Cancer Care Inc

LEADERSHIP GROUP FOR A GLOBAL HIV VACCINE CLINICAL TRIALS NETWORK

HVTN LABORATORY PROGRAM

LEADERSHIP FOR HIV/AIDS CLINICAL TRIALS NETWORKS; HIV VACCINE TRIALS NETWORK

CANCER CENTER SUPPORT GRANT (COMPREHENSIVE)

LEADERSHIP FOR HIV/AIDS CLINICAL TRIALS NETWORKS; HIV PREVENTION TRIALS NETWORK

SWOG STATISTICS AND DATA MANAGEMENT CENTER

EARLY DETECTION RESEARCH NETWORK: DATA MANAGEMENT AND COORDINATING CENTER

ADULT LEUKEMIA RESEARCH CENTER

THE PACIFIC NORTHWEST PROSTATE CANCER SPORE

MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS

HAWAIIAN, ASIAN AMERICAN, AND PACIFIC ISLANDER (HAAPI) COORDINATING CENTER - SUMMARY/ABSTRACT PEOPLE OF ASIAN, HAWAIIAN, OR PACIFIC ISLANDER (ASA-NHPI) ANCESTRY, WHILE REPRESENTING 7.7% OF THE US POPULATION, HAVE BEEN LARGELY UNDERREPRESENTED FROM NIH-FUNDED PROSPECTIVE EPIDEMIOLOGIC STUDIES. AS A RESULT, THERE ARE LARGE GAPS IN OUR KNOWLEDGE OF THE BURDEN AND CAUSES OF CARDIOVASCULAR, METABOLIC, AND MENTAL HEALTH DISORDERS IN THESE POPULATIONS. INDIVIDUALS OF THESE BACKGROUNDS HAVE EXPERIENCED, TO VARYING DEGREES, THE BARRIERS, STRESSES, AND STEREOTYPING EXPERIENCED BY OTHER MINORITIES WHILE ALSO HAVING CHALLENGES THAT ARE UNIQUE TO THEM. UNDERSTANDING THE HETEROGENEITY OF THEIR LIFESTYLES AND SOCIETAL AND ENVIRONMENTAL CIRCUMSTANCES, AS WELL AS THEIR ANCESTRY, IS A CRITICAL FIRST STEP IN DETERMINING THEIR HEALTH NEEDS AND HOW TO ADDRESS THEM. THE HETEROGENEITY IN THESE POPULATIONS, FOLLOWED LONGITUDINALLY AND CONTRASTED WITH OTHER POPULATIONS, MAY ADD UNIQUE INSIGHTS INTO THE ETIOLOGY OF BOTH PHYSICAL AND MENTAL HEALTH CONDITIONS. IN THIS APPLICATION FOR THE HAWAIIAN, ASIAN AMERICAN, AND PACIFIC ISLANDER COORDINATING CENTER (HAAPI-CC), WE PROPOSE TO: (1) BRING EXCEPTIONAL SCIENTIFIC, STATISTICAL, AND CULTURAL EXPERTISE TO THE EFFORT OF ASSESSING THE PHYSICAL AND MENTAL HEALTH AND THEIR DETERMINANTS IN PEOPLE OF HAWAIIAN, ASIAN, AND PACIFIC ISLANDER ANCESTRY; (2) PROVIDE THE OPERATIONAL, DATA SCIENCE, AND BIOREPOSITORY INFRASTRUCTURE AND LEADERSHIP TO SUPPORT THE SCIENTIFIC PRIORITIES OF THE COHORT AND STIMULATE AND ENHANCE ANCILLARY STUDY OPPORTUNITIES BROADLY; (3) COORDINATE AND SUPPORT CLINICAL OR COMMUNITY FIELD CENTER (CCFC) ACTIVITIES TO ENHANCE RECRUITMENT AND RETENTION AND BROADER COMMUNITY ENGAGEMENT; AND (4) ENHANCE CAREER DEVELOPMENT OF EARLY STAGE INVESTIGATORS, PARTICULARLY THOSE FROM UNDER-REPRESENTED BACKGROUNDS. THROUGH THIS EFFORT, WE CAN ESTIMATE THE PREVALENCE OF CARDIOVASCULAR DISEASES AND RISK FACTORS AND MENTAL HEALTH CONDITIONS, STUDY THEIR INTERPLAY AND TRAJECTORIES OVER TIME, AND EXAMINE ASSOCIATIONS WITH NOVEL EXPOSURES DERIVED FROM DATA LINKAGES AND BIOSPECIMENS. WE ANTICIPATE LEADING A NUMBER OF ANCILLARY STUDIES TO OBTAIN ADDITIONAL RICH DATA FROM NOVEL SOURCES (WEARABLES, MHEALTH, GENOMICS, PROTEOMICS, METABOLOMICS, MICROBIOME, CARDIAC AND BRAIN IMAGING). THROUGH THESE EFFORTS, WE AND OUR CCFC COLLEAGUES, WILL ADVANCE THE KNOWLEDGE OF THE HEALTH CONDITIONS OF ASIAN, HAWAIIAN, AND PACIFIC ISLANDERS AND PROVIDE THE INFRASTRUCTURE FOR DEEPER UNDERSTANDING OF THEIR BIOLOGICAL, ENVIRONMENTAL, AND SOCIOLOGICAL UNDERPINNINGS. ,

SEATTLE VACCINE TRIALS UNIT

CELL AND GENE THERAPY FOR HIV CURE

PARTNERSHIP FOR THE ADVANCEMENT OF CANCER RESEARCH: NMSU-FHCRC (2 OF 2)

COLORECTAL CANCER GENOME-WIDE ASSOCIATION STUDIES CONSORTIUM

CANCER IMMUNOTHERAPY TRIALS NETWORK CENTRAL OPERATIONS AND STATISTICAL CENTER

FRED HUTCHINSON CANCER RESEARCH CENTER LUNG SPORE

HEMATOPOPIETIC STEM CELL TRANSPLANTATION

BREAST AND OVARY CANCER CLINICAL VALIDATION CENTER

CELL AND GENE THERAPY FOR NONMALIGNANT BLOOD DISORDERS

NUTRITION AND PHYSICAL ACTIVITY ASSESSMENT STUDY (NPAAS)

