
REVIEW BOARDS THAT DR. MOODY
TALKED ABOUT THAT YOU CAN SIT IN
ON.
THERE'S THE INSTITUTIONAL REVIEW
BOARD, AND IN ORDER TO DO A
CLINICAL TRIAL YOU HAVE TO BE
APPROVED AND TAKE THE CITY
TRAINING, AN ONLINE TRAINING TO
GET APPROVED SO THAT YOU CAN BE
INVOLVED IN HUMAN SUBJECT
RESEARCH.
THERE ARE ALSO DATA SAFETY
MONITORING BOARDS THAT ACTUALLY
MONITOR CONDUCT OF THE STUDY
WHILE IT'S GOING ON.
SO HOW DO YOU DO IT?
WHAT ARE THE NUTS AND BOLTS AND
HOW DO YOU ACTUALLY TAKE YOUR
IDEA IN THE LAB TO A PHASE 1, 2
TRIAL OR GET A DRUG APPROVED?
I'M GOING TO SHARE A LITTLE BIT
OF WHAT I DO AND HOW I'VE DONE
IT WITH SOME EXAMPLES.
THE FIRST THING YOU NEED TO DO,
THIS IS FROM THE NCI WE'RE
TALKING ABOUT CANCER, YOU NEED
TO THINK ABOUT WHAT TARGET
YOU'RE GOING TO LOOK AT.
THERE'S PLENTY OF TARGETS HERE.
YOU CAN CHOOSE YOUR FAVORITE
TARGET, IN SIGNALLING OR
RECEPTOR, OR CHOOSE A DIFFERENT
PATHWAY LIKE APOPTOSIS AND WORK
ON A PATHWAY, ON YOU PICK A
PARTICULAR CANCER ITSELF, AND
YOU ARE GOING TO FOCUS ON BREAST
CANCER OR LUNG CANCER, WHATEVER.
I MEAN, MY RESEARCH IS FOCUSED
PRIMARILY ON GROWTH RECEPTORS ON
CANCER, AND I ALSO FOCUS MOSTLY
ON PANCREATIC CANCER.
THESE ARE JUST SOME OF THE FACES
OF PANCREATIC CANCER, AND WE CAN
SEE HOW OLD THE AUDIENCE IS.
I'M SURE MOST OF YOU GUYS KNOW
THESE TWO GUYS DOWN HERE.
DOES ANYBODY KNOW WHO THEY ARE?
DOES ANYBODY KNOW WHO THIS GUY
IS?
WHO?
THAT'S DIZZY GILLESPIE, AGUES
MUSICIAN, JULIA PRODUCES, HER
MAN MUNSTER, JACK BENNY, MICHAEL
LANDON, THE FACES OF
PANCREATIC CANCER.
THE REASON I BECAME INTERESTED,
YOU HAVE TO IDENTIFY WITH
WHATEVER YOU'RE WORKING ON,
WHAT'S THE PROBLEM?
THAT'S WHERE YOU COME UP WITH
THE IDEA.
THERE'S A PROBLEM HERE AND I'M
GOING TO FIX IT.
WELL, THE PROBLEM WITH
PANCREATIC CANCER IS THE
SURVIVAL FROM PANCREATIC CANCER
HAS NOT IMPROVED IN OVER 50
YEARS.
IN SPITE OF OUR TECHNOLOGY, THE
GWA STUDIES, IN SPITE OF ALL THE
MRI'S, CAT SCANS AND ALL THE
TECHNOLOGY THERE'S BEEN NO
IMPROVEMENT.
WHY?
ARE WE GOING THE WRONG WAY?
THERE'S ONE CAR ON THIS HIGHWAY
THAT'S DRIVING THE WRONG
DIRECTION.
YOU KNOW, THE PROBLEM IS THERE'S
NOT BEEN ANY IMPROVEMENT IN
SURVIVAL.
OVER 70 REGIMENTS HAVE BEEN
THROWN AT PANCREATIC CANCER BUT
THE PROBLEM IS CHEMOTHERAPY HAS
BEEN NONSELECTIVE AND
NONSPECIFIC FOR PANCREATIC
CANCER, AND IN THE END
PANCREATIC CANCER IS RESISTANT
TO CHEMOTHERAPY, AND IT WINS
OUT.
SO BECAUSE OF THIS CONGRESS HAS
ACTUALLY NAMED PANCREATIC
CANCERS AS ONE OF THE
RECALCITRANT MALIGNANCIES AND
ASKED THE NIH TO IMPROVE FUNDING
FOR PANCREATIC CANCER BECAUSE OF
THIS.
THERE WAS A RECENT ARTICLE
PUBLISHED IN CANCER RESEARCH TWO
MONTHS AGO THAT SHOWED BY THE
YEAR 2020 PANCREATIC CANCER WILL
SURPASS BREAST AND COLON CANCER,
AND AFTER LUNG CANCER WILL BE
THE NUMBER TWO KILLER IN THE
UNITED STATES, IF WE DON'T DO
SOMETHING.
SO NOTHING'S CHANGED FOR 50
YEARS.
AND IF YOU KEEP DOING THE SAME
THING AND FOR THOSE WHO ARE INTO
CLONING IN THE LAB, YOU KNOW IF
YOU KEEP DOING THE SAME THING
YOU'RE GOING TO GET THE SAME
RESULTS.
SO WE NEED TO CHANGE OUR
STRATEGY WITH THIS DISEASE.
SO THAT'S WHERE I CAME IN AND
SAID THERE'S A PROBLEM HERE.
OKAY.
SO WHAT ARE YOU GOING TO DO?
WHEN YOU'RE DOING RESEARCH, IT'S
REALLY IMPORTANT, YOU ALWAYS
WONDER WHY DO I HAVE TO TAKE ALL
THOSE BASIC SCIENCE COURSES AND
WHY DO I HAVE TO UNDERSTAND THAT
AND WHATEVER.
