TRACO 2019 – Epigenetics and Tumor imaging


OUR FIRST SPEAKER TODAY IS DR. VERMA, DCCPS, CHIEF OF THE METHODS AND TECHNOLOGIES BRANCH. HE GOT HIS Ph.D. IN INDIA AND THEN HE WAS AT GEORGE WASHINGTON UNIVERSITY AND THEN HE WAS IN THE DIVISION OF CANCER PREVENTION WHERE HE LED THE SMALL BUSINESS INNOVATION RESEARCH PROGRAM AND THAN HE JOINED THE EGRP AS PROGRAM DIRECTOR IN 2004. AND HE CURRENTLY THE PROGRAM DIRECTOR EPIDEMIOLOGY AND GENOMICS RESEARCH BRANCH. HIS TITLE EPIGENETICS AND CANCER CONTROL PREVENTION, ARE WE READY FOR THE PRIME TIME? Q. THANKS A LOT FOR GIVING ME THIS OPPORTUNITY TO TALK ABOUT EPIGENETICS. AS THE TITLE INDICATES, I WILL GO AND EXPLAIN ABOUT WHERE WE STAND IN TERMS OF USING EPIGENETIC APPROACHES IN CANCER CONTROL AND PREVENTION. SO JUST TO INTRODUCE THIS TOPIC, EPIGENETICS, WHENEVER GENE EXPRESSION CHANGES THERE IS NO CHANGE IN GENE STRUCTURE. LIKE IN GENETICS YOU DELETION MUTATION, STEPS WILL BE THERE SO THEY ARE SEQUENCED OVER DNA CHANGES. IF IT IS NOT CHANGE IN GENE EXPRESSION CHANGES, IT’S CALLED EPIGENETICS. GENETICS YOU KNOW WHAT EPIGENETICS HAS TWO MAJOR GOALS, ONE IS CALLED METHYLATION CODE, ANOTHER IS CALLED HISTONE CODE. METHYLATION HAPPENS MOSTLY IN DNA PROMOTER REGION WHERE CGCG SEQUENCES THEY ARE CALLED CPRR AND THAT CITED IN METHYLATED AT 5 PRIME END, CALLED HYPERMETHYLATION. WHICH CHANGES GENE EXPRESSION. IN HISSTONE SEVERAL MODIFICATIONS I WILL DISCUSS LATER ALSO EFFECT GENE EXPRESSION. ALL TOGETHER THERE’S A BALANCE OF METHYLATION AND HISSTONE MODIFICATIONS. IN GENERAL IF YOU WANT TO KNOW GENETICS TELLS US WHAT IS — WHAT WE ARE CAPABLE OF, WHAT WE CAN DO. BUT EPIGENETICS WILL TELL WHEN WE SHOULD DO SOMETHING AND WHEN WE SHOULD STOP. SO AS I MENTIONED THERE IS BALANCE OF METHYLATION CODE AND HISTONE CODE. TIME TO TIME YOU WILL SEE INTERESTING OR THOSE ARTICLES WHICH DISTINGUISH GENETICS WITH EPIGENETICS LIKE WHY ARE DNA IS IN DESTINY. STUDIES WERE CONDUCTED IN MONOZYGOTIC PRINTS ARE GENOME IS THE SAME BUT IS STILL DISCORDANCE WAS FOUND IN — IT WAS FOUND THAT DUE TO PROMOTER METHYLATION AND AND HISTONE TONE MODIFICATION, ONE DEVELOP CARDIOVASCULAR DISEASE, THE OTHER DID NOT. THAT’S MOW THEY SHOWED GENETICS AND EPIGENETICS ARE DIFFERENT AND DISTINGUISHED. BASED ON THAT, MANY THINGS CAME LATER ON LIKE PHARMACO EPIGENOMICS AND PHARMACOGENOMICS, OR GENOME WIDE ASSOCIATION STUDIES AND EPIGENOME WIDE ASSOCIATION STUDIES. SO IN CANCER AS YOU KNOW THAT CANCER AFFECT ALMOST ALL ORGAN SITES AND PROSTATE CANCER IN MEN AND BREAST CANCER IN WOMEN, THAT IS THE MOST HIGHEST EFFECTOR ONE WHERE INCIDENCE AND MORTALITY IS HIGH, IN OTHER CANCERS IT ALSO HAPPENS, IT IS ESTIMATED BY 2022, ABOUT 18 MILLION PEOPLE WILL BE AFFECTED BY CANCER. IN OUR DIVISION, DIVISION OF CANCER CONTROL AND POPULATION SCIENCES WE COVER ALL CANCER CONTINUUM STARTING FROM PREVENTION HOW YOU CAN PREVENT THAT OR EARLY DETECTION OR DIAGNOSIS ANDABLE AFTER TREATMENT ALSO WHAT IS QUALITY OF LIFE HOW WE CAN IMPROVE IT AND END OF LIFE AFTER MORTALITY ALSO — SERE DATA WHICH IS CALLED SURVEILLANCE EPIDEMIOLOGICAL DATA THAT COMES FROM — DIVISION. SO CANCER PREVENTION CAN BE AT TWO PLACES LIKE CANCER RECURRENCE TO STOP THAT OR STOP IN SECONDARY CANCER. AND PREVENTION REDEFINED EITHER TRANSCRIPTION OR PROGRESSION AND STOPPING METASTASIS. WHILE WE EMPHASIZE IN CANCER IN OUR PROGRAM ESPECIALLY, THESE CANCERS CELLS ARE MAJOR CANCERS TAKE LONG TIME TO DEVELOP FROM THE INITIATION OF FULLY DEVELOP SO WE WANT TO EMPHASIZE ON THOSE STAGES WHICH ARE EARLY STAGES OF CANCER DEVELOPMENT. AND THE IDEA IS IF WE IDENTIFY SOME BIOMARKERS THEN WE HAVE SOME OPTION FOR TREATMENT OR CONTROLLING THAT CANCER. IN GENETICS, IT HAS BEEN SHOWN LIKE IN EPIGENE MUTATION OR PI 3 IN THOSE COLORECTAL CANCER THEY WERE IDENTIFIED SIMILARLY, NOW IN EPIGENETICS ALSO WE KNOW FEW MARKERS WHICH CAN BE USED FOR EARLY DETECTION. THERE IT IS SHOWN HOW MANY YEARS AFTER WHAT AGE THIS START COMING OR SHOWING SYMPTOMS AND BASED ON THAT SUBTYPING OR NAME OF THE CANCER IS GIVEN SEEM 1, SEEM # SEEM 3 ALL THOSE ARE THERE FOR MAJOR CANCERS. REGARDING EPIGENETICS ONE MAJOR THING YOU HAVE TO UNDERSTAND FOR UNDERSTANDING GENETICS YOU DON’T HAVE TO KNOW EPIGENETICS BUT IF YOU WANT TO KNOW THE ROLE OF EPIGENETICS GENETIC BACKGROUND SOME FIRST. SO THAT IS THE MAIN THING. IF YOU SEE HOW HISTORICALLY IT WAS DEVELOPED. 1850 TO 1900 MENDELIAN, YOU HEARD ABOUT THAT, THEN 1900 TO 1950, THE GENE CANCER MUTATION GENOTYPE PHENOTYPE CONCEPT CAME AND FROM 50 TO 2000 DISEASE THE DNA SEQUENCE AND DNA GENETIC CODE THAT CAME. AFTER 2000, THE EPIGENETICS IDEA HAS COME. THIS GENETICS AND EPIGENETICS THEY GO SIDE BY SIDE IN GENE ELEVATION OR CANCER DEVELOPMENT. SO IN GENOME WE KNOW IN DIFFERENT ORGAN SITES MUTATIONS HAVE BEEN IDENTIFIED AND IN FACT MAJOR PATHWAYS ARE HELD WHICH IDENTIFY I THINK PATHWAYS WHICH LEVEL ITSELF CELL FATE OR GENOMIC MAINTENANCE. WHEN GENOME WIDE ASSOCIATION STUDIES WERE DONE FOR DIFFERENT CANCERS AT DIFFERENT LOCI, THOSE MUTATIONS OR SNPS WERE IDENTIFIED SO 2005 OR SIX OR SEVEN, THESE ARE DIFFERENT CHROMOSOMES IN WHICH DIFFERENT MUTATIONS WERE IDENTIFIED AND SOMEWHAT DISEASE ASSOCIATED, SOMEWHAT NOT DISEASE ASSOCIATED. BUT THAT MEAN THIS PROGRESS WAS DONE IN GENETICS AND WHAT WE WANT TO DO BASED ON THAT BACKGROUND WE WANT TO SEE HOW MUCH EPIGENETIC CHANGES ARE THERE BECAUSE SOME GAPS WERE THERE, AND WHEN EPIGENOME WIDE ASSOCIATION STUDIES WERE DONE, SINGLE NUCLEOTIDE POLYMORPHISMS WERE IDENTIFIED, MANY TIMES THOSE GENETIC CHANGES WERE NOT IN THE GENE REGION WHICH CODES FOR GENE. MANY TIMES THEY WERE OUTSIDE THE GENE. SO THEN THE IDEA CAME FOR WHICH WE HAVE ONE MAJOR PROGRAM ALSO, CALLED COMMON FUND PROGRAM. THIS CALLED 4D NUCLEOME. ALONG WITH METHYLATION CHANGES, AND HISTONE CHANGES, NUCLEOME STRUCTURE ALSO CHANGES EITHER BECOMES COMPACT OR RELAXED. SO NOW WHAT WE ARE DOING THAT TAKING DIFFERENT IMAGES IS STRUCTURE OF CHROMATIN IS SEEN WHICH ONE IS IN HETERO CHROMATIC FORM OR HOMO CHROMATIC FORM. ONE IS ACTIVE CHROMATIN OR REPRESSSIVE CHROMATIN, WHICH PRESENT. ACTIVE TRANSCRIPTION. SO UNIT OF CHROMATIN THE NUCLEOSOME, IT’S ABOUT 146 NUCLEOTIDE BASE PAIR LONG AND AROUND DNA THIS HISTONE AND NON-HISTONE PROTEINS SURROUND THAT TO GIVE STABILITY. HISTONE TOES ARE FOUR — ADJUVANT IS A LINKER. IN 74 — (INDISCERNIBLE) FOR NUCLEOSOME STRUCTURE. AND INITIALLY I INDICATED THAT IN PROMOTER REGIONS CERTAIN CG SEQUENCES ARE THERE AND WHEN SEES METHYLATED IT IS CALLED HYPERMETHYLATION. WHENEVER THIS IS THE PROMOTER REGION OF THE GENE, WHENEVER HYPERMETHYLATION IS THERE GENE GETS INACTIVATED. EXAMPLE IS TUMOR SUPPRESSOR GENES. TUMOR SUPPRESSOR GENE IN GENERAL FUNCTION TO SUPPRESS TUMOR BUT IF CHROMATIN IS HYPERMETHYLATED GENE GET INACTIVATED. SIMILARLY SOMETIME IN THE PROMOTER REGION ALREADY CPG HYPERMOTILITY, THIS METHYLATION GROUP IS — HYPOMETHYLATION HAPPENS REPORTED IN ON CODING. SO DEPENDING WHAT INSTITUTION IS THERE THEY CONTINUE TO CANCER DEVELOPMENT. ALONG WITH METHYLATION AND HISTONE, LONG NON-CODING RNA ARE ALSO PART OF EPIGENETIC MECHANISM WHICH ARE LIKE MICRORNA OR LONG NON-CODING RNA. METHYLATION OCCURS BY DNA METHYLATION TRANSFERASE, SOME FOR INITIATION OF METHYLATION SOME ARE FOR METHYLATION. SIMILARLY, HISTONE IS MODIFIED BY UBIQUITINATION, PHOSPHORYLATION, METHYLATION, ACETYLATIONS. SO DIFFERENT MODIFICATIONS OUT THERE. FEW MORE ARE USING EPIGENETICS. MORE THAN 40% IN THE PROMOTER REGION ARE THERE, THESE ARE CALLED CPR SEQUENCE. WILL THE TERM CAME CPG ISLAND LESS THAN 2 KB FROM CPG ISLAND AND THEN THEY ARE LOCATED BETWEEN TWO TO FOUR KB AND OTHER REGION IS CALLED OPEN C. SO THESE ARE THE TERMS O. HERE WHAT I HAVE SHOWN WHAT WHAT ARE FACTORS WHICH CONTRIBUTE TO EPIGENETIC REGULATION. DIFFERENT CANCER DEVELOPMENT STAGES THEY ARE AFFECTED BY EPIGENETICS. DNA TRANSFERASE I TOLD YOU, HISTONE MODIFICATIONS ARE BY DEACETYLATIONS SO IN HISTONE ALSO GROUP ATTACH OR DETACH AND THAT ALSO REGULATE GENE TRANSCRIPTION. SOME HISTONES ARE PROTEINS SOME ARE NON-HISTONE PROTEINS. ONE EXAMPLE IS POLYCHROME GROUP OF PROTEINS. SO THEY ARE ALSO AFFECT CHROMATIN RELAXATION AND SIMILARLY ANOTHER PROTEIN ALSO IDE IFFIED IS — IN COMBINATION THEN TARGETS CAN BE MADE FOR THESE PROTEINS. I WILL SHOW YOU LATER HON CLINICAL IMPLICATION AND HOW MUCH IT HAS BEEN USED. MICRORNAs ARE ALSO PART OF THIS REGULATION. YOU KNOW LIKE IN GENOME WE HAVE OTHER SEQUENCE LIKE SIGN AN LINE SEQUENCES. EXPERTS SEQUENCES SO THEY ARE ALREADY METHYLATION AND WITH AGE OR WITH DISEASE DEVELOPMENT THEY GET HYPOMETHYLATED. SOD JONES AND FINEBERG THEY DID INITIAL