NCI CANCER SCREENING RESEARCH NETWORK: COORDINATING AND COMMUNICATION CENTER - SUMMARY/ABSTRACT THIS APPLICATION IS BEING SUBMITTED IN RESPONSE TO THE NOSI IDENTIFIED AS NOT-CA-24-111. THE NCI-INITIATED CANCER SCREENING RESEARCH NETWORK (CSRN) IS A COOPERATIVE GROUP DEVELOPED TO ADVANCE EARLY DETECTION RESEARCH INTO POPULATION-LEVEL TRIALS AND RELATED STUDIES TO EVALUATE NOVEL APPROACHES TO CANCER SCREENING. THE VANGUARD TRIAL IS THE FIRST CSRN STUDY AND ITS PRIMARY OBJECTIVES ARE 1) TO DETERMINE THE FEASIBILITY OF A RANDOMIZED CONTROLLED TRIAL OF TWO NOVEL MULTICANCER DETECTION (MCD) ASSAYS AND 2) TO ENSURE EQUITABLE PARTICIPATION THROUGH RECRUITING AND RETAINING DIVERSE POPULATIONS. FRED HUTCHINSON CANCER CENTER SERVES AS THE COORDINATING AND COMMUNICATIONS CENTER (CCC) FOR THE VANGUARD STUDY AND CSRN, PROVIDING SCIENTIFIC LEADERSHIP, TRAINING, IMPLEMENTATION SUPPORT AND MONITORING FOR NINE ACCRUAL AND ENROLLMENT SITES (“ACCESS HUBS”) LOCATED ACROSS THE UNITED STATES IN DIVERSE GEOGRAPHICAL, SOCIOECONOMIC, AND CULTURAL COMMUNITIES. IN YEAR 1, THE CCC HAS DEVELOPED AND SUPPORTED THE CSRN COMMITTEE STRUCTURE, LED PROTOCOL DEVELOPMENT, INITIATED STAFF TRAINING AND SERVED AS THE PRIMARY POINT OF CONTACT FOR ACCESS HUBS. THROUGH THESE INTERACTIONS, THE CCC HAS BECOME AWARE OF THE LARGER NUMBER AND GREATER DIVERSITY AND COMPLEXITY OF THE ACCESS HUBS AND THEIR RECRUITMENT PLANS TO REACH UNDER-REPRESENTED AND UNDERSERVED POPULATIONS. EACH ACCESS HUB WILL COORDINATE MULTIPLE RECRUITMENT SITES, SOME CONCENTRATED IN WELL-CIRCUMSCRIBED URBAN AREAS AND OTHERS DISPERSED REGIONALLY OR EVEN NATIONALLY. SOME WILL RECRUIT FROM A SINGLE, CLOSED HEALTH SYSTEM WHILE OTHERS WILL USE A COMBINATION OF ACADEMIC MEDICAL CENTERS, PRIVATE CLINICS AND FEDERALLY QUALIFIED HEALTH CENTERS. AN ADDITIONAL COMPLEXITY OF THE VANGUARD TRIAL IS IN SUPPORTING DIAGNOSTIC WORKFLOWS FOR MCD TESTS, SINCE NEITHER THE SCREENING PROGRAM SENSITIVITY NOR THE ACCURACY OF TISSUE OF ORIGIN PREDICTIONS ARE KNOWN AND THE FACILITIES AVAILABLE AND ASSOCIATED COSTS CONCERNS VARY CONSIDERABLY ACROSS SITES. TO MEET THE UNANTICIPATED DEMANDS OF THIS FIRST RCT OF MCD ASSAYS IN THE US, WE PROPOSE TO: 1) EXPAND COMMUNITY ADVISORY BOARD (CAB) PARTICIPATION; 2) PROVIDE ADDITIONAL LANGUAGE TRANSLATIONS OF PARTICIPANT MATERIALS; 3) PROVIDE ADDITIONAL RECRUITMENT AND RETENTION MATERIALS; 4) INCREASE TRAINING AND MONITORING RESOURCES; 5) INCREASE INVESTIGATOR TIME FOR COMMITTEE WORK, ENGAGEMENT WITH HUBS, AND IMPLEMENTATION OF A DIAGNOSTIC REVIEW BOARD.

POLYGENIC RISK SCORES FOR DIVERSE POPULATIONS - BRIDGING RESEARCH AND CLINICAL CARE

PREVENTION OF LETHAL METASTATIC BREAST CANCER BY IDENTIFYING AND ERADICATING CLINICALLY RELEVANT DISSEMINATED TUMOR CELLS

PREVENTION OF LETHAL METASTATIC BREAST CANCER BY IDENTIFYING AND ERADICATING CLINICALLY RELEVANT DISSEMINATED TUMOR CELLS