WELL, YOU DO HAVE TO UNDERSTAND
THAT.
YOU KNOW, THE MED STUDENTS, WHY
DO YOU NEED GROSS ANATOMY.
YOU HAVE TO UNDERSTAND
PHYSIOLOGY AND BIOLOGY TO
UNDERSTAND THE NORMAL BEFORE YOU
UNDERSTAND THE ABNORMAL.
IN THE AREA I'M WORKING ON, WITH
GROWTH RECEPTORS, THERE'S A
COUPLE OF GASTROINTESTINAL
PEPTIDES THAT INVOLVE GROWTH OF
THE GASTROINTESTINAL TRACT.
ONE OF THEM IS CALLED CCK, JUST
TO REVIEW SINCE I'M SURE YOU'RE
UP ON PHYSIOLOGY OF THE G.I.
TRACT, CCK IS RELEASED FROM THE
HIGH CELLS WHEN THERE'S FATTY
ACIDS AND CERTAIN AMINO ACIDS IN
THE DUODENUM.
IT GETS IN THE BLOOD SYSTEM AND
CIRCULATES IN THE BLOOD AND ACTS
ON RECEPTORS IN THE PANCREAS.
WHEN IT DOES THAT IT RELEASES
DIGESTIVE ENZYMES THAT HELP YOU
DIGEST FOOD.
THE OTHER THING IT DOES IS IT
REACTS TO THE RECEPTORS THAT ARE
ON YOUR SPHINCTER AND THE
GALLBLADDER AND CAUSES
CONTRACTION OF THE GALLBLADDER
SO THE BILE IS RELEASED AND
HELPS YOU EMULSIFY THE FAT SO
YOU CAN DIGEST YOUR FAT.
THIS IS WHAT CKC CK DOES, IT
REGULATES INSULIN RELEASE.
ONE AREA I WAS INTERESTED IN, MY
MENTOR WAS WORKING ON GROWTH AND
REGENERATION OF THE PANCREAS,
AND THEY KNEW THAN THE CCK
WORKED ON ITS RECEPTOR TO HELP
THE NORMAL PANCREAS GROW.
IF YOU HAVE A BOUT OF
PANCREATITIS, CKS WORKS TO
RESTORE THE NORMAL CELLS.
THE OTHER RELATED PEPTIDE THAT
ACTS ON THE SAME RECEPTORS IS
GASTRIN.
YOU MAY BE FAMILIAR WITH IT
BECAUSE IT STIMULATES THE
RELEASE OF GASTRIC ACID.
GAS TRIN WAS PRESENT IN THE
FETAL PANCREAS, IT SHUT OFF AT
WEEK 14.
HOWEVER, IT GETS TURNED BACK ON
AGAIN IN CANCER AND ACTUALLY
STIMULATES THE GROWTH OF CANCER.
IT ALSO STIMULATES THE GROWTH OF
THE STOMACH, AND FOR ANY OF YOU
WHO TAKE CHRONIC PROTON PUMP
INHIBITORS, I DON'T WANT TO
SCARE ANYBODY, BUT EMIPROZOLE,
THE OTHER DRUGS, I DON'T WANT TO
NAME THEM ALL, ANY OF THE DRUGS
THAT BLOCK PROTON PUMP IN THE
STOMACH TO BLOCK ACID RELEASE
OVER TIME, WHAT HAPPENS IS THAT
GASTRIN LEVELS ARE ELEVATED
BECAUSE THE BODY SEE THERE'S NOT
ENOUGH ACID SO YOU BLOCK THE
NORMAL FEEDBACK LOOP.
I'M A GASTROENTEROLOGIST.
WHAT WE SEE IS THEY GROW POLYPS
IN THE STOMACH AFTER BEING ON IT
A LONG TIME.
THEY ARE BENIGN POLYPS, AND YOU
CAN GROW CARCENOIDZ, BUT IT
ABILITIES ON THE CCK RECEPTORS
AND CAUSE GROWTH.
IF THEY ARE ELEVATED, THEY
STIMULATE GROWTH.
WHAT DOES CCK DO BESIDES THAT?
THE OTHER THING IS THAT CCK CAN
CAUSE PANCREATITIS, AND ONE OF
THE THINGS THAT DR. MOODY TALKED
ABOUT IS INFLAMMATION CAN
PREDISPOSE TO CANCER.
THERE'S A COMPOUND ON THE SKIN
OF THIS PRETTY GREEN FROG.
CERULEIN, IT'S A CCK PEPTIDE, A
DEKAPEPTIDE.
IF YOU TAKE THAT CCK AND INJECT
IT INTO YOUR LABORATORY ANIMAL,
YOU WILL GET PANCREATITIS.
AND IF YOU CONTINUE TO DO THAT
OVER A LONG PERIOD OF TIME, YOU
CAN GET CHRONIC PANCREATITIS,
WHICH CAN INCREASE RISK FOR
PANCREATIC CANCER.
SO IF YOU HAVE A LITTLE BIT OF
CCK THAT HELPS YOU DIGEST YOUR
FOOD AND CONSIDERATE YOUR
GALLBLADDER, IT'S GOOD, LIKE
IT'S A BIT OF WINE MIGHT BE
GOOD.
IF YOU HAVE A LITTLE BIT TOO
MUCH, THESE ARE MY LIVER
PATIENTS.
TOO MUCH CCK IS NOT GOOD, AND IT
MAY STIMULATE CHRONIC
PANCREATITIS AND PANCREATIC
CANCER.
SO THE OTHER THING THAT I WANTED
TO TELL YOU, NOT ONLY DOES CCK
CAUSE PANCREATITIS, IT HAS
ANOTHER PROPERTY, HOW DOES IT
CAUGHT GROWTH?