WORK. THEY SHOW TRANSCRIPTION FIRST STARTS WITH ACETYLATIONS. IN HISTONE S 2, S 3 AND 4, S 3 STARTS ACTIVE CHROMATIN ACTIVE HISTONE IS ACTIVATED. THEN DEACETYLATIONS IS DEACTIVATION AND THEN COMPLETELY SILENCED WHEN IT IS METHYLATED. SO IF YOU SEE THIS PART THEN NUCLEOSOME WHICH ARE IN CHROMATIN, THEY ARE QUITE APART YELLOW COLOR SHOWS ACETYLATIONS SO ACETYLATIONS GENE IS ACTIVE BECAUSE IN BETWEEN CHROMATIN YOU HAVE NUCLEOSOME YOU HAVE SPACE BUT AS YOU COME TO THIS STAGE GRADUALLY THIS SHOWS HYPERMETHYLATION. DEACETYLATIONS BY REMOVING METHYLATION, AND COMPACT CHROMATIN CAUSES THAT GENE TRANSCRIPTION INHIBITION. THAT’S STEP WISE IT HAPPENS. NOW MANY MORE PROTEINS ALSO HAVE BEEN IDENTIFIED. AND ALSO THE SEQUENCE WHEN SOME PROTEIN BINDS AFTER HOW MUCH TIME IT WILL BIND THOSE HAVE BEEN IDENTIFIED. WHENEVER METHYLATION EXPERIMENTS ARE DONE THEN GENERALLY SEQUENCING IS DONE TO METHYLATION ON BOTH TRENDS. BECAUSE THERE IS NOT ALL OF NONE ONE TIME IT START AND ONE THEN IT STARTS IN ANOTHER STRAIN. THE WAY ROLES IN GENOMIC REVELATION REPORTS LIKE GATEKEEPER GENE OR HOUSEKEEPING GENE SIMILARLY FOR EPIGENETIC REGULATION, MODIFICATIONS ARE CALLED — READERS OR — LIGHTERS ARE THOSE WHICH WILL PUT DNA EPIGENETIC MARK. LEADERS WHICH WILL LEAD THOSE PROTEINS ORGANIZE THAT, LIKE DEACETYLASE WHICH WILL REMOVE THAT. SO THIS TERMINOLOGY ALSO YOU WILL SEE. AND I HAVE PUT THIS REFERENCE ALSO IN INITIAL REVIEW IF YOU PUT EPIGENETICS, THOSE WILL COME. SO ENVIRONMENT DIET OR LIFESTYLE AFFECTS EPIGENETIC CHANGES. AND ONE MORE POINT I WANT TO MAKE, THAT IF YOU ARE STUDYING GENOME FROM ANY CELL OF YOUR BODY YOU ISOLATE CELL AND GENOME SEQUENCE WILL BE THE SAME. SO ONE TIME ONLY YOU HAVE THE SEQUENCE GENOME. BUT EPIGENOME CHANGES WITH ORGANS OR CELL. SO THAT IS THERE. ANOTHER THING, WHEN STUDIES WERE DONE FOR DIFFERENT DISEASES, IT WAS FOUND THAT IN DISEASE LIKE CANCER MOSTLY EPIGENETIC REGULATION IS DOMINATING WHILE IN MENTAL DISORDERS OR NEUROLOGICAL DEVELOPMENT, IT IS MORE GENETIC. EXERCISE AND DIET ARE ALWAYS GOOD FOR YOU. INITIALLY WHEN ZYGOAT OR EMBRYONIC STAGE THEN THE TIME YOU DON’T SEE DURING DEVELOPMENT ANY MUTATION OR SNP OR ANY OTHER THINGS WHICH ARE BY ENVIRONMENT, GENETICS IS DIFFERENT. BUT EPIGENETICS IS STARTS DEVELOPING BY METHYLATION OR HISTONE MODIFICATION SO MOSTLY INITIALLY ENVIRONMENTAL OR MATERNAL FACTOR, BUT GRADUALLY IT IS MOSTLY LIFESTYLE AND DIET. DIFFERENT STAGES, WE CAN COLLECT SOME BIOFLUID WHICH CAN BE USED TO DETECT EPIGENETIC BIOMARKER WHICH WE CAN USE WHETHER YOUR MEAN IS TOO BLURRED OR — IN THIS CASE I HAVE SHOWN HOW ENVIRONMENTAL FACTOR LIFESTYLE AFFECTS SUPPOSE A PREGNANT MOTHER IS SMOKING NOT ONLY HER LIFE IS BECOMES SENSITIVE OR RESPONSIVE TO CANCER BUT THAT INFANT IS ALSO AFFECTED AND STEM CELLS ARE ALSO INFECTED. IN THREE GENERATIONS WILL BE AFFECTED. ONE EXAMPLE IS THAT ALDEHYDE AND NITRIC OXIDE PRESENT SIMILAR TO SMOKE AND THEN USE PHOSPHORYLATION OF HISTONES. SO THAT’S HOW IT HAS BEEN IDENTIFIED. PAPER IS THERE, MATERNAL SMOKING THAT AFFECT DNA METHYLATION. IN THESE CHILDREN AND THERE THE WAY LIKE GENOME WIDE ASSOCIATION STUDIES WHEN THEY ARE DONE, THEN FOR ALL CHROMOSOME IN DIFFERENT LOCI CERTAIN SNPS ARE SEEN THAT WHETHER THEY ARE THERE OR NOT ARE ASSOCIATED WITH DISEASE OR NOT SIMILARLY GENOME WIDE ASSOCIATION STUDIES WERE DONE. IN COHORT WHERE DISEASE NOT DEVELOP AND THOSE PEOPLE WHO ARE FOLLOWED, AND THERE METHYLATION HAS CHROMATIN COMPUTATIONAL ALL THOSE THINGS WERE SEEN WHETHER DONE OR NOT, THIS STUDY WAS DONE THERE. ANOTHER EXAMPLE WAS MATERNAL ANXIETY ALSO AFFECTED METHYLATION OF THIS GENE. SO THOSE KINDS OF PAPERS ARE COMING. VAPEING CAN DAMAGE WIDE IMMUNE SYSTEM UNAND DIRECTLY AFFECT EPIGENETICS. TO UNDERSTAND EPIGENETICS MORE STUDIES WE NEED HEALTHY POPULATION TO FOLLOW FOR A LONG TIME AND WE NEED SUCH BIOSPECIMEN WE CAN COLLECT EASILY LIKE MURINE OR BLOOD OR SKIN. WE NEED LONG TIME FOLLOW-UP SO IN THE SAME PERSON WE CAN SEE CHANGES AND VARIATION IS LESS. THOSE THESE ARE EXPENSIVE THIS IS THE WAY WE GO AND THESE ARE CALLED COHORT STUDIES. IN EPIGENETIC BIOMARKER IF WE WANT TO USE FOR DISEASE DETECTION DIAGNOSIS OR FOLLOW-UP OF TREATMENT, WHAT WE WANT THAT SENSE THESE ARE ENVIRONMENTALLY INDUCED AND TISSUE IS SPECIFIC ESTROGEN RISK FACTOR AND — RISK FACTOR ALL THOSE IN COHORTS THEY ARE. WHAT WE DO IN OUR PROGRAM AS I MENTION INITIALLY, THAT PROGRAM IS EPIDEMIOLOGY AND GENOMICS SO IN EPIDEMIOLOGY WE COLLECT BIOSPECIMEN AND RELATED IN FORMATION FROM DIFFERENT RACIAL AND ETHNIC GROUPS. THESE ARE COUNTRIES WE CHECKED SAMPLES MORE THAN 2.3 MILLION SUBJECTS ENROLLED EITHER WE DO COHORT STUDIES OR CASE CONTROL STUDIES SO THOSE KINDS OF STUDIES WE DO. THESE ARE THE NAMES OF SOME COHORTS LIKE NURSES HEALTH STUDY, PHYSICIAN HEALTH STUDY MULTI-ETHNIC COHORT, OF 62 COHORTS WE SUPPORT IN OUR PROGRAM. AND WHAT IS THE CRITERIA FOR MEMBERSHIP THAT MORE THAN 10,000 PEOPLE SHOULD BE IN SOME COHORT. IN THAT WE STUDY POLYMORPHISM, GENETIC SUSCEPTIBILITY OR GENE GENE INTERACTION OR GENE ENVIRONMENTAL INTERACTION AND EPIGENETIC MARKERS ALSO. HIGHEST LEVEL NIH ALREADY STARTED ONE PROGRAM CALLED ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOME OR ECHO. THIS IS A CONGRESSIONALLY MANDATED PROGRAM ABOUT 160 MILLION PER YEAR, WHAT WE WANT IN THAT IDEA IS THAT EARLY EXPOSURE IS SO SENSITIVE TO THE PREMAY TALL NATAL POSTNATAL INFANT THAT MAY DEVELOP DISEASE, ALONG WITH CANCER WHAT THEY ARE FOLLOWING ASTHMA, NEUROLOGICAL DEVELOPMENT IRREGULARITIES AND OBESITY, THOSE ARE ALSO BEING FOLLOWED IN 50,000 PREGNANT WOMEN, THOSE ARE BEING ENROLLED AND SOME INFANTS ARE BORN THEY WILL BE FOLLOWED FOR 7 OR 10 YEARS. THIS IS AN EXTENSION OF NATIONAL CHILDREN STUDY. IN THAT EPIGENETIC METABALOMIC MARKERS ALL WILL BE COLLECTED. ENVIRONMENTAL INFLUENCE P SOCIAL ECONOMIC STATUS AND LIFESTYLE FACTORS AND OTHERS. THIS IS THE ORGANIZATION HOW WE HAVE CORRELATION CENTER OR DATA ANALYSIS CENTER. SO AT WHAT TIME WE ARE COLLECTING THE INFORMATION BIOSPECIMEN, PRECONCEPTION STAGE PRENATAL, LIVER THROUGH THE ONE MONTH THROUGH 11 MONTH EARLY CHILDHOOD THROUGH 59 MONTH AND SO ON. SO IN THE SAME INFANT OR BABY OR CHILD WE ARE GOING TO COLLECT THE SAMPLE AND SEE WHAT KIND OF MARKS ARE COMING. LATER ON SOME DEVELOP DISEASE, SOME WILL NOT, SO WHETHER THE DISEASES DEVELOP WE CAN GO BACK TO THOSE SAMPLES WHICH ARE COLLECTED IN A GROUP TO IDENTIFY DISEASE EARLY. SO THAT IS IN UTERO AND EARLY LIFE AND OTHER TRANSITION PERIOD, THAT WE ARE COVERING. THESE ARE THE BIOSPECIMEN CORED BLOOD NAIL HAIR SALIVA URINE. BY DOING NMR AND MS EVEN FROM — IT CAN BE IDENTIFIED WHAT KIND OF EXPOSOME IN THE ENVIRONMENT THEY HAVE OR DIDN’T HAVE. SO HOSE KIND OF THINGS. IN BEHAVIOR OR EMOTION SOCIAL EPIGENETICS EVOLUTION HAS BEEN REPORTED THIS PAPER CAME ABOUT MATERNAL ANXIETY AS I MENTION IN IGF 2 IN HISTONE. AND EPIGENOME WIDE ASSOCIATION STUDIES HAVE BEEN DONE WHERE THEY SHOW AGGRESSIVE BEHAVIOR IS REFLECTED IN TERMS OF EPIGENETIC MARKS. SO IT IS NOT LIKE OTHER KINDS OF THINGS WHICH WE SEE DISEASES THERE, MANY THINGS AS YOU UNDERSTAND BY PSYCHOLOGICAL PRESSURE AND OTHER THINGS HAPPEN SO IN THAT ALSO EPIGENETIC REGULATION IS THERE. THIS ALSO I HAVE WRITTEN WITH ONE FELLOW ABOUT EPIGENETIC REVELATION IN BIOPSYCHOSOCIAL PATHWAYS. NOW ONE TIME WE USE EPIDEMIOLOGY CALLED SOCIAL EPIGENOMICS. THE THING WE COLLECT THAT MANY POPULATIONS YOU PINED IN DIFFERENT ETHNIC GROUP THEY HAVE SUCH A PLACE EVEN HEALTHY FOOD ARE NOT AVAILABLE ALONG WITH SOCIAL ECONOMIC STATUS AND OCCUPATION AND OTHERS. GENERALLY GENETIC MARKS COME LATER BUT EPIGENETIC MARKS COME FIRST. SO WE ARE FOLLOWING IN THIS POPULATION AND THAT WE CALL SOCIAL ONLY GENOMICS. — EPIGENOMICS. ONE ARTICLE I WROTE, THAT WAS GENOME WIDE ASSOCIATION STUDIES OR GWAS SHOULD BE STUDIED TOGETHER TO CONCLUDE BETTER. IN ENVIRONMENT HOW EPIGENOME IS AFFECTED IN AGENTS IDENTIFIED