SELF-AMPLIFYING MRNA-BASED VACCINES TO ELICIT VRC01-CLASS BNABS - ABSTRACT OVERALL THE MAIN GOAL OF OUR IPCAVD PROGRAM GRANT IS TO EVALUATE IN HUMANS SELF-AMPLIFYING MRNA (SARNA) VACCINES THAT EXPRESS TWO HIV-1 ENV-DERIVED PROTEIN IMMUNOGENS THAT ACTIVATE AND INITIATE THE MATURATION OF VRC01-CLASS B CELL RECEPTORS (BCRS). THE FIRST IMMUNOGEN, 426C.MOD.CORE, WAS SPECIFICALLY DESIGNED TO BIND WITH HIGH AFFINITY TO THE UNMUTATED (GERMLINE, GL) FORMS OF THOSE BCRS AS THEY ARE EXPRESSED ON THE SURFACE OF NAÏVE B CELLS. THE SECOND IMMUNOGEN, HXB2.WT.CORE, ALTHOUGH UNABLE TO BIND GERMLINE VRC01-CLASS BCRS, BINDS THE VRC01-CLASS BCRS THAT BECAME ACTIVATED BY 426C.MOD.CORE AND HAVE ACCUMULATED SOME SOMATIC MUTATIONS. AS A RESULT, THE BOOST IMMUNIZATION WITH HXB2.WT.CORE FURTHERS THE MATURATION OF THE VRC01-CLASS ANTIBODIES ELICITED BY THE 426C.MOD.CORE. THESE OBSERVATIONS WERE MADE WITH THE ADJUVANTED RECOMBINANT (REC) FORMS OF THESE TWO IMMUNOGENS. AS MRNA- BASED VACCINES ARE LESS COSTLY AND MORE EASILY GMP-MANUFACTURED THAT REC PROTEINS, WE BELIEVE THAT THEY WILL ACCELERATE THE PRECLINICAL AND CLINICAL EVALUATION OF HIV-1 ENV-DERIVED IMMUNOGENS. HERE, WE PROPOSE TO FIRST COMPARE PRECLINICALLY THE VRC01 B CELL AND ANTIBODY RESPONSES ELICITED BY THESE TWO ENV IMMUNOGENS WHEN DELIVERED BY SARNA VACCINES TO THOSE ELICITED BY THE CORRESPONDING ADJUVANTED REC PROTEINS. AND THEN, IF THE RESULTS ARE PROMISING, THE SARNA VACCINES EXPRESSING THE TWO IMMUNOGENS WILL BE GMP-MANUFACTURED FOR CLINICAL EVALUATION. AS THE 426C.MOD.CORE ADJUVANTED REC PROTEIN WILL BE EVALUATED CLINICALLY (PHASE I) IN THE SPRING OF 2022 (HVTN301) AND THE HXB2.WT.CORE REC PROTEIN IS CURRENTLY BEING GMP MANUFACTURED FOR A FOLLOW-UP PHASE I CLINICAL EVALUATION IN 2023, WE WILL BE IN A UNIQUE POSITION TO COMPARE THE VRC01 B CELL AND ANTIBODY RESPONSES ELICITED BY HUMANS IMMUNIZED WITH THESE TWO HIV-1 ENV-DERIVED IMMUNOGENS WHEN DELIVERED AS ADJUVANTED REC PROTEINS AND AS EXPRESSED BY SARNA VACCINES. TO ACCOMPLISH OUR GOALS IN THIS IPCAVD GRANT WE WILL TAKE ADVANTAGE OF OUR EXPERTISE IN IMMUNOGEN-DESIGN AND TESTING, EXPERTISE IN THE ANALYSIS OF B CELL AND ANTIBODY RESPONSES ELICITED BY VACCINATION AND DURING INFECTION, OUR ABILITY TO RAPIDLY SEQUENCE BCR GENES USING HIGH THROUGH PUT TECHNOLOGIES, THE AVAILABILITY OF APPROPRIATE ANIMAL MODELS, OUR EXPERTISE IN SARNA VACCINE TECHNOLOGY, OUR UNIQUE EXPERTISE IN CONDUCTING CLINICAL TESTING OF HIV-1 VACCINES, THE EXISTING COLLABORATION AMONG THE PARTICIPATING GROUPS AND THE DOCUMENTED EXPERTISE OF THE PARTICIPANTS TO SUCCESSFULLY MANAGE COMPLEX PROGRAMS.

COLABORACION EVITA: HPV-RELATED CANCER PREVENTION PARTNERSHIP CENTER

CAREER DEVELOPMENT IN PEDIATRIC AND MEDICAL ONCOLOGY

1/2 GANCICLOVIR TO PREVENT REACTIVATION OF CYTOMEGALOVIRUS IN PATIENTS WITH ACUTE RESPIRATORY FAILURE AND SEPSIS - PROJECT SUMMARY SEPSIS-ASSOCIATED ACUTE RESPIRATORY FAILURE IS A LEADING CAUSE OF MORBIDITY, MORTALITY AND HEALTH CARE EXPENDITURE WORLD-WIDE, AND IS INCREASING IN INCIDENCE. DESPITE INTENSIVE INVESTIGATION, THERE ARE FEW PHARMACOLOGIC INTERVENTIONS, AND CARE IS LARGELY SUPPORTIVE. CYTOMEGALOVIRUS (CMV) IS A HUMAN HERPESVIRUS THAT INFECTS 50- 80% OF HEALTHY ADULTS AND ESTABLISHES LIFELONG LATENCY IN THE LUNG, GENERALLY CAUSING OVERT DISEASE ONLY IN SEVERELY IMMUNOSUPPRESSED PATIENTS. CMV REACTIVATION (VIRAL REPLICATION) FROM LATENCY OCCURS IN ~40% OF CMV SEROPOSITIVE, OTHERWISE IMMUNOCOMPETENT PERSONS DURING CRITICAL ILLNESS AND IS ASSOCIATED WITH WORSE CLINICAL OUTCOMES INCLUDING INCREASED MORTALITY, PROLONGED MECHANICAL VENTILATION, AND INCREASED ICU LENGTH OF STAY. COMPELLING EVIDENCE IMPLICATING CMV REACTIVATION AS A CAUSAL CONTRIBUTOR TO MORBIDITY AND MORTALITY IN SEPSIS- ASSOCIATED RESPIRATORY FAILURE COMES FROM ANIMAL MODELS AND OUR RECENTLY COMPLETED NHLBI-FUNDED PHASE 2 RANDOMIZED PLACEBO-CONTROLLED TRIAL (RCT) OF GANCICLOVIR PROPHYLAXIS. IN THIS TRIAL, AMONG CMV SEROPOSITIVE ADULTS WITH SEPSIS-ASSOCIATED RESPIRATORY FAILURE, GANCICLOVIR EFFECTIVELY SUPPRESSED CMV REPLICATION, HAD AN ACCEPTABLE SAFETY PROFILE, AND WAS ASSOCIATED WITH IMPROVED CLINICAL OUTCOMES, INCLUDING INCREASED VENTILATOR-FREE DAYS (VFD), SHORTER DURATION OF MECHANICAL VENTILATION AMONG SURVIVORS, SHORTER ICU LENGTH OF STAY, AND IMPROVED PAO2/FIO2 RATIO IN DAY-7 SURVIVORS. WE HYPOTHESIZE THAT IV GANCICLOVIR ADMINISTERED EARLY IN CRITICAL ILLNESS WILL EFFECTIVELY SUPPRESS CMV REACTIVATION IN CMV SEROPOSITIVE ADULTS WITH SEPSIS-ASSOCIATED ACUTE RESPIRATORY FAILURE, THEREBY REDUCING LUNG DAMAGE, ACCELERATING RECOVERY, AND LEADING TO IMPROVED CLINICAL OUTCOMES. WE PROPOSE TO CONDUCT A PHASE 3 RCT TO DETERMINE WHETHER THE ANTIVIRAL DRUG GANCICLOVIR GIVEN AS PROPHYLAXIS IMPROVES VFDS AND OTHER CLINICALLY RELEVANT OUTCOMES WHEN ADMINISTERED WITHIN 5 DAYS OF ICU ADMISSION TO CMV SEROPOSITIVE IMMUNOCOMPETENT ADULTS WITH SEPSIS-ASSOCIATED ACUTE RESPIRATORY FAILURE. WE WILL MEASURE THE EFFECT OF THE STUDY INTERVENTION ON THE PRIMARY TRIAL OUTCOME (VFDS) AND SECONDARY OUTCOMES (MORTALITY AT 28 DAYS, DURATION OF MECHANICAL VENTILATION IN SURVIVORS, OXYGENATION, STATIC RESPIRATORY SYSTEM COMPLIANCE, CMV PLASMA AND LUNG REACTIVATION, AND A CORE SET OF LONGER-TERM OUTCOMES AT 6 MONTHS). IN EXPLORATORY ANALYSES, WE WILL ASSESS BASELINE FACTORS AS PREDICTORS FOR CMV REACTIVATION, AND CHARACTERIZE THE RELATIONSHIP OF CMV VIRAL LOAD KINETICS WITH VFDS AND OTHER CLINICAL OUTCOMES. OUR INTERDISCIPLINARY TEAM HAS UNIQUE EXPERIENCE IN SUCCESSFULLY COORDINATING MULTI-SITE MULTI-PI ICU-BASED RCTS. WE HAVE ESTABLISHED A NETWORK OF 19 CLINICAL SITES IN THE US, ALL OF WHICH HAVE ROBUST INFRASTRUCTURE FOR ICU CLINICAL TRIALS AND PROVEN ABILITY TO RECRUIT PATIENTS INTO RCTS. IF IT IS EFFECTIVE, THIS INEXPENSIVE AND FEASIBLE INTERVENTION HAS THE POTENTIAL TO SIGNIFICANTLY IMPROVE CARE OF PATIENTS WITH SEPSIS-ASSOCIATED RESPIRATORY FAILURE, SUBSTANTIALLY CHANGE CLINICAL PRACTICE, AND OFFER NEW INSIGHTS INTO THE SEPSIS-CMV REACTIVATION RELATIONSHIP.