IN ORDER TO UNDERSTAND HOW THESE
PEPTIDES CAUSE GROWTH YOU HAVE
TO UNDERSTAND THE DIFFERENCE
BETWEEN HYPERTROPHYY AND H
YPERPLASIA, AN EXAMPLE OF HYPER
TROPHY, IT'S WHEN YOU INCREASE
IN SIZE BUT NOT IN NUMBER, THAT
HAPPENS TO MANY OF US AT MIDDLE
AGE.
THIS IS AN EXAMPLE OF
HYPERPLASIA.
SHE DOUBLED, MORE THAN DOUBLED,
IN NUMBER, YOU'RE INCREASING THE
DNA CONTENT, SO ONE OF THE
THINGS THEY KNEW A LONG TIME AGO
IS THAT CCK AND GASTRIN BECAUSE
HYPERTROPHYY AND HYPERPLASIA.
IF YOU TREAT ANIMALS CAN CCK, IT
INCREASES THE DNA CONTENT AND
TRITIATED THYMIC UP TAKE,
STIMULATING SYNTHESIS.
THEY USED TO THINK LET'S GIVE
ANIMALS CCK AND MAYBE THE
INFLAMMATION IN THE PANCREAS IS
INCREASING THE CANCER, BUT THEY
NOW KNOW THAT IT'S NOT JUST
BECAUSE OF THE INFLAMMATION
THAT'S INDUCED, IT'S BECAUSE CCK
HAS THE OTHER PROPERTY THAT
CAUSES HYPERPLASIA.
IF THEY GIVE CCK TO ANIMALS
RECEIVING A CARCINOGEN THEY FIND
THEY CAN SIGNIFICANTLY INCREASE
THE NUMBER OF ANIMALS GETTING
PANCREATIC CANCER BY DOING THIS.
SO THAT'S BECAUSE CCK HAS
PROPERTIES OF BOTH HYPER PLASIA
AND CAUSING INFLAMMATION, BOTH
CAN PREDISPOSE TO CANCER.
WHEN I WAS A POSTDOC, I SAID
THIS WAS INTERESTING.
PANCREATIC CANCER DOESN'T HAVE
TREATMENT.
I TESTED HUMAN PANCREATIC CANCER
CELLS AND TREATED THEM WITH CCK
AND WITH GASTRIN AND LO AND
BEHOLD CANCER CELLS RESPONDED TO
PEPTIDES AND WE STIMULATED
GROWTH OF CANCERS AND COULD
BLOCK THE EFFECT BY USING
RECEPTOR ANTAGONIST.
SO THIS SHOWED PEPTIDES ARE
DRIVING THE GROWTH OF PANCREATIC
CANCER.
SO JUST A LITTLE BIT ABOUT THE
RECEPTORS THAT ARE INVOLVED,
THERE'S THREE MAIN RECEPTORS FOR
THIS CCK RECEPTOR, AND THEY ARE
EASY TO REMEMBER.
A, B AND C.
A WAS DISCOVERED IN THE
ALIMENTSARY TRACT, B IN THE
BRAIN, C DISCOVERED IN CANCER.
THAT'S HOW YOU CAN REMEMBER
THEM.
AND THE C RECEPTORS, OUR LAB
DISCOVERED THAT, I'LL TALK A
LITTLE BIT MORE ABOUT THIS C
RECEPTOR, BUT THE RECEPTORS
THEMSELVES ARE SIGNIFICANTLY
OVEREXPRESSED IN PANCREATIC
CANCER, JUST LIKE ESTROGEN
DRIVES BREAST CANCER, ANDROGEN
DRIVES PROSTATE CANCER,
GASTROINTESTINAL HORMONES DRIVE
G.I. CANCERS, COMPARED TO THE
NORMAL PANCREAS, THE NUMBER OF
RECEPTORS INCREASE IN PANCREATIC
CANCER.
SO WHAT HAPPENS IN THE NORMAL
SITUATION, IF THIS IS A NORMAL
PANCREAS AND HAS NORMAL
RECEPTORS ON IT, AND WHEN CCK IS
RELEASED INTO THE CIRCULATION,
OR GASTRI, IT BINDS TO THE
RECEPTOR AND AS WE LEARNED, IT
RELEASES ENZYME.
BUT IN CANCER, THE RECEPTORS ARE
MARKEDLY OVEREXPRESSED, SOME OF
THEM HAVE THIS VARIANT OF
RECEPTOR, WHICH I'LL MENTION IN
A MINUTE.
WHEN THEY RESPOND TO THE LIGANDS
THEY DON'T RELEASE DIGESTIVE
ENTIMES BUT CANCER DOESN'T CARE
IF YOU DIGEST YOUR FOOD.
GASTRIC GETS TURNED BACK ON.
IT WAS ORIGINALLY IN THE CANCER
CELLS AND IT'S SUPPRESSED, AND
THE MESSENGER RNA GETS TURNED
BACK ON IN EARLY PRE-CANCEROUS
LESIONS AND REGULATES ITS OWN
GROWTH BY AN AUTOCRINE
MECHANISM.
ONE OF THE THINGS WE DISCOVERED
IS THAT NOT ONLY ARE THE
RECEPTORS OVEREXPRESSED BUT SOME
PANCREATIC CANCERS MAKE A MUTANT
REKEPTOR, CCC-C RECEPTOR, THE
FOURTH INTRON IS NOT SLICED OUT.
HUMANS HAVE AN OPEN READING
FRAME THROUGH THE FOURTH INTRON,
WHEREAS ANIMALS, MICE IN
PARTICULAR HAVE A STOP CODE AND
DO NOT TRANSCRIBE THE INTRON.
THIS OCCURS IN 35% OF PEOPLE
WITH PANCREATIC CANCER, AND I
WON'T GO INTO THE DETAILS BUT WE
DID SOME DNA SEQUENCING AND WE
ACTUALLY IDENTIFIED THE SNP THAT
CAUSES THIS SLICE VARIANT.
FOR THE PEOPLE THAT DON'T SLICE
OUT THE FOURTH INTRON IT CAUSES
THE ADDITION OF 69 AMINO ACIDS
TO BE ADDED TO THE THIRD
INTRACELLULAR LOOP.