IDENTIFIED, ARSENIC BENEFIT ZEAL CADMIUM CHROME CHROME, ALL IDENTIFY EPIGENETIC OR GENETIC CHROMATIN. THAT’S IDENTIFIED. WE HAVE ANOTHER INSTITUTE LIKE NCI, NIEHS NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SO WE WORK WITH THEM. SO ONE PROGRAM I WROTE FOR ENVIRONMENTAL INFLUENCES ON EPIGENETICS. CROSS GENERATION AFFECTS ALSO HAVE BEEN STUDY IN SOME CASES LIKE ALCOHOL DEPENDENCE, IS REGULATED BY METHYLATION. TOXIC GENOMICS LIKE WHENEVER DEVELOPED DOES NOT WORK IN ALL PEOPLE THE SAME SO GENETIC BACKGROUND AFFECT WHICH WILL BE THE — WHICH PERSON WILL GIVE RESPONSE TO TREATMENT OR NOT, SIMILARLY WE ARE PROMOTING THAT EPIGENOMIC BACKGROUND ALSO WHETHER SOME DRUG WILL WORK OR NOT EPIGENOMICS. SO WHENEVER THERE IS A ENVIRONMENTAL INSULT OR OTHER THINGS THERE, FIRST THING WILL CHANGE ARE TRANSCRIPTION FACTORS CELL CYCLE REGULATOR. THEN CHROMATIN CHANGES LIKE PROMOTER AND METHYLATION. AND HISTONE, IT IS AFTER LONG TIME THEN ONLY GENETICS THINGS COME, AND THIS WILL TAKE ABOUT TWO MINUTES FIVE MINUTES OR TEN MINUTES. THESE TAKE EIGHT TO 12 HOURS, METABALOMIC CHANGES 24 HOURS BUT IT TAKES FEW MONTHS BY THE TIME YOU SEE GENETICS CHANGES SO THAT ALSO EMPHASIZE IF WE UNDERSTAND EARLY STAGES — IN GENETICS, DIFFERENT MODIFICATIONS LIKE TRANSLOCATION DELETION AMPLIFICATION INDEX ARE ALSO IDENTIFIED. SO IN EPIGENETICS WHAT WE SAY BETWEEN GENOTYPE AND PHENOTYPE, THESE TWO STAGES ARE ALSO THERE, EPIGENOTYPE FIRST AND METABALOMICS COMES SECOND. THOSE EPIGENETIC MODIFIERS WHICH ARE THERE WE WANTED TO SEE HOW MUCH GENETICS AND EPIGENETIC INTERACTION IS THERE. SO IN THOSE STAGES ARE GENES WHERE EPIGENETIC REGULATION HAS BEEN STUDIES, THOSE ARE SHOWN HERE. SO IN SOME CASES THAT HAS BEEN DONE. GENERALLY WHEN DISEASE DEVELOP THEN GENERAL GLOBAL HYPOMETHYLATION IS THERE BECAUSE OF LINE IN SIGN SEQUENCES BUT IN PROMOTER SPECIFIC HYPERMETHYLATION WILL BE WILL AND HISTONE ALTERATION ALSO INCREASES WITH CANCER DEVELOPMENT. HERE LINE ONE METHYLATION HAS BEEN CORRELATED WITH MOTILITY OF PERSON IN PROSTATE CANCER. DNA METHYLATION HAS THREE STAGES, LIKE IT CAN BE ABNORMAL INCREASE OR DECREASE OR NO CHANGES. EITHER METHYLATION OF BOTH ALLELES OR ONE METHYLATED AND ONE MUTATED OR HYPOMETHYLATION OF ALLELE AND MICROCOME BYMATION IN OTHERS WHEN DECREASES THERE THE WIDE INSTANCE ESPECIALLY — WHEN GENES RECOMBINANT VIRUSES MANY TIME DID NOT WORK, THE REASON WAS THAT THEY ARE — PROMOTER GET HYPERMETLATED THAT’S WHY THAT WAS IN ACTIVATED, SO IN RETRO VIRUSES LENTIVIRUSES THAT HAS BEEN STUDIES, WHEN THERE IS NO CHANGE THAT IS WHICH CHEMICALLY INDUCED CHANGES OR POOR REPAIR OF METHYLATED OR DEAM NATION. SO DIFFERENT STATES OF METHYLATION BUT NOW TECHNOLOGIES ARE SUCH THAT EVEN FOR CONFOCAL PATHWAY YOU CAN IDENTIFY WHICH GENES WILL GET REGULATED BY METHYLATION. AND IN THOSE EXPERIMENT WHAT YOU KEEP IN MIND THAT METHYLATION CONTENT OR METHYLATION LEVEL OR PATTERN OR PROFILE PATTERN PROFILE YOU DO TO REDUCE FALSE NEGATIVE OR FALSE POSITIVE RESULTS. JOHNS HOPKINS IDENTIFIED DIFFERENT PROTEINS AND THEY DELETION OF SEQUENCE TO REGULATE HETERO CHROMATIN AND U CHROMATIN. AND THEN EXAMPLE PRC 1 PROTEIN IF THIS TRI METHYLATION YOU SEE AFTER LYSINE 27 IT WILL BE ENROLLED IN DIFFERENTIATION, SIMILARLY, IF S 3 FOLLOWED BY LYSINE MONOMETHYLATION, NEXT SALINE PHOSPHORYLATION, THIS CHANGE IS PERMANENT SO THOSE ANALYSIS HAVE BEEN DONE. BASE BASIC IDEA IS HISTONE MODIFICATION WHEN THEY HAPPEN CAN LEAD TO CANCER DEVELOPMENT. MICRORNA, TEN YEARS AGO REPORTED ONLY IN DROSOPHILA BUT THEN IN HUMAN THEY ARE REPORTED AND NOW WE KNOW THAT DIFFERENT CANCERS ALSO MICRORNAs ARE THERE. THERE ONLY 20 TO 25 NUCLEOTIDES LONG AND THEY HAVE ESTABLISHED STRUCTURE THAT WE CAN USE EITHER GENES OF MICRORNA ENCODING GENES WHERE THERE IS A POLYMORPHISM OR JUST MICRORNA PROFILING. A SET OF MICRORNA WILL INDICATE QUITE EARLY WHETHER CANCER IS DEVELOPED OR NOT. HERE IT IS SHOWN SOMETIME MICRORNA WILL ACTIVATE SOME GENES OR SOMETIME INACTIVE SO THEY ALSO PLAY A ROLE SIMULTANEOUSLY. ONE MORE CONCEPT FOR (INDISCERNIBLE), IN THAT BODY DIFFERENT ORGANS THEY WILL RELEASE A DEVELOP PROTEIN BUT THEY WILL CONTAIN SOME DNA OR RNA PROTEIN OR MICRORNA, THESE ARE EASILY ACCESSIBLE AND THOSE CAN ALSO BE USED AS A BIOSPECIMEN TO SEE EPIGENETIC MODIFICATION OR GENETIC MODIFICATIONS ARE THERE OR NOT. THIS ARTICLE I DID FOR REVIEW PURPOSES. THIS SHOW A STRUCTURE THESE ARE DIFFERENT MODIFICATIONS IN HISTONE S 2, S 3 ET CETERA, WE INITIATED ONE PROGRAM CALLED EPIGENOME ROADMAP WHICH EPIGENOME PROFILE OF HEALTHY PEOPLE WAS DONE, THEN MODIFICATION OF THESE HISTONES SO AGAINST THESE MODIFICATIONS MONOCLONAL ANTIBODIES WERE RAISED AND DISTRIBUTED TO INVESTIGATORS SO THEY CAN INSTANTLY WHICH MODIFICATION IS CONTRIBUTING TO, THIS IS DEVELOPMENT. IN HISTONE THEY WILL — WHERE THE ACTIVE PROMOTER OR INACTIVE PROMOTER ENHANCES DIFFERENT KIND IN THAT THIS HELP TO UNDERSTAND THAT. S 1 PROTEIN IS — THAT WAS JUST LIKE A THIS IS ANOTHER REPRESENTATION OF HISSTONE, IN HISSTONE TECHNOLOGIES ARE FOR DIFFERENT HISTONE AT DIFFERENT TIME WE CAN FOLLOW MODIFICATIONS ARE THERE. THESE ARE SOME OF THE EXAMPLE WHERE HISTONE MODIFICATIONS ARE SHOWN, MONODIMETHYLATED OR TRIMETHYLATED HISTONE OR ACTIVATE OR INACTIVATED GENE. SOME TECHNOLOGIES HAVE COME. THEY ARE DIFFERENT SAMPLES SINGLE CELL EPIGENOME YOU CAN DO FOR BASIC STUDIES, THESE KINDS OF APPROACHES ARE NEEDED. NOW HISTONE MODIFICATIONS CAN BE USED FOR DIAGNOSIS ALSO. SO THAT ARTICLE I WROTE FOR THAT PURPOSE IN DIFFERENT CANCERS. AT DIFFERENT TIMES I HAVE DIFFERENT BOOKS HOW CANCER EPIGENETICS IS DEVELOPED AND HOW MUCH DOSE HOST SPECIFIC MARKERS OR ENVIRONMENTAL MARKERS HOW WE CAN PREVENT BIOMARKER WHILE IN PRECISION MEDICINE HOW WE CAN USE THAT. ONE TIME I WAS — EPIGENETICS IS MORE IMPORTANT THAN GENETICS. THEN I MENTION IF YOU STUDY GENETIC CHANGES YOU CAN USE THE MOST FOR DIAGNOSIS OR FOLLOW-UP BUT EPIGENETIC CHANGES BRING DRUGS OR CHEMICALS THAT CANNEDLY THOSE CHANGES SO CANCER CONTROL PREVENTION. ANOTHER TIME ALSO HAY INTERVIEWED, THE DIFFERENT COMPANIES ARE NOW DEVELOPING APPROVE ALSO SOME DRUGS WHICH ARE CALLED EPIGENETIC DRUGS SO THEY ARE VERY EFFECTIVE. GENETIC CHANGES YOU CANNOT DO BUT EPIGENETIC CHANGES YOU CAN MODIFY. SOMETIME EXFOLIATED CELLS FROM TUMOR TIME TO TIME ARE DISPOSED, THOSE CAN BE COLLECTED DIFFERENCE STAGES OF CANCER DEVELOPMENT AND THEN YOU CAN SEE WHAT BIOMARKERS ARE EXPRESSED. T THESE ARE GROUP OF GENES WHICH ARE REGULATED BY EPIGENETICS AND IN DIFFERENT CANCERS AND A NUMBER OF ARTICLES HAVE DONE SO, IF YOU WANT TO KNOW MORE ABOUT THAT YOU CAN READ THOSE. THESE ARE THOSE PROTEINS EPIGENETIC MODIFIERS AND THESE ARE THE GENES WHICH ARE AFFECTED, THOSE ARE SUMMARIZED THERE, THE REASON OF SUMMARIZING AS I MENTION, EPIGENETIC MODIFICATION, CAN BE DEVELOPED SO WHENEVER WE SEE SOME CHANGES THEN DIFFERENT PHARMACEUTICAL COMPANIES ARE MAKING. INTERVENTION AGENTS OR THERAPEUTICS TARGETS AGAINST THOSE. THESE ARE SOME EXAMPLES, THESE ARE NAMES OF THOSE DRUGS WHICH ARE BEING DEVELOPED IN DIFFERENT PHASES. AS IT HAPPENS BY DEVELOPING DRUG THAT SOMETIMES REACTIONS WILL BE THERE BUT IS STILL, THESE ARE NAMES OF THOSE DRUGS WHICH ARE IN THE PIPELINE FOR DIFFERENT EPIGENETIC MODIFIER. WHETHER IT WAS PLOW OR MARK, OR ANOTHER PHARMACEUTICAL COMPANY, ASTRA ZENECA, EVERY COMPANY HAS A BIG PROGRAM IN EPIGENETIC DRUGS OR EPIGENETIC MODIFIERS. THEY COVER DIFFERENT CLASSES OF CHEMICALS LIKE SHORT CHAIN FATTY ACIDS OR CYCLIC THESE ARE FOR CELL CYCLE ARREST OR DIFFERENTIATION MIGRATION APOPTOSIS. THEY ARE TAKING DIFFERENT STAGES AND DURING THAT TIME WHAT KIND OF MODIFICATIONS ARE THERE AND THEN THERE ARE DEVELOPED TARGETS. I WILL GIVE YOU TWO EXAMPLES NOW LATER ON WHAT WAS OBSERVED, EITHER SINGLE AGENT CAN BE USED FOR TREATMENT OF CANCER OR COMBINATION IN SOME SUCH CASES WHERE REAGENTS OR REGULAR ANTI-CANCER DRUGS WERE NOT WORKING, IN THIS CASE 55 PEOPLE RESEARCH AND VALPROIC ACID AND FOR METHYLATION, WHEN IN COMBINATION THAT WAS USED DAY 110 AND 128 LIKE METHYLATION SEQUENCES OR HISTONE SEQUENCES OR MICRORNA YOU CAN DO HIGH THROUGH PUT, WHERE WAS THE USED AND FOLLOWED CAN BE TREATED. SIMILARLY IN ANOTHER EXAMPLE, RETINOIC ACID, IN LEUKEMIA OR MYELOPALACIC MYELODISPLASTIC SNDROME, RETINOIC ACID CAN BE USED IN THIS CASE MORE THAN 50 PATIENTS ARE TREATED. SOMETIME THESE AGENTS WORK AS SENSITIZERS, ANTI-CANCER DRUG IS NOT WORKING BUT IF YOU TREAT IT WITH THIS EPIGENETIC DRUGS THEN THEY START GIVING RESPONSE. THESE DRUGS ARE DONE IN SOLID TUMORS AS WELL AS LYMPHOMA, LEUKEMIA, BREAST CANCER, GLEE OWE BLASTOMA, MYELOBLASTOMA, HERE I HAVE SHOWN HISTONE INHIBITORS. THESE ARE METHYLATION INHIBITORS. SO IN DIFFERENT CATEGORIES THOSE HAVE BEEN DONE SO THESE ARE NOT ONLY EXPLAINED, ABOUT EPIGENETIC INHIBITORS BUT THEY ARE BEING USED IN DIFFERENT COMPANIES ARE MAKING THESE DRUGS. SO WHENEVER NOW ADAY TREATMENT IS DUNGEON TICK ASPECT ADS WELL AS EPIGENETIC ASPECT BOTH KINDS OF INHIBITORS ARE BEING USED. INITIALLY FDA APPROVED FOUR INHIBITORS, TWO FOR METHYLATION PATHWAY, TWO FOR HISTONE PATHWAY. THESE ARE THE NAMES. WHENEVER AS YOU KNOW SEQUENCE CAN BE USED, IN PATIENTS. BUT NOW FOUR COMPOUNDS OR FOUR DRUGS HAVE BEEN APPROVED WHICH ARE AS INHIBITOR HISTONE INHIBITORS TWO FOLD METHYLATION INHIBITORS. THOSE ARE (INDISCERNIBLE). IF YOU WANT TO STUDY MORE ABOUT THAT, NATURE REVIEW GIVES THIS ARTICLE, YOU ARE WHEN YOU TYPE CANCER.GOV AND TYPE CLINICAL TRIALS AND EPIGENETIC DRUGS YOU CAN SEE ABOUT THAT. SO THEY WILL TELL YOU ABOUT WHICH THERAPIES THERE, WHAT IS COMBINATION OF DRUG, HOW PATIENTS WERE SELECTED AND HOW MUCH GIVE RESPONSE. THESE ARE SOME EXAMPLES OF DIFFERENT CANCER WHERE CLINICAL TRIALS ARE BEING DONE FOR NEW DRUGS ALSO. PHARMACEUTICAL PATIENTS ALSO IN COMBINATION DRUGS ESPECIALLY LIKE THESE ARE EPIGENETIC DRUGS AND THESE ARE THE REGULAR DRUGS. THAT HAS BEEN DONE. EVEN LIKE HERE IN CASE OF LEUKEMIA, EML, SUBTYPING IS ALSO DONE BASED ON FOUR DIFFERENT SUBTYPES DIFFERENT COMBINATIONS IS WORKING. NOW THE WAY THEY WORK IS WHICH AGENT BRING FIRST AND HOW MUCH WILL BE DOSE. THAT IS THERE. SO I HAVE SLIDE ABOUT COLORECTAL CANCER ABOUT EPIGENETIC THERAPY, THIS IS AN EXAMPLE OF ONE REVIEW ARTICLE I WANT YOU TO READ, COMBINATION EPIGENETIC THERAPY IN LUNG, NON-SMALL CELL LUNG CANCER OR THIS ONE IS MORE MALIGNANCIES. SO FEW EXAMPLES I WILL GIVE YOU, LIKE IN COLORECTAL CANCER, THOSE GENES HAVE BEEN SHOWN, WHICH IS DIFFERENT STAGES REGULATED BY EPIGENETICS. IN NUMBER — LARGE NUMBER OF PEOPLE WHEN METHYLATION PROFILING, ALONG WITH THAT, SIMPLE PHENOTYPE CPGR METHYLATED PHENOTYPE, OR KRAS MUTATION AND BRF MUTATION AND MICROSATELLITE INSTABILITY ALL IN COMBINATION WAS DONE, IN BIOMARKER UNDERSTAND UNDERSTOOD USING ONE BIOMARKER MORE THAN BIOMARKER THEN SENSITIVITY AND SPECIFICITY IS MORE AND YOU CAN MAKE IT BETTER WHO HAS RESPONSE TO TREATMENT OR WHO HAS DISEASE SO DIAGNOSIS PROGNOSIS DETECTION IS THERE. SO THIS WAS SHOWN IF YOU COMBINE METHYLATION PROFILING WITH MSI OR MUTATION, THEN YOU CAN SELECT A COMBINATION OF GENES TO DIAGNOSE COLORECTAL CANCER. SIMILARLY METHYLATION PROFILING WOULD DISTINGUISH FROM ALL MIXTURE OR ALL ONLY. ANOTHER EXAMPLE IN LUNG CANCER COMBINATION OF PROTEIN MARKERS METHYLATION MARKERS WAS DONE AND THERE THESE ARE THE GENES WHICH ARE REGULATED EPIGENETICS. AND IT WAS COLLECTED FROM THAT BECAUSE IT WAS NOT INVASIVELY COLLECTED TO IDENTIFY DIFFERENTIAL METHYLATION. MESOTHELIOMA IS ALSO A TYPE OF LUNG CANCER IN THOSE PEOPLE WHO WERE EXPOSED TO ASBESTOS, ALSO METHYLATION PROFILING INDICATED WHO IS AT HIGH DEVELOPMENT, MESOTHELIOMA. ANOTHER CANCER ESOPHAGEAL CANCER EARLY STAGE ESOPHAGEAL CANCER, IN THAT ALSO DIFFERENT GENES WERE FOLLOWED FOR METHYLATION PROFILING. AND AS YOU SEE WHENEVER DARKER REGION IN SAME PERSON, ALSO SAME PERSON SO DIFFERENT STAGES METHYLATION PROFILE CAN BE. METHYLATION PROFILING IS CORRELATED WITH SURVIVAL AS WELL, IN — WHAT HAPPENS THAT OVARIAN CANCER AND PANCREATIC CANCER ARE SUCH THAT BY THE TIME YOU DETECT THEN IT IS TOO LATE AND SURVIVAL IS FIVE YEARS OR FOUR YEARS OR SO SO WHAT WE DO AND WHY PATIENT RELATED IN FORMATION IS IMPORTANT, IF SOMEBODY IS (INAUDIBLE) AND THEY HAVE KRAS MUTATION AND P 16 AND P 14 METHYLATED THEN THE PERSON IS HIGH RISK OF PANCREATIC CANCER. AND THAT HAS ALSO BEEN SEEN TO DISTINGUISH DIFFERENT STAGES BY CHROMATIN ESTATES. MORE TRANSCRIPTION IS THERE CHROMATIN IS STATUS, COMPUTATION AND RELAXATION. IN BREAST CANCER RESPONSE TO TREATMENT WAS INDICATED BY METHYLATION OF SELECTED GENES. BASED ON THAT YOU CAN DO NEOPLASIA AND DISTINGUISH FROM INSTITUTE AND SOMETIME TREATMENT IS THERE TO DISTINGUISH WHICH POPULATION OR WHICH PERSON SHOULD BE TREATED OR NOT TREATED, TO DISTINGUISH FROM AND ALSO METHYLATION PROFILING. IN TEN TO 15% IN CANCER INFECTIOUS AGENTS ARE ENROLLED, AS YOU KNOW HPV 16 AND 18 CANCER HBV LIVER CANCER OR EPSTEIN VIRUS CARCINOMA IS BREAST CANCER, SO LATENCY ASSOCIATED NUCLEAR ANTIGEN, THESE ARE THE GENES WHICH ARE ASSOCIATED WITH THAT,, WHAT WE WANTED TO DO TO UTILIZE EPIGENETICS THOSE BIOMARKERS SO THAT WE CAN IDENTIFY ASYMPTOMATIC PEOPLE WHO ARE FROM ENTIRELY BEING AFFECTED AND WE CAN IDENTIFY EITHER IN EARLY GENES OR LATE GENES HOW MUCH METHYLATION IS THERE, WHICH GENES IS METHYLATED, THAT CAN BE INDICATED WHICH STAGE CERVICAL CANCER THEY ARE, AND CERVICAL CANCER WILL DEVELOP. THAT INFORMATION WILL USE FOR TRIAGE, WHERE TREATMENT OR NOT TREATMENT SHOULD BE DONE AND WHICH GENES ARE METHYLATED MORE. IN BREAST CANCER VERSUS CERVICAL CANCER HPV INFECTION IS THERE BUT PERSON DID NOT IDENTIFY CANCER TO — FOR DIFFERENT VIRUSES, WHERE CANCER IS ASSOCIATED, THOSE HAVE BEEN STUDIED AND EPIGENETIC REGULATION HAS BEEN IDENTIFIED. THIS IS EXAMPLE IS FOR LIVER CANCER BECAUSE HEPATITIS B AND C ARE THERE. AND IN LIVER CANCER THESE ARE THE GENES WHICH ARE REGULATED BY METHYLATION. IN T-CELL METHYL TRANSFERASE CANCER HAS BEEN IDENTIFIED SO MANY GENES WHICH ARE REGULATED IMMUNOLOGICALLY ALSO HAVE BEEN STUDIED. IN PROSTATE CANCER PSA IS THE MAIN BIOMARKER BUT WHENEVER LEVEL IS MORE THAN LESS THAN FOUR NANOGRAM PER ML IT IS DIFFICULT TO TELL WHETHER THE PERSON WILL DEVELOP PROSTATE CANCER OR NOT. IN THIS CASE GSP WAS ONE WE CAN DETECT EARLY. AND QUEST DIAGNOSTICS FROM EPIGENOMICS COMPANY IS NOW OUT WHICH IS USED TO DETECT PROSTATE CANCER. IN BLADDER CANCER EXFOLIATED CELLS FROM EUROPEAN ARE COLLECTED AND METHYLATION OF LAMINATED GENE THAT WAS FOLLOWED TO DETECT BLADDER CANCER, SIMILARLY IN SOME EXAMPLE DIFFERENT TISSUES SIMULTANEOUSLY YOU CAN TELL IN CANCER WHAT HAPPENS IF YOU START IN ONE ORGAN SOME PEPTIDES AND PROTEINS AND OTHER THINGS WILL GO ANOTHER ORGAN AND SECOND IS CANCER WILL START COMING SO THAT SIMULTANEOUSLY YOU CAN STUDY THOSE. IT IS TIED TO 40% CANCER PREVENTABLE BY CHANGING LIFESTYLE AND DIET. SO THEY ARE ALSO EMPHASIZE SO MUCH AND THESE ARE SOME OF THOSE FOOD AND THEIR BIOACTIVE COMPONENTS. WHICH HAVE EMPTY METHYLATION OR HISTONE MODIFICATION PROPERTIES SO THOSE ALSO HAVE BEEN STUDY THIS ARTICLE I WROTE FOR CANCER CONTROL AND MUTATION AND EPIENGINE TICKS. IN THAT ALSO WE HAVE EMPHASIZED THAT WHAT ARE THE FOOD COMPONENTS WHICH HAVE DEMETHYLATING ACTIVITIES OR DEACETYLATION ACTIVITIES. IN CASE OF LIVER CANCER WHEN ONLY DONOR SWELLING UTILIZE WITHOUT ANY CARCINOGEN SUCH MODEL WAS CREATED WHICH WAS SIMILAR TO LIVER CANCER. SO IN HEPATOCELLULAR CARCINOMA, HOW YOU CAN PREVENT THAT HAS BEEN EXPLAINED IN THIS PAPER, THIS SHOWS — SOME HAVE HISSTONE MODIFICATION PROPERTIES AND SOME HAVE DNA MODIFICATION, SOME HAVE BOTH. SO MANY TIMES IT IS ADVISABLE ON DIET EMPHASIZE SO MUCH, NOW ORIGINALLY WE — THESE FOOD HAVE THOSE PROPERTIES. SO WITH THIS KIND OF STUDY IS WHAT ADVANTAGE WE HAVE OR WHAT KIND OF RESEARCH WE CAN PURSUE, THAT TO IDENTIFY THESE EPIGENETIC MARKS WHETHER THAT I SHALL DISTINGUISH THOSE RACE OR ETHNIC GROUPS WRITE HIGH RISK OF DEVELOPING CANCER. OR TO INDICATE WHETHER CASE CONTROL STUDIES OR COHORT STUDIES WE SHOULD DO FOR THOSE STUDIES. OR HOW MUCH GENETICS AND EPIGENETICS CORRELATED. OR WHETHER MICRORNAs OR NON-CODING RNA TO DISTINGUISH RACE AND ETHNICITY SPECIFIC RESPONSIVENESS OR HOW MUCH USEFUL IT IS. WILLED WE CAN PREDICT VIGILANCE OR SECONDARY CANCER NOWADAYS THAT IS ALSO DIFFICULT TO HARMONIZE DATA FROM DIFFERENT POPULATIONS THAN WE COLLECT TO DEVELOP BIOINTOR MA ACTIVE TECHNOLOGIES. WHICH IS THE WINDOW OF SUSCEPTIBILITY. OR SINCE THESE INHIBITORS MIGHT AFFECT NORMAL CELLS HOW TO AVOID THAT. WHAT IS THE ROLE OF NON-HISTONE PROTEINS, CANCER STEM CELLS EPIGENETIC REGULATION. THOSE CHALLENGES SUPPORT OPPORTUNITIES AND NOW WRITTEN LAST FIVE SEVEN YEARS I TELL NCI AND NIH HOW WE ARE ADDRESSING THOSE CHALLENGES. BUT NIH (INDISCERNIBLE) 2004 OR 5 HE INITIATED ONE PROGRAM AND PROPOSE THAT ALL INSTITUTES OF NIEHS WILL CONTINUE 1.1 PERCENT THEIR BUDGET AND RESEARCH DONE ON SUCH TOPIC WHICH AFFECTS MANY DISEASES AND COMMON MECHANISM ARE THERE. SO AS FIRST STEP MICROENVIRONMENT EPIGENETICS WERE SELECTED. AND THE IDEA WAS THAT EPIGENETIC WAS SELECTED BECAUSE BY THE TIME WE NEW DIFFERENT KIND OF CANCER NEUROLOGICAL DEVELOPMENT CARDIOVASCULAR DISEASE, DIABETES, EVERY YEAR SOME INDICATION ARE THERE THEY ARE BEING DEVELOPED EPIGENETICALLY. SO THIS PROGRAM PROVIDED SUCH RESOURCES SO THESE STUDIES CAN BE DONE. AND HEALTHY PEOPLE ENROLL PATHOLOGICALLY NOT HAVE ANY DISEASE AND THEN FROM THOSE, LET ME SHOW YOU ONE SLIDE, FROM THOSE WHAT WAS DONE THAT THESE ARE DIFFERENT ORGANS SO 111 KINDS OF CELLS COLLECTED FROM DIFFERENT ORGANS AND METHYLATION PROFILING AND HISTONE PROFILING AND MICRORNA PROFILING WAS DONE IN THAT. THESE WERE CALLED ROADMAP PROGRAMS, AFTER THAT OTHER TOPICS WERE ALSO CAME. FIRST ONE WAS EPIGENOMICS LATER WHICH I ENROLLED, I HAVE PRESENTED AT NCI ONE IS CALLED MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY WHICH EPIGENOMIC PROFILING ALONG WITH METABALOMIC PROFILING, GENOMIC