USING FUNCTIONAL GENOMICS TO INFORM GENE ENVIRONMENT INTERACTIONS FOR COLORECTAL CANCER

MOLECULAR ANALYSIS OF GENETIC RECOMBINATION AND DNA BREAK REPAIR

UNDERSTANDING ADENOMA PROGRESSION: INTERPLAY AMONG TISSUE MICROENVIRONMENT, CLONAL ARCHITECTURE, AND GUT MICROBIOME - SUMMARY COLORECTAL CANCER (CRC) AFFECTS ~145,000 PEOPLE/YEAR IN THE US AND IS THE 3RD MOST COMMON CAUSE OF CANCER RELATED DEATHS. CRC ARISES FROM EARLY LESIONS THAT ARE PRE-CANCEROUS; THESE EARLY LESIONS ARE COLON ADENOMAS AND SERRATED SESSILE LESIONS (SSL). COLON ADENOMAS ACCOUNT FOR 80-85% OF THE CRC PRECANCEROUS LESIONS AND PROGRESS TO CRC VIA AN EARLY ADENOMAAADVANCED ADENOMAACRC SEQUENCE. IN LIGHT OF THE WELL CHARACTERIZED CLINICAL NATURAL HISTORY OF ADENOMAS, WE PLAN TO STUDY THEM AS EARLY LESIONS AND TO DETERMINE THE MECHANISMS INVOLVED IN THE FORMATION AND PROGRESSION OF EARLY PRECANCEROUS LESIONS. NOTABLY, ONLY A FEW EARLY ADENOMAS WILL PROGRESS TO ADVANCED ADENOMAS (AA) AND EVEN FEWER WILL PROGRESS TO CRC. OUR GROUP AND OTHERS HAVE SHOWN THAT MUTATIONS ALONE ARE NOT SUFFICIENT TO CAUSE ADENOMA INITIATION AND/OR PROGRESSION IN THE MAJORITY OF CASES. THERE ARE LIKELY MULTIPLE ADENOMA NONAUTONOMOUS MECHANISMS THAT COOPERATE WITH THE DNA ALTERATIONS IN THE ADENOMAS TO CAUSE PROGRESSION, AND THESE MECHANISMS ARE LIKELY OPERATIVE IN DISCRETE SUBSETS OF AFFECTED INDIVIDUALS. WE AND OTHERS HAVE OBSERVED ALTERATIONS, SUCH AS TISSUE SENESCENCE, HIGH CANCER DRIVER GENE MUTATION LOADS, ABERRANT DNA METHYLATION PATTERNS, AND DYSBIOTIC GUT MICROBIOMES, IN THE NORMAL COLON OF PEOPLE WITH ADVANCED ADENOMAS AND CRC PATIENTS. WE HAVE TERMED NORMAL COLONS WITH THESE FEATURES “PRIMED COLONS” AND PROPOSE THAT THESE FEATURES ARE PLAUSIBLE MECHANISMS THAT AFFECT ADENOMA INITIATION AND PROGRESSION. BASED ON THESE OBSERVATIONS AND OUR PRIOR STUDIES, WE HYPOTHESIZE THAT EARLY LESION PROGRESSION REQUIRES A SUITE OF HALLMARK BEHAVIORS AND THAT THESE BEHAVIORS ARE INDUCED BY ADENOMA AUTONOMOUS FACTORS (E.G. CANCER DRIVER GENE MUTATIONS) AND ADENOMA NONAUTONOMOUS FACTORS FROM THE “PRIMED COLON” OR ADENOMA MICROENVIRONMENT. OUR PROPOSED STUDIES WILL INTEGRATE BASIC AND TRANSLATIONAL CANCER RESEARCH PROJECTS TO ITERATIVELY EXAMINE THE DIRECT CAUSAL RELATIONSHIPS AND INTERACTIONS OF ADENOMAS, THE COLON “PRIMED” MICROENVIRONMENT, AND HOST- SYSTEMIC FACTORS AS “CO-ORGANIZERS” OF ADENOMA INITIATION AND/OR PROGRESSION. THE SPECIFIC AIMS ARE: AIM 1) TO DETERMINE THE ADENOMA CELL AUTONOMOUS MOLECULAR FACTORS THAT DISTINGUISH NONADVANCED ADENOMAS FROM ADVANCED ADENOMAS AND THAT REGULATE NONADVANCED ADENOMA PROGRESSION. (PROJECTS 1 AND 2) AIM 2) TO DETERMINE THE ADENOMA NONAUTONOMOUS FACTORS FROM THE “PRIMED” COLON AND FROM THE ADENOMA MICROENVIRONMENT THAT ASSOCIATE WITH ADVANCED HUMAN COLON ADENOMAS AND REGULATE ADENOMA PROGRESSION. THESE FACTORS WILL INCLUDE THE FOLLOWING “PRIMED” COLON STATES: 1. SENESCENCE STATE; 2. CANCER DRIVER GENE MUTATION BURDEN; 3. GUT MICROBIOME STATE; 4. COLON METHYLOME, AND 5. COLON IMMUNE ACTIVITY STATE. (PROJECTS 1-3) AIM 3)TO DETERMINE HOW ADENOMA AUTONOMOUS AND NONAUTONOMOUS FACTORS FROM THE ADENOMA MICROENVIRONMENT AND THE “PRIMED” COLON COOPERATE TO DRIVE ADENOMA FORMATION AND PROGRESSION.(PROJCTS 1-3)