FOR ANY WHO WORK ON G-PROTEIN
COUPLED RECEPTORS YOU KNOW THE
THIS THIRD INTRACELLULAR LOOP IS
INVOLVED IN GTP PROTEIN
COUPLING, AND THAT'S WHAT CAUSES
THE GROWTH AND PROLIFERATION.
SO WHEN THIS ADDITIONAL PIECE IS
ADDED ON HERE, IT MAKES THE
RECEPTOR ACTIVE.
SO WE ACTUALLY RAISED AN
ANTIBODY AGAINST THIS SPECIFIC
RECEPTOR, AND WE FOUND THAT WE
COULD GET STAINING IN THE PEOPLE
WHO HAD THE ASNP BUT PEOPLE WITH
THE WILD GENOTYPE DID NOT HAVE
BINDING TO OUR ANTIBODY.
I'M STILL TRANSLATING AS A
HUMAN, WE'VE MADE THIS INTO A
MONO CLONAL ANTIBODY.
IF WE TREAT THE MICE, THE RED
BARS, THOSE TREATED WITH
CONTROLS CONTINUED TO GROW.
SO THIS JUST GIVES AN EXAMPLE OF
HOW IT WORKS IN THAT WE FOUND
THAT THE SNP BECAUSES A
MISBINDING TO SPLICING PROTEIN,
SO IF YOU HAVE THIS C VARIANT IT
DOES BIND TO THE SPLICING
PROTEIN BUT WITH THE A GENOTYPE
OR SNP THERE'S NO BINDING.
THAT'S JUST ANOTHER EXAMPLE OF
IT.
IS THIS CLINICALLY RELEVANT?
WE DID GO BACK AND WE DID AN
ANALYSIS, WHICH IS ANOTHER TYPE
OF RESEARCH YOU CAN DO, AND WE
WENT INTO OUR TUMOR DATA BANK
AND WE ANALYZED PATIENTS WITH
PANCREATIC CANCER AND SAID,
WELL, WE KNOW IF YOU HAVE THIS
SLICE VARIANT IT SEEMS TO
STIMULATE GROWTH, DOES THAT
REALLY AFFECT THE SURVIVAL OF
PATIENTS?
AND INDEED WE FOUND THAT IT DID.
SO PEOPLE WHO HAD THE SLICE
VARIANT RECEPTOR DID NOT LIVE AS
LONG, IT WAS STATISTICALLY
SIGNIFICANT.
THIS MAY BE ONE OF THE REASONS
WHY PATIENTS WITH PANCREATIC
CANCER HAVE SUCH A POOR
SURVIVAL.
SO NOW WE'VE IDENTIFIED IT'S A
GERMLINE MUTATION FOR PANCREATIC
CANCER.
AND YOU HAVE TO CORRECT FOR THE
STAGE OF DISEASE WHICH WE DID
AND SHOWED IT WAS STILL
STATISTICALLY SIGNIFICANT.
SO THE OTHER RECEPTOR THAT I
WORKED ON, SINCE MY WORK HAS
BEEN WITH G PROTEIN COUPLED
RECEPTORS IS WITH AN OPIOID
RECEPTOR, ALSO A G PROTEIN
COUPLED RECEPTOR AND WE
IDENTIFIED A PROTEIN, OGF, THAT
WHEN IT BINDS TO ITS RECEPTOR IT
INHIBITS GROWTH OF PANCREATIC
CANCER.
AND WE DID RECEPTOR BINDING
STUDIES TO SHOW IT WAS
PHYSIOLOGICALLY RELEVANT, AND
THEN YOU CAN SEE IN THESE NICE
MICE THAT IF WE TREATED THE MICE
WITH THIS OGF TUMORS SHRUNK,
5 MILLIGRAMS PER KILOGRAM THREE
TIMES A DAY.
I WANT TO DO A PHASE 1 TRIAL,
HOW MUCH DO I GIVE TO A HUMAN
BEING?
YOU HAVE TO CALCULATE, WELL, IF
THIS IS HOW MUCH I GIVE MY
22-GRAM MOUSE, HOW MUCH DO I
HAVE TO GIVE TO MY 70-KILOGRAM
MAN AND DECREASE THAT BY A
THOUSAND-FOLD AND START LOW AND
WORK MY WAY UP.
SO WE HAD IDENTIFIED THE
PROBLEMS THAT PANCREATIC CANCER
HAD A DISMAL PROGNOSIS,
HYPOTHESIS WAS OGF COULD INHIBIT
GROWTH BUT COULD IT WORK IN
HUMANS?
WE WENT INTO A PHASE 1 TRIAL.
BEFORE YOU DO PHASE 1 TRIAL, YOU
HAVE TO APPLY TO THE FDA, YOU
HAVE TO GET AN INVESTIGATIONAL
NEW DRUG NUMBER OR IND NUMBER,
AND YOU HAVE TO FILL OUT WHAT
THEY CALL A 1571, AND 1572 FORM.
YOU WRITE A PROTOCOL.
YOU GET A CONSENT FORM.
YOU HAVE TO GET IRB APPROVAL.
YOU FIND A SPONSOR WHO IS GOING
TO FUND YOUR STUDY.
THAT'S PROBABLY THE HARDEST
PART.
AND THEN, YOU KNOW, YOU HAVE
DIFFERENT RESPONSIBILITIES OF
THE PRINCIPAL INVESTIGATORS AND
YOU HAVE TO REGISTER YOUR TRIAL
ON THE CLINICALTRIALS.GOV
WEBSITE.
IF YOU DO NOT REGISTER BEFORE
YOU ENROLL YOUR FIRST PATIENT
YOU'RE NOT ALLOWED TO PUBLISH
YOUR RESEARCH.
THIS IS A 1571 FORM, YOU GET
ASSIGNED AN IND NUMBER AND YOU
HAVE TO INCLUDE THAT NUMBER WITH
EVERYTHING SINGLE TIME YOU
SUBMIT A FORM, TO THE F.D.A.