PROFILING HOW THEY ARE AFFECTING PHYSICAL ACTIVITY THAT IS THERE. OR METABALOMIC AS SUCH HOW THEY AFFECT THE CANCER. SO THIS IS THE PROGRAM AND ENROLL ABOUT HALF BILLION. FOR EPIGENOMIC PROGRAM IT WAS STARTED FROM 2008 OF 2015 AND THEN TWO YEARS IT WAS EXTENDED FOR FUNCTIONAL EPIGENOMICS. THAT’S HOW IT WAS DONE. I MENTION ABOUT HISTONE MODIFICATION, THOSE WERE DONE BY THIS PROGRAM. IN ONE ISSUE OF NATURE,, THE WAY GENOME WAS DONE SIMILARLY EPIGENOME MAP WAS DONE SO THAT’S BEEN PUBLISHED THERE, AND AROUND 15 ARTICLES CAME AROUND THAT TIME FOR DIFFERENT ORGAN SITES. THIS I SHOWED YOU. AND WITH THAT PROGRAM, A NUMBER OF HIGH QUALITY PUBLICATIONS& ALSO CAME IN CELL NATURE SCIENCE OR OTHERS. SO IF YOU PUT EPIGENOME THEN THOSE THINGS YOU CAN LEAVE. AFTER THAT ONE SYMPOSIUM ALSO STARTED CALLED INTERNATIONAL HUMAN EPIGENOME CONSORTIUM, IN THERE THOUSAND ONLY GENOMES ARE BEING CONSTRUCTED THEY ARE MAPPED FOR DIFFERENT STAGES. THEY ARE WORKING ON AGING RELATED EPIGENETIC CHANGES AS WELL M. FIRST MEETING WE HAD WHERE THESE COUNTRIES PARTICIPATED AND DIFFERENT SUNDAY UPHANDING AGENCIES WE PUT MONEY, WE WANTED WHATEVER AT NIH SHOULD NOT OVERLAP TO I PRESENT IN THERE IN IHAP PROGRAM AND THEN EPIMETRICS PROVIDED IMPROVEMENT TO DO METHYLATION ANALYSIS AND OTHER NOVARTIS ALSO SUPPORTED THAT. AT THE TIME ABOUT THIS PROGRAM IT WAS PUB ACCOMPLISHED IN — PUBLISH IN NATURE AND SCIENCE. THIS IS THE WEBSITE FOR IHAP. ANOTHER IMPORTANT THING IS TO UNDERSTAND BASIC SCIENCE HUMAN ANIMAL BOTH STUDIES BOTH EPIGENOME ARE BEING STUDIED. TIME TO TIME WE WRITE ARTICLE ALSO TO SHOW IN WHICH AREA WE ARE EMPHASIZING OR PRY YEAR ADVERTISING, PRIORITIZING WE WROTE IN CANCER EPIDEMIOLOGY WHAT ARE TRENDS AND CHALLENGES, SIMILARLY I DID THIS ONE FOR MOLECULAR PROFILING AND COMPANION DIAGNOSTICS. HOW YOU CAN USE EPIGENETIC BIOMARKERS. THIS WAS ABOUT MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY, WE CALL IT — (INDISCERNIBLE) IN THAT TISSUE SAMPLES LIKE HUMAN BLOOD MUSCLE ADIPOSE TISSUE AND ANIMAL MODEL ALSO THERE WILL BE DONE AND ALL THESE THINGS LIKE GENES PROTEIN PEPTIDE LIPID EPIGENOMICS MICRORNA, METABALOMICS, ALL WILL BE DONE SO A GROUP OF PEOPLE WILL DO EXERCISE, FOR CERTAIN TIME AND HOW MUCH THESE MOLECULES CHANGE THAT WILL BE IDENTIFIED. HOW MUCH IT IS ESSENTIAL OR NOT. THESE ARE DIFFERENT COMPONENTS AND AMOUNT, TISSUE, THIS IS SIX TO SEVEN YEARS THIS WILL CONTINUE THREE YEARS AGO WE STARTED. FEW MORE PROGRAMS BEING DONE, ONE IS CALLED MOON SHOT. HE CARTED AFTER HIS — DEDICATED ABOUT 300 MILLION PER YEAR, NCI GOT FOR SEVEN YEARS AN IDEA WAS THAT WHATEVER WE ARE DOING WE CONTINUE THAT WHAT CAN WE DEVELOP DRUGS OR TREATMENT OR DIAGNOSE MOWSIS, WHATEVER WE ARE DOING TEN YEARS WHETHER WE CAN DO IN FIVE YEARS IF ADDITION OF — PROVIDED OR NOT. SO TWO AND A HALF YEARS AGO THIS WAS STARTED THAT THIS IS GOING ON. SIMILARLY ONE PROGRAM WAS STARTED CALLED ALL OF US. IN WHICH ONE MILLION PEOPLE ARE ENROLLED. THEY ARE BEING FOLLOWED WHICH DISEASE THEY DEVELOP AND THAT I SHALL SOCIOECONOMIC STATUS AND FAMILY HISTORY WILL BE DONE. ONE IS CALLED CANCER GENOMIC SIMILARLY PRE-CANCER GENOMIC ATLAS SO THESE TWO PROGRAMS ARE ALSO ENROLLED. SO THAT’S HOW WE ARE ADDRESSING THOSE CHALLENGES SO NOW I WILL TAKE ANY QUESTIONS. THANK YOU.>>THANK YOU. [APPLAUSE]>>ANY QUESTIONS AS MUCH — ANY QUESTIONS?>>SO IN TERMS OF CLINICAL WORK FLOW CAN YOU SPEAK ON WHAT THE CHALLENGES WOULD BE DOING WHAT EPIGENETIC PROFILING VERSUS GENETIC PROFILING OF A PATIENT CANCER AND HOW THOSE ARE DIFFERENT, HOW FEASIBLE THEY ARE?>>WHEN GENETIC BACKGROUND WAS DONE THAT WAS DONE INITIALLY BY MUTATION ANALYSIS AND LATER MUTATION COVERED SMALL PART OF GENOME THEN THEY THOUGHT WE SHOULD USE A SNP OR NUCLEOTIDE POLYMORPHISM AND GENOME WIDE ASSOCIATION STUDIES WERE DONE. THAT WE SPENT EIGHT OR SEVEN YEARS TIME AND FOR DIFFERENT CANCER AND DIFFERENCE DISEASES BUT MOST SNPS AND OTHER THINGS WERE COMING OUTSIDE THE GENOMEMENT SO WHENLY WHEN TARGET DRUGS ARE PRODUCED THEY ARE IN THE CODING REGION, THEY ARE NOT THERE. THERE’S STILL MANY THINGS NOT COVERED. AS INDICATED INITIALLY WHEN MONOZYGOTIC TWINS WERE FOLLOWED AND DISCORDANCE WAS STUDY, IT WAS FOUND EPIGENETIC REGULATION IS SO MUCH PREVALENCE AND BY GENETIC STUDY 8 TO 10% IN CANCER IS — REMAINING IS ENVIRONMENT AND LIFESTYLE SO THEN EPIGENETICS CAME SECOND POINT, GENETIC CHANGES YOU CAN JUST FOLLOW HOW THE PERSON IS DOING, WE CAN USE THE MUTATION FOR FARM GENOMIC DIAGNOSIS OR DEVELOPMENT BUT EPIGENETICS YOU CAN REVERSE. SO THAT WAS ONE IN COMBINATION THERAPIES WORKING. IN TERMS OF CHALLENGES THAT EPIGENETICS THESE REGULATIONS ARE DIFFERENCE FOR DIFFERENT ORGANS OR CELL. HOW MUCH IT WILL WORK WHICH ORGAN WILL WORK FOR THAT THEY ARE WORKING ON DIFFERENT HISSTONE MODIFICATIONS OR MICRORNA WHETHER THEY CAN MAKE IT ORGAN SPECIFIC OR NOT. MOST OF THE SUCCESSES IN COLON CANCER AND PROSTATE CANCER BUT UNIVERSITIES — SO COMBINATION THERAPIES PROMISING INDICATED SO MANY TRIALS ARE BEING DONE AND SIX DRUGS HAVE BEEN APPROVED ALSO.>>THAT ONE MORE QUESTION. IF YOU HAD A GENE COMMONLY HYPERMETHYLATED, FOR EXAMPLE, IS THERE ANY WAY TO TARGET JUST THAT GENE OR THESE PHARMACOLOGICAL AGENTS MORE GENERAL AND YOU HOPE THAT GENE IS AFFECTED IN THE CANCER CELLS?>>WHENEVER PATIENTS ARE TREATED, NOT ONLY THESE DRUGS BUT FAMILY HISTORY, LIFESTYLE, EXEXPOSURE, WHETHER HE HAS ANOTHER DISEASE ALSO OR NOT, ALL THOSE THINGS ARE ALSO KEPT IN MIND. THEN IN COMBINATION ALSO WHICH SHOULD COME FIRST WHICH SHOULD COME AFTER THAT. AND HOW MUCH DOSE STARTED, AND MOST OF THE DRUGS WHEN THEY WERE IDENTIFIED OR DISCOVERED THEN FIRST THEY WILL USE FOR THOSE PATIENTS WHERE NO AGENT OR NO ANTI-CANCER AGENT WAS WORKING. WHEN THIS ALSO THEN THEY STARTED GIVING TO OTHERS AND THEN THEY FOUND ESPECIALLY WITH PARP INHIBITORS THESE INHIBITORS WORK VERY NICE BUT AS IT HAPPEN THAT IT IS DIFFICULT TO GET DRUGS AND EVERYBODY DOESN’T RESPOND THE SAME WAY. SO WE EMPHASIZE, GENES SUCH GENETIC BACK GROUND WILL TELL, WHETHER HE RESPONSE TO DRUG OR NOT, WE DON’T HAVE ANY SO NOW WE ARE WORKING ON DEVELOPING EPIGENOMIC PROFILING WHETHER HELP IDENTIFY OR STRATIFICATION OF PATIENTS>>THANK YOU.>>I THINK WE WILL MOVE ON. THANK YOU.>>THANKS. OUR NEXT SPEAKER IS PETER CHOYKE, DIRECTOR OF THE MOLECULAR IMAGING PROGRAM, HE GOT HIS M.D. FROM JEFFERSON MEDICAL COLLEGE, THEN HE DID A DIAGNOSTIC RADIOLOGY RESIDENCY AT YALE NEWHAVEN HOSPITAL. HE DID IMAGING FELLOWSHIP AT THE UNIVERSITY OF PENNSYLVANIA, HE JOINED THE FACULTY OF GEORGETOWN UNIVERSITY AND THEN HE CAME TO NIH. SO HE WILL TALK TO US TODAY A NEW TOPIC NEAR INFRARED PHOTO IMMUNOTHERAPY, A LIGHT BASED TREATMENT FOR CANCER.>>THANK YOU. I’M SHAKING IT UP. TERRY VERY EXCITED ABOUT THIS TOPIC. A NEW THERAPY DEVELOPED IN OUR LAB. SO NO FINANCIAL CONFLICTS OF INTEREST, PATENTS THAT I’M GOING TO TALK ABOUT HAVE BEEN LICENSED TO A COMPANY THAT’S NOW CALLED ROCKET 10 MEDICAL. AND I’M WANT TO START BY ACKNOWLEDGING MY COLLEAGUE, DR. HK AS WE CALL HIM. SO LIGHT THERAPY IS NOTHING NEW. OF COURSE WE USE LIGHT TO BURN TISSUE, FOR INSTANCE LASER ABLATION, IT’S COMMONLY USED IN PLASTIC SURGERY TO ABLATE DISCOLORED LESIONS, AND IT REQUIRES VERY EXPERT CONTROL OF THE LASER BEAMS SO IT DOESN’T BURN INAPPROPRIATELY. THERE’S ANOTHER THERAPY CALLED PHOTO DYNAMIC THERAPY, IN WHICH A COMPOUND CALLED A PHOTO PERFORIN IS INJECTED. IT CIRCULATES AND PREFERENTIALLY TAKES UP IN TUMORS MORE THAN NORMAL TISSUE. HOWEVER IT ALSO TAKES UP A NORMAL TISSUE. THERE FOR A THERAPEUTIC WINDOW, THERE CAN BE HUGE PROBLEMS WITH THIS. WITH PHOTO TOE DYNAMIC THERAPY YOU INJECT THIS PHOTO TOE SEN ADVERTISER, IT SUPPOSEDLY CONCENTRATES IN THE TUMOR, YOU THEN APPLY LIGHT TO IT. IN THEORY THE TUMOR SELECTIVELY DESTROYED. THERE ARE VERY BAD SIDE EFFECTS ASSOCIATED WITH THIS WHICH LIMIT ITS EFFICACY. I WILL SHOW YOU A PICTURE IN A SECOND. IT ALSO KILLS BY PROCESS CALLED APOPTOSIS WHICH IS NOT PARTICULARLY IMMUNOGENIC. THE PATIENT REMAINS PHOTO SENSITIVE FOR TWO TO EIGHT WEEKS SO THEY CAN’T GO OUT IN SUNLIGHT. ALL IN ALL IT’S NOT A VERY APPEALING THERAPY. SO THIS IS A ACTUALLY MIRE BETS WHO INJECTED HIMSELF WITH HEMATOPERFORIN AND EXPOSED THEMSELVES TO TEN MINUTES OF INDIRECT OR DIRECT SUNLIGHT YOU CAN SEE AS WELL AS UP, HE WAS PROBABLY MISERABLE FOR SEVERAL WEEKS AFTER THIS IS PRETTY MUCH WHAT HAPPENS TO ORGANS TREATED WITH PHOTO DYNAMIC THERAPY. SO WE USED TO DO IT AT THE CLINICAL CENTER, ELABORATE SETUPS WITH LASER CATHETERS THAT WERE APPLIED DURING SURGERY, ET CETERA. AND THEY ARE ACTUALLY SOME PICTURES OF BILL SENDALAR SURGERY BRANCH IN 