EXPANSION AND TARGETED MATURATION OF GERMLINE HIV-1 BNAB-ASSOCIATED BCRS

CORE CENTER FOR STEM CELL AND TRANSPLANTATION BIOLOGY

IMPROVING OUTCOMES ASSESSMENT IN CHRONIC GVHD

THE ROLE OF ANTIBODIES IN MOTHER TO CHILD HIV TRANSMISSION

PROTEOGENOMIC STUDIES AIMED AT UNDERSTANDING OVARIAN TUMOR RESPONSES TO AGENTS TARGETING THE DNA DAMAGE RESPONSE AND TRANSLATING THIS KNOWLEDGE INTO CLINICAL BENEFIT

MODULATING THE IMPACT OF CRITICAL EVENTS IN EARLY HIV INFECTION: EFFECT OF EARLY ART INITIATION AND ALCOHOL USE

GENETIC REQUIREMENTS OF HELICOBACTER PYLORI INFECTION

GENETIC AND MOLECULAR BASIS FOR SRSF2 MUTATIONS IN MYELODYSPLASIA

UPGRADING INSTITUTIONAL CAPACITY WITH A BSL-3 FACILITY FOR MULTIDISCIPLINARY BIOMEDICAL RESEARCH - PROJECT SUMMARY/ABSTRACT: THE FRED HUTCHINSON CANCER CENTER (FRED HUTCH) PROPOSES THE CONSTRUCTION OF AN ENHANCED BIOSAFETY LEVEL 3 (BSL-3)/ANIMAL BSL-3 FACILITY TO ADDRESS CRITICAL GAPS IN REGIONAL CAPACITY FOR HIGH-CONTAINMENT RESEARCH ON PATHOGENS OF SIGNIFICANT PUBLIC HEALTH CONCERN, PARTICULARLY HIGHLY PATHOGENIC AVIAN INFLUENZA (HPAI) AND OTHER EMERGING INFECTIOUS AGENTS. DESPITE FRED HUTCH’S LEADERSHIP IN INFECTIOUS DISEASE RESEARCH, THE ABSENCE OF AN ON-SITE BSL-3 FACILITY LIMITS THE INSTITUTION’S ABILITY TO FULLY SUPPORT MULTIDISCIPLINARY BIOMEDICAL RESEARCH AND RESPOND RAPIDLY TO OUTBREAKS. NOTABLY, SEATTLE CHILDREN’S RESEARCH INSTITUTE LACKS SHOWER-OUT AND EFFLUENT DECONTAMINATION SYSTEMS, AND THE UNIVERSITY OF WASHINGTON’S BSL-3 FACILITY ALSO LACKS AN EFFLUENT DECONTAMINATION SYSTEM. THE PROPOSED 5,145-SQUARE-FOOT FACILITY, LOCATED ON THE FRED HUTCH CAMPUS IN SEATTLE, WASHINGTON, WILL INCORPORATE NEXT-GENERATION BIOSAFETY FEATURES, INCLUDING A SHOWER-OUT SYSTEM, AN EFFLUENT DECONTAMINATION SYSTEM (EDS), AND DEDICATED CONTAINMENT ZONES. THE DESIGN INCLUDES FLEXIBLE LABORATORY SPACES, SPECIALIZED AREAS FOR PATHOGEN-SPECIFIC RESEARCH, AND ADVANCED FACILITIES FOR AUTOMATION, FLOW CYTOMETRY AND WASTE PROCESSING. THESE FEATURES ENSURE COMPLIANCE WITH NIH, CDC AND USDA BIOSAFETY STANDARDS, FURTHER ENABLING CUTTING-EDGE RESEARCH. THIS NEXT-GENERATION BSL-3 FACILITY WILL SERVE AS A REGIONAL HUB FOR COLLABORATION, LEVERAGING EXPERTISE FROM SEATTLE CHILDREN’S RESEARCH INSTITUTE, THE UNIVERSITY OF WASHINGTON, AND OTHER STAKEHOLDERS. BY APPLYING LESSONS FROM THE COVID-19 PANDEMIC AND EXPANDING RESEARCH CAPACITY FOR HIGH-PRIORITY PATHOGENS, THE FACILITY WILL STRENGTHEN PUBLIC HEALTH PREPAREDNESS, SUPPORT SUSTAINABLE INFRASTRUCTURE, AND BOLSTER THE SEATTLE AREA’S LEADERSHIP IN INFECTIOUS DISEASE RESEARCH. THE PROJECT DIRECTLY ALIGNS WITH FRED HUTCH’S MISSION TO ADVANCE GLOBAL HEALTH AND BIOMEDICAL INNOVATION BY PROVIDING CRITICAL INFRASTRUCTURE TO ADDRESS PATHOGENS WHICH CAUSE SEVERE DISEASE IN OUR IMMUNOCOMPROMISED TRANSPLANT PATIENTS AS WELL AS EMERGING INFECTIOUS DISEASE CHALLENGES. ITS CONSTRUCTION WILL POSITION FRED HUTCH AND ITS PARTNERS AS LEADERS IN COLLABORATIVE AND HIGH-IMPACT RESEARCH, DRIVING LONG-TERM SCIENTIFIC AND PUBLIC HEALTH ADVANCEMENTS.