THIS FORM HAS TO ACCOMPANY EVERY
COMMUNICATION TO THE FDA
CONCERNING YOUR PROTOCOL.
AND THEN EVERY TIME YOU SUBMIT
IT, YOU HAVE TO KEEP A RECORD
OF -- THIS IS NUMBER ONE I
SUBMITTED, THIS IS MY SECOND
COMMUNICATION, AND YOU'RE GIVEN
A SERIAL NUMBER, AND THE FDA
RECORDS ALL OF THESE.
BUT IT'S VERY IMPORTANT TO KEEP
GOOD RECORDS WITH YOUR F.D.A.
SO THEN WHEN YOU DO THE -- THESE
ARE THE THINGS YOU HAVE TO PUT
ON THE 1571 AND 1572 FORM, AND
SOME OF THE DETAILS ABOUT THAT.
AND THEN YOU GO INTO WHAT THE
AIMS OF THE STUDY ARE.
SO WE WANTED TO LOOK AT THE
SAFETY AND TOXICITY OF OGF, WE
DIDN'T KNOW WHAT DOSE TO USE.
SO WE WANTED TO CALCULATE WHAT
WAS THE RIGHT DOSE, WE DID
PHARMACO KINETICS, WE TEST THE
IV AND SUB-CU.
WE TESTED CHRONICALLY TO SEE HOW
WELL IT WAS TOLERATED OVER TIME.
WHEN YOU'RE DOING A PHASE 1
TRIAL YOU HAVE TO DECIDE WHO IS
YOUR POPULATION, A LOT OF PHASE
1 TRIALS ARE DONE IN HEALTHY
CONTROLS.
WELL, SINCE WE WERE INTERESTED
IN GETTING INFORMATION ON CANCER
PATIENTS, WE TESTED THIS IN
PANCREATIC CANCER PATIENTS.
AND YOU JUST COME UP WITH THE
CRITERIA THAT YOU THINK THAT
WILL BE GOOD, WHO YOU'RE GOING
TO INCLUDE AND WHO YOU'RE GOING
TO EXCLUDE FROM YOUR STUDY.
BASICALLY YOU WANT TO MAKE SURE
YOU'RE GOING TO HOPEFULLY
INCLUDE PATIENTS THAT ARE GOING
TO LIVE LONG ENOUGH SO THAT
YOU'LL GET SOME INFORMATION FROM
THE STUDY.
WHAT WE DID IN OUR PHASE 1 STUDY
WHERE YOU ENROLL THREE PATIENTS,
GIVE THEM THE FIRST DOSE AND
STARTED A 25 MILLIGRAMS PER
KILOGRAM AND IF THREE PEOPLE
TOLERATE THAT DOSE YOU MOVE UP
TO THE NEXT DOSE.
THE VERY FIRST PERSON THAT I
GAVE THIS DRUG TO WAS A LITTLE
LADY WITH PANCREATIC CANCER AND
SHE ENDED UP IN THE HOSPITAL
THAT WEEKEND WITH ABDOMINAL
PAIN.
AND I HAD TO MAKE A DECISION,
WOW, DID I DO THIS TO HER?
IS IT HER CANCER?
AM I GOING TO DOSE THE NEXT
COUPLE PATIENTS?
AND I ENDED UP GOING AHEAD AND
DOSING THE NEXT COUPLE PATIENTS,
AND IF I HADN'T TAKEN A RISK, OR
MOVED AHEAD, THIS STUDY WOULD
HAVE NEVER GONE FURTHER.
SO SHE DID FINE AND RECOVER, IT
WAS PROBABLY HER CANCER THAT
CAUSED HER TO BE THAT WAY
BECAUSE NO ONE ELSE HAD THAT
PROBLEM.
WE DID ESCALATED AND FOUND OUT
250 WAS OUR MAXIMUM TOLERATED
DOSE.
WE DID PHARMACO KINETIC STUDIES
WHERE WE MEASURED AND SOMETIMES
YOU NEED TO DO THIS IN YOUR
PHASE 1 TRIAL, WE PROVED IT WAS
INCREASING IN THE BLOOD.
WHEN WE KNEW THE MAXIMUM
TOLERATED DOSE WE WENT INTO A
PHASE 2 TRIAL AND YOU WANT TO
KNOW PHASE 2, AS I SAID BEFORE,
EFFICACY.
DOES IT REALLY WORK?
WE ENDED UP DOING AN OPEN LABEL
STUDY, AND WE USED THE DOSE THAT
WE HAD FOUND IN THE PATIENTS IN
THE PHASE 1 STUDY.
OUR PATIENTS COULDN'T BE
RESPECTABLE.
I WENT ROUND AND ROUND WITH THE
F.D.A.
I WANTED TO COMPARE IT TO
STANDARD OF CARE, BUT THEY SAID
THAT I COULDN'T DO THAT BECAUSE
WE DIDN'T PROVE YET THAT IT WAS
EFFICACIOUS.
THE FDA MADE US TREAT PATIENTS
WHO HAD ALREADY FAILED THERAPY,
WHICH IF YOU KNOW ANYTHING ABOUT
PANCREATIC CANCER, YOU KNOW THEY
ARE NOT DOING TOO WELL AT THAT
STAGE BUT WE TOOK WHAT WE COULD
GET AND DID THIS STUDY, AND
ACTUALLY WE LOOKED AT SURVIVAL
IN THOSE PATIENTS, WE LOOKED AT
OTHER OUTCOMES LIKE TIME
PROGRESSION, QUALITY OF LIFE,
CLINICAL BENEFIT WHICH IS
SOMETHING ELSE WE LOOK AT OFTEN
IN CANCER STUDIES, AND WE LOOKED
AT CAT SCANS, THERE'S THE RECIST
CRITERIA TO SEE IF YOU'RE HAVING
SHRINKAGE OF TUMORS BY MEASURING
THEM PERIODALLY ON TUMORS.