1908s DOING PHOTO DYNAMIC THERAPY IN THE THORAX AND IN PRE-CLINICAL STUDIES IN DOGS. THEN HARVEY PASS ALSO DID THIS WORK. BUT CLEARLY THERE’S MUCH TO BE IMPROVED IN PHOTO DYNAMIC THERAPY. IF WE BORROW OFF THE IDEA OF FLUORESCENCE WE CAN USE A DYE WE EXCITE WITH LIGHT AND THAT WILL EMIT LIGHT AT A SLIGHTLY DIFFERENT WAVELENGTH SO YOU MIGHT COME IN AT THIS CAR IT EMITS AT SLIGHTLY DIFFERENT CALLER. THE WHOLE CONCEPT IS THAT THERE’S AN EXITATION BY THE LIGHT THAT PUTS THE ELECTRONS IN A HIGHER ENERGY STATE. ELECTRONS ARE TURNED BACK TO THEIR BASAL STATE AND IN THAT CASE RELEASE LIGHT. BUT THEY CAN ALSO DO OTHER THINGS WHEN THEY COME BACK THEY CAN INDUCE CHEMICAL REACTIONS. THIS LADDER IS WHAT WE WILL BE TALKING ABOUT. IN PHOTO DYNAMIC THERAPY. WE ARE AN IMAGING LAB AND OUR INITIAL IDEA WAS TO DEVELOP TARGETED IMAGING FLUORESCENT DYES SO WE TOOK ANTIBODIES IN PARTICULAR AS AS TRASTUZIMAB OR HERCEPTIN AND BOUGHT OUT PHOTO SENSITIZERS WE CAN FIND IN THE NEAR INFRARED RANGE BEING IDEAL BECAUSE IT TRAVELS TO TISSUE FURTHER. SO WE SET UP DIFFERENT AMOUNTS OF THIS DYE CONJUGATE WITH PHOTO SENSITIZER AND APPLY LIGHT TO THESE VARIOUS WELLS. AT THE TIME THIS WAS ABOUT 2010, HIS PICTURE HERE WITH MICHELLE LONGMIEYER WHO IS A DERMATOLOGIST BUT A SCIENTIST IN JAPAN. THEY WERE — THEY DID THE ORIGINAL WORK WITH US. AND WHAT WE FOUND WAS THAT YOU HAD DYES THAT WERE VERY PRETTY BRIGHT, THEY LOOKED PRETTY GOOD. ONES THAT WERE MODERATELY BRIGHT, THEN NOT SO BRIGHT, THEN THERE WAS THIS ONE, THIS — THESE CELLS THAT WERE DEAD. WHEN YOU APPLY THE LIGHT. SO THE LIGHT KILLED THE CELLS. FIRST WE THOUGHT THAT’S NOT A GREAT THING, SOUNDS TOXIC BUT WE REALIZE IT’S CANCER CELLS BEING KILLED THAT’S A GOOD THING. MAYBE WE WERE ON TO SOMETHING SO THIS VERY PARTICULAR DYE IR 700 BECAME VERY INTERESTING TO US. SO THIS IS THE CHEMICAL STRUCTURE OF THIS DYE, IT’S A THAT WILL LOCI MEAN DYE WITH TWO SIDE CHAINS HERE. IT TURNS OUT WHEN LIGHT HITS THIS THESE SIDE CHAINS ARE JET SON AND THESE MOLECULES HYDROPHYLIC BECOMES HYDROPHOBIC RAPIDLY. WE BELIEVE THAT’S THE REASON IT’S SO EFFECTIVE SO WHEN WE APPLY LIGHT TO THIS CONJUGATE, ESPECIALLY WHEN THE ANTIBODY IS AT THE CELL MEMBRANE, IT CAUSES DAMAGE TO THE CELL MEMBRANE LEADING TO CANCER CELL DEATH. THIS IS A VIDEO HAPPENS TO THE CELL SPEEDED UP BUT NOT TERRIBLY SPEEDED UP. SO THERE’S THE EXCITING LIGHT, YOU SEE THE CELLS BUD AND YOU SEE THEM BURST. THE DYE IN THE CELLS WILL FADE OUT ADS IT DISPERSES IN TO THE EXTRA CELLULAR SPACE. SO IT’S A VERY UNIQUE KIND OF CELL KILLING THAT CAUSES A NEAR INSTANT CELL DEATH SO TAKES ABOUT 30 SECONDS FOR THIS TO HAPPEN AND OVER COURSE OF ONE TO TWO MINUTES IT’S COMPLETED. SO IT’S MUCH MORE RAPID THAN MOST OTHER KIND OF CELL DEATH. BUT VERY IMPORTANTLY, IT DOESN’T DENATURE THE CONTENT OF THE CELLS, IT DOESN’T DAMAGE THE CONTENTS OF THE CELLS IN ANY WAY, IT SIMPLY RELEASES THEM INTO THE EXTRA CELLULAR SPACE. IT’S VERY SPECIFIC SO BEFORE I GET INTO THAT, HERE WE SEE IT AT 37-DEGREES YOU CAN SEE SWELLING OF THE CELLS SO IT WORKS ROOM TEMPERATURE, BUT — AND IT WORKS AT FOUR DEGREES CENTIGRADE WHICH TELLS US IT’S A PROCESS THAT IS VERY MUCH ON THE SURFACE OF CELLS BECAUSE IF IT’S AT A LOW TEMPERATURE, THE CONJUGATE CAN’T GET INSIDE THE CELL. IT’S MEMBRANE EFFECT. WE HAVE CELLS OF TWO DIFFERENT TYPES HERE, ONE IS HER 2 POSITIVE, ONE HER 2 NEGATIVE RIGHT NEXT TO EACH OTHER AND THE LIGHT IS APPLIED. ONLY HER 2 POSITIVE CELLS ARE AFFECTED. THE IMMEDIATE ADJACENT CELLS DON’T SEEM TO HAVE ANY EFFECT ON IT. IT’S SUPER SELECTIVE FOR THE CANCER CELL OF INTEREST. A TRANSMEMBRANE EFFECT. WHAT WE THINK HAPPENS IS THE ANTIBODY WITH THE IR 700 BINDS TO ITS COGNATE RECEPTOR IN THE CELL MEMBRANE. AFTER THE NEAR INFRARED IRRADIATION, THERE’S DAMAGE TO THE CELL MEMBRANE MAKING MICROPERFORATIONS IN THE MEMBRANE ALLOWING WATER TO FLOW INTO IT CAUSING CELL EXPANSION AND CELL DEATH. SO THE CONTENTS OF THE CELL CAN EMERGE. HERE IS OOHED EXAMPLE OF A CELL BEING TREATED WITH THIS. YOU CAN SEE HOW THE CELL GROSSLY EXPANDS AND BURSTS. WITHIN JUST A FEW SECONDS OF THE EXPOSURE. THIS IS A MOVIE THAT I CREATED AT GREAT EXPENSE TO MY BRANCH. BUT IT’S NOT EVEN PLAYING HOW BAD IS THAT? IT’S GOT A PLAY, TOO EXPENSIVE NOT TO PLAY. SO HOPEFULLY IT WILL PROGRESS. SO THE SOUND IS NOT THAT IMPORTANT, I CAN TALK OVER IT BUT YOU CAN SEE THE ANTIBODY AND WE ATTACH THESE IR 700 MOLECULES, AND WE INJECT IT INTO THE PATIENT. IT TRAVELS AROUND THE BODY AND FINDS THE RECEPTOR THAT IS INTERESTING — INTERESTED IN AND ACCUMULATES THERE, ESCAPES FROM THE BLOOD VESSELS, AND BINDS TO THE CELLS AT THESE RECEPTORS. THEN THIS IS THE BEST PART, THE LIGHT IS APPLIED AND THE DAMAGE TO THE MEMBRANE STARTS TO TAKE PLACE AND THE CELLS START TO SWELL EVENTUALLY THERE WE GO. BURSTS AND RELEASES THE CELLULAR CONTENTS. WE HAVE GOOD REASON TO BELIEVE THAT THAT’S WHAT HAPPENS WE HAVE ABLE TO SEE THESE SMALL FILL-UP MEDIA AMONG CANCER CELLS, DISAPPEAR RAPIDLY AFTER THE APPLICATION OF LIGHT YOU CAN SEE THEM GETTING TRIMMED AWAY. A CONTROL WHERE THE FILL, PHILIPODIA DOESN’T GET DAMAGED AT ALL. THIS IS THE HAIRCUT SLIDE WITH THIS VERY FURRY LOOKING CELL THEN YOU APPLY THE PIT AND ALL THE LITTLE FILIPODIA DISA PEER RIGHT AWAY, WHEREAS THE CONTROL NOTHING HAPPENS AFTER THE EXPOSURE TO LIGHT. WE PUT THIS IN TO — WE WERE EXCITED BY THIS FINDING. AND WE DID WHAT EVERYBODY WOULD DO, THEY PUT IT INTO A MOUSE MODEL SO WE IMPLANT TWO TUMORS IN THIS MOUSE, ONE IS A CONTROL THAT DOESN’T RECEIVE NEAR INFRARED LIGHT AND THIS TUMOR WILL RECEIVE THE NEAR INFRARED LIGHT AFTER THE ADMINISTRATION OF THIS CONJUGATE. PANATUBMAB IR 700. HEARSAY THE WHITE LIGHT IMAGE THE TUMORS ARE FLOURESCEING, WE APPLY THE THERAPY YOU CAN SEE THE DIMINUTION AND SIGNAL AND THE DECREASE IN THE SIZE OF THE TUMOR COMPARED TO CONTROLS. TO BE HONEST THIS WAS A GOOD RESULT BUT IT WASN’T SUPER SPECTACULAR BECAUSE YOU CAN SEE THE REGROWTH OF THE TUMOR. ONE THING YOU CAN DO IS DO IT AGAIN AND THAT WOULD KNOCK IT DOWN AGAIN AND YOU HAVE AN AFFECT LIKE THAT. THERE IS PROLONGATION OF SURVIVAL AND THINGS LIKE THAT. WE WERE EXCITED ABOUT IT BUT WE DIDN’T THINK IT WAS GOING TO BE THE ANSWER TO ALL OF OUR DREAMS. BUT THERE WAS A VERY THOUGHTFUL COMPANY THAT INITIALLY NAMED SPIRION NOW PURCHASED BY ROCKOTAN THAT WAS WILLING TO TAKE A CHANCE ON IT AND LICENSE THE PATENT, WANTED TO DO TOXICITY STUDIES USING SETUXMAB EGFR ANTIBODY IR 700 CONJUGATE, THEY TRIED IT IN NON-HUMAN PRIMATES AT HP AND THERE WAS NO APPARENT TOXICITY WITH IT. NO SYSTEMIC TOXICITY SO THEY BEGAN — THEY FUNDED A PHASE 1 DOSING STUDY, INOPERABLE HEAD AND NECK CANCER. SO JUST BRIEFLY ABOUT HEAD AND NECK CANCER, IT’S A VERY COMMON CANCER, TWO-THIRDS — THIS IS A — NOT JUST UNITED STATES, THIS NUMBER IS WORLDWIDE, TWO-THIRDS OCCUR IN DEVELOPING COUNTRIES BUT IN THE UNITED STATES IT’S STILL ACCOUNTS FOR 12,000 DEATHS, WE TALK HEAD AND NECK CANCER THE VARIOUS ORGANS AROUND THE MOUTH BACK OF THE MOUTH, THE GLOTTIS, LARYNX, ARE — CAN BE AFFECTED WITH HEAD AND NECK CANCER. IT’S A VERY DEBILITATING TUMOR BECAUSE OUR BREATHING OUR SWALLOWING, OUR TASTING, ALL THESE SENSES ARE IN THIS AREA AND THE TREATMENTS WE GIVE PATIENTS OFTEN RESULT IN SEVERE DAMAGE TO ONE OR MORE OF THOSE FUNCTIONS. THE CURRENT TREATMENT IS CHEMO RADIATION FOLLOWED BY SURGERY. THEN IF THE TUMOR RECURS, COMBINATION CHEMOTHERAPIES AND YOU CAN SEE PRETTY POOR RESPONSE RATE 10 TO 36% IN THAT SETTING. PEOPLE RECEIVE IMMUNOTHERAPY. AND ANTIBODY THERAPY. REIRRADIATION CAN CAUSE SIGNIFICANT TOXICITY, OUR FRONT PHOTO DYNAMIC THERAPY IS USED BUT THERE CAN BE SEVERE SIDE EFFECTS, CAROTID RUPTURE FISTULAS, ET CETERA. SO THIS IS A SPACE THAT NEEDS IMPROVEMENT, EAT NOT VERY GOOD SITUATION RIGHT NOW. THAT WAS THE SPACE WE ENTERED. IN THE PHASE 1 STUDY AS YOU KNOW THE — YOU ARE TRYING TO FIND A DOSE LIMITING TOXICITY. SO YOU STARTED A LOW DOSE, YOU GO TO HIGHER AND HIGHER DOSES. YOU START TO SEE TOXICITY, BECAUSE THIS IS A TWO PART THERAPY IT HAS CONJUGATE AND LIGHT, WE THOUGHT WE HAD TO INCREASE BOTH OF THEM. A MULTI-CENTER TRIAL BEGUN. BY WAY NOT ALL THE LIGHT NEEDS TO BE EXPOSED TO THE SURFACE, WE COULD INSERT FIBER OPTIC PROBES INTO THE TUMOR TO DELIVER LIGHT INTO THE TUMOR IF IT WAS NOT AMENABLE TO SURFACE ILLUMINATION THIS IS JUST THE PRE-CLINICAL SET UP THAT WE HAD JUST THE SIMPLE BOX WITH LED LIGHTINGS WHEN WE GO INTOICALLY I —