NOVEL GENE EDITING APPROACHES FOR HEMOGLOBINOPATHIES

PHYSICAL ACTIVITY TO IMPROVE CV HEALTH IN OLDER WOMEN: A PRAGMATIC TRIAL - THIS IS A COMPETITIVE RENEWAL APPLICATION FOR THE WOMEN’S HEALTH INITIATIVE (WHI) STRONG & HEALTHY (WHISH) TRIAL. AMERICA’S 65-AND-OLDER POPULATION IS PROJECTED TO DOUBLE IN SIZE FROM 49 MILLION TODAY TO 95 MILLION BY 2060, WITH WOMEN FAR OUTNUMBERING MEN, PARTICULARLY AMONG ADULTS AGED 85-AND-OLDER. COMPELLING EVIDENCE SUPPORTS THE HYPOTHESIS THAT PHYSICAL ACTIVITY (PA) REDUCES CARDIOVASCULAR (CV) DISEASE (CVD), PRESERVES PHYSICAL FUNCTION (PF) AND PROMOTES OTHER ASPECTS OF CV HEALTH IN OLDER ADULTS. WHISH IS A LANDMARK, PRAGMATIC RANDOMIZED CONTROLLED TRIAL TESTING WHETHER A CENTRALIZED, PUBLIC HEALTH INTERVENTION DESIGNED TO INCREASE AND/OR MAINTAIN PA LEVELS AND REDUCE SEDENTARY BEHAVIOR WILL REDUCE MAJOR CVD (MI, STROKE, CV DEATH) IN OLDER WOMEN. USING A RANDOMIZED CONSENT DESIGN TO SIMULATE REAL-WORLD PROGRAMMATIC IMPLEMENTATION, WHISH RANDOMIZED 49,333 ELIGIBLE PARTICIPANTS IN THE WHI EXTENSION STUDY TO A BEHAVIORAL INTERVENTION VERSUS USUAL FOLLOW-UP IN MAY 2015. A PASSIVE CONSENT PROCESS IN THE INTERVENTION GROUP (N=24,663) RESULTED IN <4% OF WOMEN “OPTING OUT” OF RECEIVING INTERVENTION MATERIALS. WHISH DELIVERS A TARGETED, ADAPTIVE, INSTRUCTIONAL INTERVENTION, BASED ON 2008 AND 2018 DHHS PA GUIDELINES AND DESIGNED TO COMPLEMENT THE NATIONAL INSTITUTE ON AGING’S (NIA) GO4LIFE® CAMPAIGN, USING SEASONAL NEWSLETTERS, MANUALS, PEDOMETERS, RESISTANCE BANDS, TELEPHONE AND E-MAIL MOTIVATIONAL MESSAGES, AND A WEBSITE DESIGNED FOR OLDER WOMEN. THE INTERVENTION ADAPTS TO PARTICIPANT FEEDBACK FROM ANNUAL SURVEYS AND OTHER INPUT REGARDING ACTIVITY PREFERENCES AND IS CUSTOMIZED AND TARGETED TO THEIR CURRENT PF AND PA LEVELS. PRIMARY EFFECTIVENESS AND SAFETY OUTCOMES (CVD, FRACTURE) ARE EVALUATED USING INTENTION-TO-TREAT IN THE ENTIRE RANDOMIZED COHORT. BY THE END OF THE CURRENT GRANT PERIOD (FEB. 2020), 4 YEARS OF FOLLOW-UP WILL BE AVAILABLE. BASED ON WHISH OBSERVED CVD EVENT RATES, INTERVENTION EFFECTS ON PA AND SEDENTARY BEHAVIOR, AND NEW WHI DATA RELATING PA BEHAVIORS TO CVD ENDPOINTS, REVISED POWER CALCULATIONS SUGGEST WE WILL HAVE ONLY 65% POWER TO EVALUATE THE IMPACT OF THE WHISH INTERVENTION ON CVD EVENTS. WE ESTIMATE THAT 4 ADDITIONAL YEARS OF FOLLOW-UP (8 YEARS OVERALL) WILL YIELD 85-89% POWER TO PROVIDE A DEFINITIVE TEST OF THE PRIMARY WHISH HYPOTHESIS. THIS APPLICATION PROPOSES TO EXTEND THE WHISH INTERVENTION AND FOLLOW-UP OF OUTCOMES FOR 4 ADDITIONAL YEARS SO THAT THE TRIAL CAN REACH A DEFINITIVE CONCLUSION ON THE BENEFITS AND RISKS OF THE PA INTERVENTION. WE ALSO PROPOSE TO LEVERAGE DATA AND BIOSPECIMEN COLLECTIONS IN A PLANNED WHI EXTENSION STUDY HOME VISIT TO ENABLE EVALUATION OF KEY MARKERS OF HEALTHY CVD AGING INCLUDING PHYSICAL PERFORMANCE, SLEEP DURATION AND INSOMNIA SYMPTOMS, AND DEPRESSIVE SYMPTOMS. PILOT STUDIES WILL BE EXECUTED TO EXPLORE LONG-TERM EFFECTS OF THE WHISH INTERVENTION ON CHANGES IN ESTABLISHED AND NOVEL BIOMARKERS KNOWN OR POSTULATED TO BE INFLUENCED BY PA LEVELS AND INDICATIVE OF VARIOUS UNDERLYING MECHANISMS RELATED TO CVD AGING. THE OUTCOMES OF WHISH, WHETHER POSITIVE, NULL, OR ADVERSE, COULD HAVE IMMENSE TRANSLATIONAL IMPACT ON THE FUTURE OF PA DISSEMINATION PROGRAMS FOR HEALTHY CV AGING.