WE FOUND WITH PRIMARY END POINT
OF SURVIVAL THAT COMPARED TO
PATIENTS WHO CHOSE NOT TO GO IN
THIS STUDY, THAT WE HAD
SIGNIFICANT IMPROVEMENT IN
SURVIVAL OF OUR PATIENTS WHO HAD
THIS TREATMENT.
SO AFTER WE DID THE PHASE 2
TRIAL, WE ACTUALLY THEN WENT
BACK TO THE LAB.
AND WE THOUGHT WE WOULD TEST IT
IN COMBINATION WITH ANOTHER
STANDARD CHEMOTHERAPY AT THAT
TIME, GEMCITABINE.
AND WHAT WE FOUND IS THAT WHEN
WE GAVE THE GEMCITABINE ALONE OR
OGF ALONE, TUMORS DIDN'T SHRINK
AS MUCH AS IN COMBINATION.
YOU CAN SEE WITH THE MICE, IF
YOU WORK WITH NUDE MICE, THE
MOUSE THAT GOT THE CHEMOTHERAPY
LOST WEIGHT AND HIS SKIN WAS
KIND OF SCALY BUT THE ANIMAL WHO
GOT THE COMBINATION, IT HAD A
PROTECTIVE EFFECT AND HE DID
OKAY AND THE TUMOR WAS SMALLER.
SO TO MAKE A LONG STORY SHORT, I
WENT BACK AND APPLIED FOR
ANOTHER GRANT AND GOT MORE
APPROVAL.
WE TESTED THIS COMBINATION IN
HUMAN SUBJECTS, AND WE ACTUALLY
FOUND COMPARED TO OUR OWN
MONOTHERAPY WITH OG, IF WE COULD
IMPROVE THE SURVIVAL OF PATIENTS
WHO GOT THE COMBINATION.
SO THIS DRUG ACTUALLY -- THIS IS
WHEN I WAS AT PENN STATE.
PENN STATE HAS THE INTELLECTUAL
PROPERTY FOR THIS BUT THIS IS AN
IMPORTANT POINT BECAUSE BEFORE
YOU GO OUT AND DISCLOSE ANY
RESEARCH THAT YOU DO, INCLUDING
AN ABSTRACT, YOU WANT TO MAKE
SURE THAT YOU HAVE FILED AN
INVENTION DISCLOSURE OR
PROVISIONAL PATENT TO PROTECT
IT, IF -- I MEAN IF YOU'RE
WORKING -- AND THE DISCOVERY
ACTUALLY BELONGS TO YOUR
EMPLOYER, NOT TO YOU UNLESS YOU
OWN YOUR OWN COMPANY.
SO ANYWAY, THAT'S IMPORTANT,
WITH THE OG, IF WE DID
INTELLECTUAL PROPERTY, PENN
STATE GOT THE PATENT, AND THEY
ACTUALLY HAVE LICENSED THE
PATENT, IT'S GOING ON NOW FOR
DEVELOPMENT THROUGH THE F.D.A.
SO IT IS MOVING FORWARD.
I'M AN INVENTOR, EVENTUALLY I
MAY GET ROYALTIES.
THAT'S WHAT HAPPENS WHEN YOU
WORK FOR A COMPANY.
YOU CAN ALSO -- YOU HAVE TO FIND
A COMPANY, YOU HAVE TO LICENSE
YOUR PATENT.
IF YOU REALLY WANT TO GET IT OUT
THERE, BECAUSE MOST OF US ARE --
YOU GET IT TO A STAGE AND THEN
YOU HAVE TO FIND A COMPANY THAT
CAN ACTUALLY TAKE IT TO THE NEXT
LEVEL.
WHAT ARE SOME OF THE OBSTACLES
WITH DOING TRANSLATIONAL
RESEARCH TODAY?
WELL, OF COURSE THE BIGGEST
OBSTACLE IS ALWAYS MONEY.
HOW I DID IT WITH $50,000 IS
UNBELIEVABLE BUT I HAD A COMPANY
GIVE ME A LITTLE GRANT THAT
HELPED ME BUY THE DRUG AND THE
OTHER THING WE USED IS THE
CTSA'S AT THE UNIVERSITY BECAUSE
THAT HELPS KEEP COSTS DOWN.
SOY THERE ARE -- IT IS PROBABLY,
BUT IT IS EXPENSIVE.
AND FUNDS ARE HARD TO COME BY.
THE OTHER THING, I MEAN I'M A
CLINICIAN, I'M AN M.D.
CLINICIANS OFTEN DON'T GET
PROTECTED RESEARCH TIME, WHICH
IT WOULD BE NICE IF THEY HAD
MORE PROTECTED TIME, AND THE
INDIRECT COSTS WE GET ON OUR
GRANTS DON'T COVER OUR
MALPRACTICE, YOU'RE REQUIRED TO
HAVE MALPRACTICE IF YOU'RE DOING
CLINICAL RESEARCH, IT'S REQUIRED
BY THE FDA AND IRB.
YOU HAVE TO SOMEHOW PAY FOR
THAT.
THAT'S ANOTHER PROBLEM.
THERE'S ALSO THIS CHIASM BETWEEN
INDUSTRY AND NIH AND ACADEMIA.
IN ORDER FOR US TO MOVE FORWARD
WITH A LOT OF THESE DRUG
DISCOVERIES, THAT CHIASM HAS TO
COME TO A CLOSE.
IT'S ABOUT TEAM SCIENCE TODAY
AND WE ALL HAVE TO WORK TOGETHER
AND I THINK THAT INDUSTRY HAS A
LOT TO OFFER, ACADEMIA, NIH HAS
A LOT TO OFFER, BUT THEY ALL
NEED TO GET TOGETHER AND WORK
TOGETHER IF WE'RE GOING TO COME
UP.
LIKE I SAID, THERE'S NO MORE
ONE-MAN BANDS.