CLINIC WE USE FIBER OPTIC PROBES INSERTED INTO TUMOR. WE ARE SURPRISE BY THE RESULTS OF THE FIRST FOUR PATIENTS. REMEMBER WE ARE JUST TRYING TO ESTABLISH TOXICITY HERE NOT NECESSARILY TREAT THE PATIENT BUT FIRST PATIENT HAD 30% REDUCTION THE IN TUMOR SIZE THE SECOND PATIENT WAS COMPLETE RESPONSE WITH 100% TUMOR DEATH. THE THIRD PATIENT HAD A GREATER THAN 70% AND THE FOURTH PATIENT ALL AT THE LOWEST DOSES HAD A COMPLETE RESPONSE. SO WE THIS IS AN UNUSUAL RESULT IN A PHASE 1 TRIAL BECAUSE RUTS ARE GOOD AT LOW DOSE BUS MUCH BETTER THAN WE SAW IN THE MICE. SO WHAT IS THE DIFFERENCE BETWEEN A NUDE MOUSE AND A HUMAN BEING? IMMUNE SYSTEM. THERE’S AN INTACT IMMUNE SYSTEM IN A HUMAN. BUT THE MICE WE USE HAVE THE T-CELLS KNOCKED OUT SO THEY DON’T REJECT THE TUMORS. SO HERE IS SOME PICTURES FROM SOME OF THE TREATMENTS, THIS WAS A TUMOR IN THE MOUTH YOU CAN SEE THIS IS THE UVULA AND RIGHT AFTERWARDS THERE’S A WHITISH DISCOLORATION TO THE TUMOR. AND EVENTUALLY AFTER A FEW DAYS THE TUMOR SLOUGHED OFF, PATIENT COULD ACTUALLY WATCH IT IN THE MIRROR AND IT WAS ONE OF THE COMPLETE RESPONSES. THE PEOPLE PARTICIPATING IN THIS TRIAL ARE EXCITED ABOUT IT. ONE WAS RUSH MEDICAL CENTER AND THEY DID SOME EUREKA ALERTS AND THINGS LIKE THAT AND TALKED ABOUT HOW ALMOST IMMEDIATELY YOU CAN SEE THE TUMOR DYE TURN WHITE. IT’S THE CANCER CELLS CAUSING ALMOST NO DAMAGE TO SURROUNDING CELLS. THAT’S REALLY THE REMARKABLE PART OF THIS IS THAT IT DOESN’T REALLY DAMAGE OTHER THINGS EXCEPT THE TUMOR. LOT OF TESTIMONYIALS, THIS IS A PRETTY PRETTY — WE WENT TO A PHASE 2 STUDY WITH SOME REALLY AGGRESSIVE CANCERS, AND SO THIS IS A MAN WHO PRESENTED WITH RECURRENT HEAD AND NECK CANCER YOU CAN SEE THESE LUMPS IN HIS SIDE OF HIS MOUTH. WE PLACE THE FIBER OPTICS INTO THE TUMOR AS YOU CAN SEE HERE. ONE MONTH LATER THERE’S DRAMATIC SHRINKAGE OF THE LESION, THREE MONTHS YES, THEY ARE STILL SOME FISTULAS THINGS LIKE THAT BUT NO TUMOR AT THE SITE AND IN FACT HIS HAIR, THE BEARD IS STARTING TO REGROW HAIR AT THAT POINT. THE RESULTS OF THIS PHASE 2 TRIAL WERE THAT AGAIN MINIMAL SIDE EFFECTS, NO PHOTO SENSITIVITY THAT WE SEE WITH PHOTO DYNAMIC THERAPY. THERE WAS. NEARLY 100% RESPONSE RATE AND A 57% DURABLE RESPONSE RATE. SO WE’RE GOING ON TO CONDUCT A TRIAL THAT’S GOING TO OPEN SOON IN A PHASE 3 TRIAL AT NCI VERY SHORTLY. SO THE RESPONSE RATES IN THE PHASE 2 WERE QUITE GOOD, MERELY 14% COMPLETE RESPONSE RATE, 31% PARTIAL RESPONSE RATE AND 38% STABLE DISEASE. A FEW PATIENTS DID GO ON TO PROGRESSIVE DISEASE BUT OVERALL THIS IS A VERY IMPRESSIVE RESPONSE RATE IN THIS HEAVILY PRE-TREATED POPULATION. MORE IMPORTANTLY PATIENTS LIVE LONGER. SO WE CAN CONSIDER THIS AS A POTENTIAL THIRD LINE THERAPY FOR CANCER AT THIS POINT, IT’S NOT APPROVED YET, IT’S STILL PHASE 3 TESTING. SO WE GO BACK TO THIS SLIDE THAT I SHOWED BEFORE IN MICE, WHERE WE HAD THESE REGROWTH CURVES THAT I MENTIONED WERE NOT ALL THAT IMPRESSIVE. YET THE PATIENT SEEMED TO HAVE A DRAMATIC RESPONSE. SO WE SORT OF MENTIONED THE IMMUNE SYSTEM MIGHT HAVE SOMETHING TO DO WITH IT. HERE IS ANOTHER PATIENT WITH MULTIPLE NODULES AND YOU CAN SEE ONE WEEK AFTER THEY HAVE ALL TURNED COLOR. ONE MONTH LATER THEY HAVE REALLY GONE AWAY. TWO MONTHS SEEMS TO HAVE A NORMAL NECK WHICH IS PRETTY REMARKABLE. SO THIS IS THE DIFFERENCE BETWEEN A XENOGRAFT AND A SIN GENEIC MODEL. SO IF WE TAKE A HUMAN WITH A TUMOR YOU TAKE THE TUMOR OUT AND THEN PASSAGE IT SO WE CAN GROW IT INTO SOMETHING CALLED A CELL LINE WE CAN PUT IT INTO A MOUSE WITH NO IMMUNE SYSTEM BECAUSE THE MOUSE WON’T REJECT IT. IF WE WANT THAT INTACT IMMUNE SYSTEM WE HAVE TO STAY IN THE SAME SPECIES. THAT IS TAKE A TUMOR FROM A MOUSE Z, PASSAGE IT AND PUT IT IN THE SAME MOUSE AND IT WILL GROW MORE SLOWLY BECAUSE NOW IT’S BEING ATTACKED BY THE MICE RECIPIENT MOUSE IMMUNE SYSTEM. THAT’S KIND OF THE SITUATION THAT WE FIND OURSELVES IN HERE. THERE ARE MANY KINDS OF IMMUNOTHERAPY, YOU CAN I DON’T WANT TO DWELL ON THE SLIDE TOO MUCH EXCEPT TO SAY THE IMMUNE SYSTEM IS VERY COMPLEX BUT OUR IDEA BEHIND WHAT GOES ON IN CANCER IMMUNITY IS THERE WILL BE T-CELLS THAT TRAFFIC THE TO TUMORS THEY WILL INFILTRATE THE TUMOR SPACE, T-CELLS WILL RECOGNIZE CANCER CELLS, BY IMMUNE RECOGNITION AND KILL CANCER CELLS. WHEN THEY KILL CANCER CELLS THEY RELEASE ANTIGENS PICKED UP BY DENDRITIC CELLS AND THEY PRIME ADDITIONAL T-CELLS TO EFFECTUATE A IMMUNE RESPONSE. IN THE CASE OF WHAT WE ARE DOING, WE THINK WHAT’S GOING ON BECAUSE THE CELL EXPLODES MORE OR LESS, UPON THE APPLICATION OF NEAR INFRARED LIGHT THERE IS RELEASE OF MULTIPLE ANTIGENS INTO THE ENVIRONMENT. AS WELL AS VARIOUS DAMAGE ASSOCIATED MEMBRANE PROTEINS SUCH AS CRT HMGB 1 WITH DIRECT EFFECT ON DENDRITIC CELLS. THEY RECEIVED THESE ANTIGENS AND MATURE FROM IMMATURE TO MATURE AND PRESENT ANTIGENS TO T-CELLS THUS EDUCATING THEM AND THEN T-CELLS RELEASE GRANZYME AND INTERFERON GAMMA TO KILL THE CANCER CELLS. NOW, THAT’S A GREAT STORY, THERE’S SOME PROBLEMS WITH IT. ONE IS THAT THERE ARE A LOT OF INHIBITORY T-CELLS IN THE ENVIRONMENT, FOR INSTANCE T REGULATORY CELLS THAT HAVE A NEGATIVE EFFECT ON THESE T-CELLS AND THAT WILL DEGRADE THE IMMUNE RESPONSE. THERE ARE OTHER SUPPRESSOR CELLS. SO WE BELIEVE THAT WE ARE GETTING QUITE A POWERFUL IMMUNE RESPONSE BUT WHAT IF YOU CAN ALSO TAKE OUT AT SAME TIME THESE T REGULATORY CELLS, MIGHT YOU ALSO BE ABLE TO HAVE A PROFOUND EFFECT. WE STARTED TO DO THOSE EXPERIMENTS WHICH WE DID IN MICE NEAR INFRARED PIT WITH LOCAL KNOCK DOWN OF T REGULATORY CELLS USING AN ANTI-CD 25 IR 700 CONJUGATE. AGAIN WE IMPLANT TWO TUMORS, THIS TIME WE ARE GOING TO BE LOOKING WITH LUCIFERASE, BIOLUMINESCENCE IMAGING. THERE ARE TWO TUMORS AND WE TREAT THIS TUMOR. WITHIN A DAY OR SO THAT TUMOR DISAPPEARS. HAVING ONLY TAKEN OUT THE TREG CELLS, LOOK WHAT HAPPENS TO THE OTHER TUMOR, WITH DIRECT TUMOR PIT SIMPLY WENT ON TO GROW. IN THIS CASE BOTH TUMORS REGRESS. ACTUALLY PRETTY RAPIDLY WITHIN THREE OR FOUR DAYS. SO THAT WAS SORT OF AN INTERESTING RESULT AND WE REPEATED IT IN OTHER MODELS WHERE WE IMPLANTED TWO TUMORS, DIAGONALLY, THESE TWO TUMORS ARE THE SAME. THESE TWO TUMORS ARE THE SAME BUT THIS IS NOT THE SAME ADS THAT. THEN APPLIED PIT JUST TO THIS TUMOR. AND A DAY LATER NOT ONLY THIS TUMOR BUT IT’S OPPOSITE WHICH IS OF THE SAME TYPE IS GONE. WHEREAS THE OTHER TWO TUMORS ARE STILL THERE ALBEIT A LITTLE KNOCK DOWN BUT STILL VERY VIABLE. WE BELIEVE THAT IN THE PRE-TREATMENT STATE, TUMOR CELLS ARE MORE OR LESS SHIELDED BY T REGULATORY CELLS FROM CD8 AND MK CELLS MANY THE TUMOR MICROENVIRONMENT. AFTER THE NEAR INFRARED LIGHT IRRADIATION HOWEVER, WITH THE DEMICE OF THE T REGULATORY CELLS, THESE T-CELLS CAN NOW HAVE DIRECT ACCESS TO THE TUMOR CELLS. AND EVENTUALLY BECAUSE THEY EXPAND SO QUICKLY IN THE PRESENCE OF CYTOKINES, THEY SPREAD TO ANOTHER PARTS OF THE BODY WHERE THEY LOOK FOR TUMORS OF THE SAME TYPE. AND KILL THEM SO IT’S HARNESSING THE IMMUNE SYSTEM TO ITS MAXIMAL POTENTIAL. T-CELLS AS I MENTION CAN BE — CAN CAUSE ALL KINDS OF EFFECTS, THEY CAN BE ACTIVATED BY ANTIGEN PRESENTING CELLS. BUT THEY CAN BE DOWN REGULATED BY REGULATORY T-CELLS, MYELOID DERIVED CELLS, AND A VARIETY OF OTHER CELLS. SO IT’S A BALANCING ACT. YOU MAY HAVE NOTICED THAT I SPECIFICALLY REFER TO THE ANTIBODY WE USE AS FAB PRIME 2 WHICH IS NOT REALLY SAME ADS ANTIBODY IF YOU KNOW THE LYNN GO, IT’S PRAGUEMENT OF ANTIBODY. SO WHY DID WE DO THAT? IF WE USE FULL ANTIBODY WE COULD HAVE ELIMINATED THE TREGS BUT ANYBODY WOULD STILL BE AROUND AROUND ACTIVATED T-CELLS EXPRESS THE SAME ANTIBODY. SO WE WOULD IN ESSENCE DEFEAT OUR PURPOSE BY HAVING THESE ANTIBODY THAT BIND TO ACTIVATED T-CELLS AS WELL. BY USING FAB PRIME WE ELIMINATE THE FRAGMENT PASTER AND ALSO ELIMINATE ANY INTERFERENCE WITH IL 2 WHICH IS WHAT ACTUALLY THE IL — WHICH IS WHAT CD 25 BINDS TO CALLED THE IL 2 RECEPTOR. TO PROLIFERATE T-CELLS WE NEED IL 2 AND WE DON’T WANT TO BLOCK THE CD8 CELLS, IMMUNE CELLS. THIS IS A TRICK THAT WE USE TO GET KILLING OF TREGS WITHOUT DAMAGING CD8s. SO WE EXPLAINED THAT. WHAT IF YOU COMBINE TREATMENT OF TREG WITH TREATMENT OF CANCER. THAT WOULD SEEM LIKE A LOGICAL NEXT STEP. SO WE DID THAT IN A SINGENEIC MODEL WE SWITCHED FROM NUDE MICE TO SIN GENEIC MODELS BECAUSE WE NEED INTACT IMMUNE SYSTEM. AND WE HAVE VARIOUS CONTROLS. THIS IS THE COMBINED NEAR INFRARED PIT SURVIVAL CURVE. THERE IS PROLONG SURVIVAL IN THOSE TREATED MICE. THERE IS SOME GROWTH IN SOME OF THEM BUT THIS IS ONLY A SINGLE TREATMENT WITH BOTH OF THOSE TARGETS. WE CAN GET REALLY PROLONGED SURVIVAL IN THESE MICE WITH VERY GOOD CONTROL OF TUMOR GROWTH USING THAT. IN THIS MODEL WE DON’T APPLY LIGHT TO THREE OF LESIONS BUT ONE OF THEM IS EXPOSED AND YOU CAN — SO IN THE CONTROL NOTHING HAVE ALL THE TUMORS GROW, AND WE HAVE TO SACRIFICE THE