CANOE PARTNERSHIP: CANCER AWARENESS, NAVIGATION, OUTREACH, AND EQUITABLE INDIGENOUS HEALTH OUTCOMES - PROJECT SUMMARY/ABSTRACT THE CANOE PARTNERSHIP: CANCER AWARENESS, NAVIGATION, OUTREACH, AND EQUITABLE INDIGENOUS HEALTH OUTCOMES U19 COOPERATIVE AGREEMENT IS PROPOSED IN RESPONSE TO THE NEED TO IMPROVE CANCER OUTCOMES FOR AMERICAN INDIAN AND ALASKA NATIVE (AI/AN) COMMUNITIES NATIONALLY, WITH AN EMPHASIS ON THE WASHINGTON STATE (WA) CATCHMENT AREA OF THE FRED HUTCH/UNIVERSITY OF WASHINGTON/SEATTLE CHILDREN’S CANCER CONSORTIUM, A NATIONAL CANCER INSTITUTE (NCI) DESIGNATED COMPREHENSIVE CANCER CENTER. THE PROPOSED WORK BUILDS ON THE CONSORTIUM’S SUBSTANTIAL COMMUNITY ENGAGEMENT WITH TRIBES AND TRIBAL ORGANIZATIONS OVER THE PAST 22 YEARS, BEGINNING WITH THE SPIRIT OF EAGLES SPECIAL POPULATION NETWORK IN 2002, UP TO AND INCLUDING AN ONGOING R01 “ DIGITAL SMOKING CESSATION INTERVENTION FOR NATIONALLY-RECRUITED AMERICAN INDIANS AND ALASKA NATIVES: A FULL-SCALE RANDOMIZED CONTROLLED TRIAL ” (R01CA284687; PI: BRICKER) DISPARITIES IN CANCER OUTCOMES FOR THE AI/AN POPULATION ARE DUE TO MULTIPLE SOCIAL DETERMINANTS. THREE MAJOR SOURCES OF THESE DISPARITIES, AMENABLE TO INTERVENTION, ARE: 1) BEHAVIORS TO REDUCE CANCER RISK (E.G., SMOKING CESSATION), 2) ACCESS TO APPROPRIATE SCREENING BY WAY OF IMAGING TECHNOLOGIES (E.G., APPROPRIATE APPLICATION OF CHEST COMPUTED TOMOGRAPHY AND MAMMOGRAPHY) AND COLORECTAL CANCER (CRC) SCREENING PROCEDURES SUCH AS FECAL IMMUNOCHEMICAL TEST (FIT), AND COLONOSCOPY; AND 3) PRIMARY PREVENTION. WE PROPOSE A MULTIDIMENSIONAL APPROACH TO ADDRESSING THESE SOURCES OF DISPARATE CANCER OUTCOMES IN PARTNERSHIP WITH OUR TRIBAL AND COMMUNITY COLLABORATORS AT THE SOUTH PUGET INTERTRIBAL PLANNING AGENCY (REPRESENTING THE CHEHALIS, NISQUALLY, SKOKOMISH, SHOALWATER BAY, AND SQUAXIN ISLAND TRIBES) AND THE BLACK HILLS CENTER FOR AMERICAN INDIAN HEALTH (RAPID CITY, SD). TOGETHER, WE WILL USE COMMUNITY BASED PARTICIPATORY RESEARCH (CBPR) APPROACHES AND THE INDIGENOUS CANCER HEALTH EQUITY INITIATIVE MODEL TO EMPOWER AND ENGAGE TRIBES AND TRIBAL ORGANIZATIONS THROUGH OUR THREE RESEARCH PROJECTS. OUR OVERALL SPECIFIC AIMS ARE: 1) IMPROVE RATES OF CESSATION OF COMMERCIAL TOBACCO SMOKING AMONG A NATIONALLY RECRUITED SAMPLE OF AI/AN ADULTS (RESEARCH PROJECT 1); 2) IMPROVE RATES OF LUNG, COLORECTAL, AND BREAST CANCER SCREENINGS AMONG OUR TRIBAL PARTNER POPULATIONS IN THE CONSORTIUM’S CATCHMENT AREA (RESEARCH PROJECTS 2 & 3); 3)PREPARE THE NEXT GENERATION OF RESEARCHERS IN INDIGENOUS CANCER EQUITY AND PROVIDE THEM WITH RESOURCES TO OBTAIN PRELIMINARY DATA TO INFORM FUTURE CANCER EQUITY RESEARCH IN INDIAN COUNTRY (PILOT GRANT PROGRAM); AND 4) DEVELOP INFRASTRUCTURE TO SUPPORT EQUITABLE ENGAGEMENT OF TRIBAL PARTNERS AND INDIGENOUS FRAMEWORKS IN CANCER RESEARCH. (ADMINISTRATIVE AND COMMUNITY ENGAGEMENT CORES). THE OVERALL PUBLIC HEALTH IMPACT OF THE PROPOSED WORK WILL BE HIGH, GIVEN THE FOCUS ON SMOKING CESSATION, CANCER SCREENINGS AND VACCINATIONS THAT ALTOGETHER WILL PREVENT AND CONTROL CANCERS THAT ARE HIGHLY PREVALENT AND ARE RESPONSIBLE FOR A LARGE SHARE OF DISPARATE MORTALITY RATES AMONG INDIGENOUS POPULATIONS. THE PUBLIC HEALTH IMPACT OF THIS WORK WILL BE HIGH, GIVEN ITS FOCUS ON MODIFIABLE BEHAVIORS AND ON FUTURE GENERATIONS OF INDIGENOUS CANCER HEALTH EQUITY RESEARCHERS.