THIS IS ALL ABOUT TEAM SCIENCE.
SO AS WE LOOK BACK ON THE
PROBLEM, YOU KNOW, SURVIVAL OF
PANCREATIC CANCER, WHY HASN'T IT
IMPROVED, ARE WE ALL GOING THE
WRONG WAY, WELL, MAYBE YOU GOT
TO TAKE A DIFFERENT STRATEGY.
MAYBE ACTUALLY THIS GUY IS GOING
THE RIGHT WAY AND EVERYBODY ELSE
IS GOING THE WRONG WAY ON THE
HIGHWAY.
SO IN ORDER TO CHANGE THINGS,
WITH RESEARCH, I SUGGEST WE HAVE
TO TRANSFORM OUR MINDS, WE HAVE
TO THINK OUTSIDE OF THE BOX.
WE'VE GOT TO DO THINGS
DIFFERENTLY OR ELSE THINGS
AREN'T GOING TO CHANGE.
AND DON'T BE AFRAID TO TAKE SOME
RISK.
IF I HADN'T MOVED ON AND PUSHED
FORWARD WE NEVER WOULD HAVE
GOTTEN THE DRUG MOVING THROUGH
AN APPROVAL IN THE F.D.A.
YOU HAVE TO BE ABLE TO TAKE SOME
RISK.
AND THE BOTTOM LINE IS DOES
RESEARCH HAVE ANY REAL CLINICAL
RELEVANCE, DOES IT HELP PEOPLE?
THESE ARE A COUPLE OF MY
LONG-TERM SURVIVORS FROM THE
PANCREATIC CANCER STUDIES, I
HAVE THEIR PERMISSION TO SHOW
PICTURES.
BOBBY AND VICKIE.
AND YES, IT MEANS EVERYTHING
BECAUSE OF PEOPLE LIKE THIS.
SO THAT'S THE REASON WHY WE'RE
DOING THE RESEARCH IS TO IMPROVE
SURVIVAL AND HELP SAVE LIVES.
SO THE IMPORTANT THING IS DON'T
GIVE UP.
AND I'M HERE TO TELL YOU THAT.
I HAVEN'T WON THE NOBEL PRIZE
YET BUT I HAVEN'T GIVEN UP.
IF IT'S NOT ME, I HOPE IT'S ONE
OF MY STUDENTS OR SOMEBODY ELSE.
BUT AS FAR AS YOUR DREAMS,
THERE'S SOME SAYINGS, ONE IS
STRIVERS ACHIEVE WHAT DREAMERS
BELIEVE.
YOU GOT TO WORK FOR IT.
THERE'S ALSO A SAYING, I STAND
FOR FREEDOM OF EXPRESSION, DOING
WHAT YOU BELIEVE IN, AND GOING
AFTER YOUR DREAMS.
AND A DREAM DOESN'T BECOME
REALITY THROUGH MAGIC.
IT TAKES SWEAT, DETERMINATION,
AND HARD WORK.
AND THIS IS WHAT I SAID, YOU
KNOW, IF YOU DON'T BELIEVE IN
YOURSELF OR YOUR DREAMS, NO ONE
ELSE IS GOING TO BELIEVE IN THEM
EITHER.
SO YOU HAVE TO BELIEVE IN
YOURSELF.
YOU HAVE TO HAVE THE FAITH IN
YOUR WORK, AND MOST OF ALL DON'T
GIVE UP.
BE ENCOURAGED.
SO I WANT TO THANK DR. MOODY AND
DR. ZIA AND SOME OF MY
COLLEAGUES FOR HELPING WITH ALL
THIS RESEARCH AND THANK YOU FOR
YOUR ATTENTION.
[APPLAUSE]
QUESTIONS?
(INAUDIBLE QUESTION).
>> SO IT DOES -- SO THE OGF
RECEPTOR IS A NUCLEAR RECEPTOR,
AND SO THERE'S THREE CLASSIC
OPIOID RECEPTOR ON THE PLASMA
MEMBRANE.
WHEN THE OGF BINDS, IT SHUTS
DOWN OGF SYNTHESIS.
FIVE AMINO ACIDS, SMALL, IT CAN
PENETRATE THE CELL.
ENTERTAINING IT, YEAH, THAT
WOULD BE GOOD.
YES.
(INAUDIBLE).
>> I WANT TO DO THAT.
THAT'S COMING IN THE FUTURE.
THE PAPER IS STILL IN PRESS,
HOPEFULLY TO COME OUT IN A
COUPLE -- IT TAKES SO LONG.
I WANT TO SAY A COUPLE WEEKS,
THAT WE DISCOVER THIS SPLICE
VARIANT BUT NOW THAT WE KNOW
ABOUT IT, I MEAN, IT WOULD BE
IDEAL IF YOU COULD SCREEN FOR
PATIENTS AND YOU KNOW WHO MIGHT
BE AT RISK FOR DEVELOPING
PANCREATIC CANCER BECAUSE RIGHT
NOW WE'RE JUST LOOKING AT PEOPLE
WHO HAVE FAMILIAL PANCREATIC
CANCER WHICH ONLY MAKES UP 10%
OF PANCREATIC CANCERS.
ONE, IF YOU KNOW YOU HAVE THE
MUTATION, LIKE THE BRCA 2, YOU
MIGHT BE ABLE TO IMPROVE
SURVEILLANCE AND FOLLOW PEOPLE
MORE CLOSELY.
ALSO, IF WE KNOW THAT THEY HAVE
IT, AND WE HAVE THE MONOCLONA
ANTIBODY AND CAN TARGET THE
RECEPTOR, AS DR. MOODY WAS
TALKING ABOUT, NOW THAT WE KNOW
DIFFERENT MUTATIONS WE CAN DO
TARGET-SPECIFIC THERAPY AND I
THINK THAT'S WHERE THE FUTURE IS
GOING WITH ALL OF THIS
TREATMENT.
YES?