ANIMAL. IN THE TREATED MICE YOU CAN SEE THAT AFTER A FEW DAYS YOU CAN GET A COMPLETE RESPONSE IN THIS MOUSE THOUGH YOU ONLY RETE THERE HAD ONE OF FOUR TUMORS. INTERESTINGLY IF YOU TRY TO REINJECT THESE SAME CANCER CELLS INTO THIS MOUSE, YOU CAN’T DO IT, IT WILL REJECT TUMOR CELLS BECAUSE IT DEVELOPS A IMMUNE RESPONSE AGAINST CANCER CELLS THAT PREVENT REINJECTION SO IN ESSENCE A TUMOR VACCINE. SO WE ARE ON OUR WAY TO DEVELOPING EXACTLY THIS KIND OF COMBINED TREATMENT WHERE WE APPLY AN ANTIBODY TA BIND TO TUMOR, THAT STIMULATES THE ANTIBODY PRESENTING CELL ANTIGEN PRESENT CELLS RESULTING IN MATURATION OF THE DEP CRITIC CELLS AND ACTIVATION OF T-CELLS. BUT AT THE SAME TIME TAKING OUT TREG CELLS SO THAT THESE EFFECTS ARE NOT BLOCKED AND WE GET A VERY POWERFUL DIRECT TUMOR TREATMENT WITH VACCINE RESPONSE LATER ON. MULTI-STEP PROCEDURE. SO THERE ARE SOME OTHER INTERESTING ASPECTS TO THIS THERAPY. AND THAT IS THAT WHEN WE ADMINISTER WE SEE A DRAMATIC INCREASE IN PERMEABILITY IN VESSELS TO TREATED LESION. SO FOR INSTANCE WE TREATED THIS WITH PIT AND THEN PUT IN QUANTUM DOT, QUITE A BIG VERY BRIGHT FLUORESCENT CONSTRUCT. YOU CAN SEE SIDE THAT WASN’T — RECEIVED NO THERAPY, DOESN’T ENHANCE AT ALL. BUT THE ONE THAT DID RECEIVE THERAPY IS AVIDLY ENHANCING. IN FACT WHEN YOU MEASURE THIS DIFFERENCE BETWEEN HERE AND HERE AND HERE AND HERE, IT’S 24 FOLD INCREASE PERMEABILITY IN THE TREATED TUMOR. SO THAT WILL ENABLE US TO DELIVER VERY LARGE MACRO MOLECULES TO THE TREATED TUMOR PREFERENTIALLY TO OTHER TARGETS WHICH MEANS WE CAN DOSE FOR THIS. SO PHOTO IMMUNOTHERAPY IS A DISRUPTIVE TECHNOLOGY. IT CERTAINLY PRODUCES DRAMATIC RESULTS, IT’S IN HEAD AND NECK CANCER. THERE ARE ANY NUMBER OF OTHER TARGETS IT CAN BE DIRECTED TO. SO WE CAN GO ON TO OTHER TUMOR TARGETS LIKE PROSTATE SPECIFIC MEMBRANE ANTIGEN FOR PROSTATE CANCER OR EGFR AND FGF FOR BLADDER CANCER. YOUR IMAGINATION IS THE ONLY THING THAT LIMITS COMBINATIONS WE CAN DO. ANOTHER INTERESTING QUESTION IS WHO IS THIS ADDRESSED TO? IS THIS FOR SURGEONS, RADIOLOGIST? THE ANSWER IS IT PROBABLY CAN BE DONE BY A LOT OF DIFFERENT DOCTORS. INITIALLY WE ARE RELY ON SURGEONS IN OPERATING ROOMS BUT OVER TIME I THINK WE ARE GOING TO BE ABLE TO SHIFT TO OUTPATIENT DELIVERY AND STRONG ARM AND FIBER OPTIC CATHETER. WE WILL BE ABLE TO DO QUITE A NUMBER OF TREATMENTS. SO MY ACKNOWLEDGMENT SLIDE WITH PEOPLE IN MY LAB AND PEOPLE AT NIH AS WELL AS COLLABORATING INSTITUTIONS. THAT HELP US GET TO THIS POINT. THAT’S HISATAKA AND HIS CURRENT TEAM OF POST-DOCS. WITH THAT, THANK YOU. [APPLAUSE]>>ANY QUESTIONS?>>ELABORATE ON PHOTO THERAPY.>>YOU MEAN HOW IT WORKS AS MUCH>>JUST THE METHODS THAT ARE USED AND HOW LONG YOU HAVE TO WAIT AFTER THE ANTIBODY ADMINISTRATION.>>SO YOU ADMINISTER IT 24 HOURS BEFORE THE LIGHT TREATMENT. IT’S USUALLY UNEVENTFUL THAT ADMINISTRATION. ‘S EQUIVALENT TO RECEIVING A SINGLE DOSE OF ANTIBODY FOR THERAPY. BUT JUST SINGLE DOSE. 24 HOURS LATER THE PATIENT IS BROUGHT TO THE OPERATING ROOM THAT IS WHERE WE ARE SET UP TO DO IT. IF THE PATIENT NEEDS FIBER OPTIC PLACEMENT TYPICALLY UNDER ULTRASOUND OR CT GUIDANCE PRIOR TO COMING TO THE OPERATING ROOM THE FIBERS ARE PUT IN TO THE TUMOR. THEY ARE HOOKED UP TO THE LASER SYSTEM, THE APPROPRIATE WATTAGE IS DIALED IN AND THEN TUMOR IS TREATED WHILE PATIENT IS UNDER GENERAL ANESTHESIA. IF YOU DON’T DO GENERAL ANESTHESIA THERE’S PAIN ASSOCIATEIATED WITH THE PROCEDURE. — ASSOCIATED WITH THE PROCEDURE. RECOVERY IS RAPID, WITHIN TWO OUR THREE HOURS THE PATIENT IS FEELING BETTER. FROM THE ANESTHESIA AND MANY PATIENTS ARE DISCHARGED HOME AT THAT POINT. AT MINI WE ADMIT THEM AND DO TESTS. MANY ARE FEELING VERY, VERY WELL. WE HAVE HAD VERY DRAMATIC STORIES WHERE PEOPLE COME IN AND ARE NOT ABLE TO SWALLOW BECAUSE OF THE TUMOR. THEY HAVE A FEEDING TUBE OR GASTRIC TUBE. AFTER THE THERAPY THEY ARE ABLE TO SWALLOW AND ACTUALLY DRINK FOR THE FIRST TIME IN MONTHS. VERY GRATIFYING. OF COURSE, THE COMPLETE RESPONSE TAKES ONE OR TWO MONTHS FOR THE TISSUE TO HEAL AND TO GET FULL RECOVERY. THE PATIENT STARTS FEELING BETTER RIGHT AWAY. FROM — FOR WHATEVER REASON BECAUSE SYMPTOM IS REMOVED OR BECAUSE THE BAD EFFECTS, SYSTEM UK EFFECTS OF LARGE TUMOR HAVE NOW GONE AWAY. IS>>SO A RELATIVELY BENIGN THERAPY. (OFF MIC)>>NOT VERY LONG, IT’S ABOUT FIVE MINUTES OF LIGHT EXPOSURE. TO MAKE SURE WE GET EVERYTHING — WE OVER– THE LIGHT ITSELF IS NON-THERMAL, YOU CAN’T FEEL IT ON YOUR SKIN. IT DOESN’T BURN ANYTHING NO BURNING. THIS IS A CHEMICAL REACTION THAT OCCURS. IT’S INDUCED BY THE LIGHT. SO THERE’S NO HARM IN SHINING IT 10, 15 MINUTES BUT AL YOU SEEM TO NEED IS 5 MINUTES OF LASER LIGHT. (OFF MIC)>>QUESTION IS WHY DID WE CHOOSE HEAD AND NECK TUMORS. THAT IS A REALLY GOOD QUESTION AND YOU HAVE SYMPATHY FOR DRUG COMPANIES IN THIS POSITION BECAUSE THERE’S ALL THESE CANCER, ALL DESERVING OF SOMETHING. YOU CAN SEE DIFFERENT WAYS OF GETTING THERE. WHICH IS THE BEST ONE TO CHOOSE. YOU DON’T EVEN KNOW WHAT’S GOING TO HAPPEN. SO THERE’S A RISK IN DECIDING WHAT TO DO. WE FELT NUMBER ONE HEAD AND NECK CANCERS ARE KNOWN TO BE VERY HIGH EGFR EXPRESSERS. ESPECIALLY THOSE WITH HUMAN PAPILLOMA VIRUS. CETUXIMAB IS EGFR ANTIBODY. SO WE HAD A GOOD SHOT GETTING THAT ANTIBODY TO TUMOR BECAUSE OF HEAD AND NECK. SECONDLY, HEAD AND NECK CANCER AS YOU CAN SEE ARE RELATIVELY EXPOSED. SO YOU CAN APPROACH THROUGH THE MOUTH, YOU CAN APPROACH THROUGH THE SKIN. BUT WE END UP HAVING TO USE THE CATHETERS TOO YOU CAN SEE WHAT YOU DOING, IT’S NOT DEEP INSIDE THE BODY WHERE — AND THIRD, THE EAR NOSE AND THROAT DOCTORS THAT WE CHOSE TO DO — TO HELP WITH THE TRIAL HAD SOME FAMILIARITY WITH POE TOE DYNAMIC THERAPY. SO THEY HAD PRIOR EXPERIENCE WITH LASERS, AND PUTTING CATHETERS IN AND THINGS LIKE THAT. SO THEY WERE AN EDUCATED GROUP OF EMT DOCS, THEY WERE A SPECIAL GROUP OF ENT DOCS BUZZ NOT ALL DO THIS WORK. BUT ONE GUY KNEW ANOTHER GUY, YOU CAN GET FIVE GUYS PRETTY EXPERIENCED IN THIS. THAT WAS OUR CORE OF PIONEERS WHO GOT THIS OFF THE GROUND. I WILL SAY NOW IT’S IN EUROPE, UNITED STATES, JAPAN, SINGAPORE, THE TRIAL IS GOING ON, IT WILL PROBABLY BE APPROVED IN JAPAN FIRST. NEXT YEAR. BECAUSE THEY HAVE A MORE RAPID APPROVAL PROCESS THAN WE DO.>>SEEMS TO ME IT WOULD BE MOST EFFECTIVE IN PRIMARY TUMORS BUT NOT IN PATIENTS WITH LOTS OF METASTASIS.>>YES. BUT YOU DON’T GET TO TEST A NEW THERAPY, ESPECIALLY THIS, IN WHERE IT’S CONSIDERED THAT TREATMENT IS WELL ESTABLISHED. YOU ONLY GET TO TEST IT IN PATIENT WHOSE HAVE NO OTHER OPTION. SO THE IDEA, THIS IS A TERRIBLE DISEASE HEAD AND NECK CANCER, CHEMO RADIATION RESULTS IN VERY DRY MOUTH, BAD DENTAL PROBLEMS, SWALLOWING ISSUES, SPEAKING ISSUES. A LOT OF REALLY BAD THINGS. SO IF YOU CAN EVEN MOVE THIS THERAPY UP TO THAT, IT WOULD BE A BIG DEAL. AND WE ARE NOW CONSIDERING WHERE DO THESE CANCERS COME FROM? THEY COME FROM MUTATIONS THAT START FAIRLY EARLY IN SOMETHING CALLED PREMALIGNANT LESIONS. LEUKOPLAKIA. A GOOD DENTIST WHEN DOING YOUR ANNUAL DENTAL EXAM WILL TAKE A LOOK IN YOUR MOUTH FOR WHITE PLAQUES, LEUKOPLAKIA. THOSE CAN BE PRE-MALIGNANT LESIONS. THE TROUBLE IS YOU DON’T REALLY KNOW UNTIL YOU TAKE IT OUT. YOU CAN IMAGINE DOING SURGERY IN THE WALL OF THE MOUTH, IT’S A VERY DELICATE PROBLEM. NOBODY LIKES DOING THAT SURGERY AND AT THE WORST IS YOU CAN PUT SOMEBODY THROUGH SURGERY AND MAY NOT BE MALIGNANT AT THE END OF THE DAY. BUT IF ALL THE YOU DID WAS PICSD, THEY DO EXPRESS EGFR, YOU CAN STOP THE TUMOR AT THAT POINT EVEN BEFORE IT’S A PRIMARY. IT COULD BE A PREVENTIVE, FRANKLY IT COULD BE PUT IN THE HANDS OF DENTISTS. HONESTLY. IT IS NOT A TECHNICALLY DIFFICULT. WE ARE VERY EXCITED ABOUT THAT WHOLE PROCESS OF MOVING IT UP. I’M CERTAINLY THINKING ABOUT PROSTATE CANCER BECAUSE CURRENT PROSTATE CANCER THERAPIES ARE PRETTY RADICAL. IT’S EITHER RADIATION TO THE PELVIS WHICH CAUSES BLADDER RECTAL PROBLEMS OR SURGERY WHICH CAUSES ERECTILE DYSFUNCTION AND INCONTINENCE, MAJOR SIDE EFFECTS. YET MANY CANCERS THAT REMOVED ARE QUESTIONABLE BIOLOGIC SIGNIFICANCE. SO THE PATIENT PAYS A BIG COST TO BECOME CANCER FREE. SO WHY NOT DO AN ANTIBODY AGAINST PROSTATE SPECIFIC MEMBRANE ANTIGEN WHICH IS EXPRESSED BY PROSTATE CANCER INSTEAD OF ABLATING TUMORS, GO IN WITH THE LIGHT AS IF YOU WERE DOING A BIOPSY BUT PUT A FIBER OPTIC ABLATE THE CANCER, AND TREAT IT THAT WAY. WITHOUT THE NEED — WITHOUT DISTURBING THE NERVES OR THE NEUROREIT THAT OR ANY OF THAT. THERE IS A LOT TO DO.>>THANK YOU, PETE, VERY EXCITING.>>THANK YOU.>>THANK YOU FOR ALLOWING ME TO CHANGE THE SUBJECT.

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