(INAUDIBLE QUESTION).
>> THE MAXIMUM TOLERATED DOSE IS
DETERMINED BASED UPON THE SIDE
EFFECTS AND TOXICITY THAT YOU
GET WITH YOUR PATIENTS.
SO YOU ESCALATE IT TO A CERTAIN
DOSE AND WHEN YOU GET TO THE
DOSE, CERTAINLY IF YOU KILL
SOMEBODY YOU DON'T WANT TO USE
THAT DOSE.
THEN YOU HAVE TO BACK DOWN TO
THE NEXT DOSE, PRIOR TO THAT.
SO THERE'S DIFFERENT -- YOU
DESIGNED THE PROTOCOL BUT YOU
LOOK AT THE DIFFERENT THINGS
THAT YOU WOULD EXPECT FOR
TOXICITY, AND IF YOU GET THOSE
TOXIC SIDE EFFECTS, THEN YOU
KNOW THAT YOU HAVE TO BACK DOWN.
OKAY.
SO THAT'S WHAT YOU DO.
YOU GO UP TO A LEVEL WHERE YOU
FIND THAT IT'S WELL TOLERATED,
THE MAJORITY OF THE PEOPLE WILL
TOLERATE THIS.
YOU DON'T HAVE THE SERIOUS
ADVERSE EVENT.
IF YOU DO GET A SERIOUS ONE YOU
HAVE TO BACK DOWN TO THE PRIOR
DOSE.
YES?
(INAUDIBLE QUESTION).
>> OF THE OGF?
THE OFF IS ACTUALLY A PEPTIDE.
WE GAVE IT BY INFUSION.
AND WE FOUND THAT WE COULD
MEASURE IT IN THE BLOOD, THEY
HAD IT PEAKED WITHIN 30 MINUTES,
IS THIS WHAT YOU'RE ASKING?
NO?
MAYBE NOT.
OKAY.
OH, OKAY.
THE MEDIAN OVERALL SURVIVAL OF
PEOPLE WHO ARE TREATED WITH
THIS?
SO MOST OF OUR PATIENTS WERE
PEOPLE WHO HAD PRIOR THERAPY,
AND SO IN MONO THERAPY IN THOSE
PATIENTS, WE HAD SURVIVAL UP TO
NINE MONTHS AND IN OUR PATIENTS
WITH COMBINATION, IT'S MORE THAN
11 MONTHS, WHICH IS THE CURRENT
THING WITH SULFERINOX.
ARE THEY WHAT?
[ INAUDIBLE ]
YES.
SO IN THE ONLY STUDY THAT WE DID
WHEN THEY WERE TREATMENT NAIVE
WAS THE COMBINATION WHERE WE
GAVE IT ALONG WITH GEMCIDOMINIE
THAT WE HAD SEVERAL PATIENTS
LIVING SEVERAL YEARS WITH
COMBINATION THERAPY AND USING
PATIENTS WHO HADN'T D
EVELOPED DRUG RESISTANCE AND
FAILED OTHER THERAPIES.
IN THE MONO THERAPY STUDY
SURVIVAL WAS 9.1 MONTHS BUT SOME
PATIENTS ALREADY FAILED PRIOR
THERAPY.
SO, YOU KNOW, IDEALLY IF YOU
COULD USE THIS DRUG FROM THE
ONSET AND MAYBE GIVE IT WITH
CURRENT THERAPY, WHETHER YOU ARE
USING A STAIN OR SULFURONIX IT
MAY IMPROVE SURVIVAL AND
DECREASE TOXICITY, WHICH IS WHAT
WE WERE SEEING.
THEY ACT BY DIFFERENT
MECHANISMS.
SO THAT'S WHY THEY POTENTIATE
EACH OTHER.
[ INAUDIBLE ]
YES, IN A WAY.
WHEN WE WENT INTO OUR STUDY, I
WANTED TO DO IT LIKE AS A PHASE
3 STUDY, AND THE FDA ACTUALLY
MADE US GO BACK AND DO A PHASE 1
STUDY, BECAUSE THEY SAID THAT WE
HADN'T YET LOOKED AT THE SAFETY
AND TOXICITY OF THE TWO DRUGS IN
COMBINATION.
SO, YOU KNOW, THERE ARE CERTAIN
RULES YOU HAVE TO GO BACK
BECAUSE NOBODY KNEW THAT IF YOU
GAVE GEMCIDONI WITH THIS
COMPOUND WAS IT GOING TO MAKE IT
BETTER OR WORSE.
THEY DO HAVE CERTAIN
REQUIREMENTS AND UNFORTUNATELY
IT SOMETIMES SLOWS THINGS DOWN,
BUT THEY DO.
YES?
[ INAUDIBLE ]
>> I MEAN, THAT'S A GREAT IDEA.
DO YOU WANT TO COME WORK IN MY
LAB AND WE'LL FIGURE IT OUT?
YEAH.
I MEAN, AS DR. MOODY SAID, THE
STEM CELLS BECOME RESISTANT AND
THAT'S A PROBLEM WITH
RECURRENCE.
WITH PANCREATIC CANCER RIGHT NOW
MOST PEOPLE SURVIVE ONLY THREE
TO SIX MONTHS.
I MEAN, WE'RE HAPPY, YOU KNOW,
THE LATEST AND GREATEST
TREATMENT WITH A BRACK STAIN IS
8.1 MONTHS AND SULFURONOX 11
MONTHS.
WE'RE NOT AT A YEAR.
WE WOULD JUST LIKE TO GET
SOMEONE TO REGRESS.
IT'S A VERY IMPORTANT POINT
ABOUT THE STEM CELLS.
WE HAVE TO MAKE SURE WE ATTACK
THE STEM CELLS SO WHEN WE GET TO
THE POINT WE HAVE EFFECTIVE
THERAPY THEY DON'T COME BACK OR
GET RESISTANCE.
WELL, THANKS FOR YOUR ATTENTION.