LIFE AND LONGEVITY AFTER CANCER (LILAC): THE WOMEN'S HEALTH INITIATIVE CANCER SURVIVOR COHORT

TRANSLATIONAL RESEARCH PROGRAM IN COLORECTAL CANCER DISPARITIES - PROJECT SUMMARY/ABSTRACT – OVERALL RACIAL AND ETHNIC DISPARITIES IN COLORECTAL CANCER (CRC) ARE PARTICULARLY PRONOUNCED IN AFRICAN AMERICAN AND ALASKA NATIVE PEOPLE. THESE DIFFERENCES CANNOT BE EXPLAINED BY ACCESS TO SCREENING AND HEALTH CARE ALONE, SUGGESTING UNDERLYING YET UNDERSTUDIED CONTRIBUTORS TO DISEASE ETIOLOGY, PROGRESSION, AND RESPONSE TO TREATMENT. ONGOING INNOVATIONS IN BIOTECHNOLOGY THAT ENABLE DETAILED EVALUATIONS OF THE UNDERPINNINGS OF TUMOR AND HOST MOLECULAR GENETICS AND GENOMIC BIOLOGY HAVE BEEN INADEQUATELY LEVERAGED TO ADDRESS THESE DISPARITIES. COLLECTIVELY, OUR OUTSTANDING TRANSDISCIPLINARY TEAM HAS THE EXPERTISE TO USE CUTTING-EDGE TECHNOLOGIES TO DRIVE INNOVATIVE TRANSLATIONAL CANCER DISPARITIES RESEARCH DIRECTLY FOCUSED ON DEVELOPING NOVEL PREVENTION, EARLY DETECTION, DIAGNOSIS, AND TREATMENT APPROACHES. TO ACHIEVE OUR OVERARCHING GOAL OF REDUCING PERSISTENT CRC DISPARITIES, PARTICULARLY THOSE PRESENT AMONG ALASKA NATIVE AND AFRICAN AMERICAN PEOPLE, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: AIM 1: IMPROVE RISK STRATIFIED SCREENING AND EARLY DETECTION OF CRC ACROSS RACIAL AND ETHNIC POPULATIONS BY DEVELOPING RISK PREDICTION MODELS THAT PERFORM EQUALLY WELL ACROSS RACIAL AND ETHNIC GROUPS. AIM 2: REDUCE RACIAL AND ETHNIC DISPARITIES IN CRC-SPECIFIC MORTALITY BY DISCOVERING AND VALIDATING NOVEL MOLECULAR AND BIOLOGICAL CHANGES RELATED TO RISK OF LETHAL CRC AND RESPONSE TO TREATMENT IN RACIALLY AND ETHNICALLY DIVERSE PATIENTS THAT CAN GUIDE SURVEILLANCE AND TREATMENT SELECTION FOR CRC SURVIVORS. AIM 3: DISCOVER NOVEL THERAPEUTIC TARGETS FOR CRC ACROSS RACIALLY AND ETHNICALLY DIVERSE POPULATIONS AND TEST POTENTIAL CLINICAL INTERVENTIONS AIMED AT REDUCING CRC DISPARITIES BY ADVANCING OUR UNDERSTANDING OF DIFFERENCES AND SIMILARITIES IN THE GENETIC, MOLECULAR, AND MICROBIAL CHARACTERISTICS OF CRC IN DIVERSE POPULATIONS AND TESTING THE EFFECTIVENESS OF NOVEL INTERVENTIONS IN CLINICAL TRIALS THAT ENROLL DIVERSE CRC PATIENTS. OUR WORLD- CLASS INVESTIGATOR TEAM HAS EXPERTISE IN BASIC SCIENCE, CLINICAL AND TRANSLATIONAL RESEARCH, MINORITY HEALTH, AND CANCER DISPARITIES. DURING THE P20 SPORE PLANNING PHASE WE HAVE BROUGHT TOGETHER A LARGE BIOREPOSITORY OF VARIOUS BIOSPECIMEN TYPES AND DETAILED CLINICAL DATA FROM A LARGE, RACIALLY AND ETHNICALLY DIVERSE CRC PATIENT POPULATION WITH EQUAL NUMBERS OF AFRICAN AMERICAN, ALASKA NATIVE, HISPANIC AND NON-HISPANIC WHITE PATIENTS, AND THROUGH OUR LONG-TERM LEADERSHIP IN GENETIC EPIDEMIOLOGY WE HAVE ACCESS TO THE WORLD'S LARGEST AND MOST RACIALLY AND ETHNICALLY DIVERSE CRC GERMLINE GENETIC DATA SET. UTILIZING THESE UNIQUE RESOURCES, OUR PROGRAM WILL CONDUCT FOUR TRANSLATIONAL PROJECTS SUPPORTED BY THREE ESSENTIAL CORES THAT WILL PROVIDE CENTRALIZED EXPERTISE IN: A) LEADERSHIP AND ADMINISTRATION, B) BIOSPECIMENS, PATHOLOGY AND MOLECULAR TECHNOLOGIES, AND C) BIOSTATISTICS AND BIOINFORMATICS. OUR CAREER ENHANCEMENT AND DEVELOPMENTAL RESEARCH PROGRAMS WILL ENSURE THAT WE RECRUIT TALENTED AND DIVERSE INVESTIGATORS AND DEVELOP A PIPELINE OF NOVEL TRANSLATIONAL CANCER DISPARITIES RESEARCH PROJECTS. THROUGH THIS INTEGRATED EFFORT WE ENVISION REALIZING OUR GOAL OF A SUSTAINED TRANSLATIONAL RESEARCH PROGRAM FOCUSED ON ELIMINATING CRC DISPARITIES AND MORE BROADLY REDUCING CRC-RELATED MORBIDITY AND MORTALITY.

CLINICAL SIGNIFICANCE OF MHC HAPLOTYPES IN HCT

STRATEGIES TO ENHANCE ADOPTIVE TRANSFER T CELL CLONES

MYOTONIC DYSTROPHY LOCUS CONTROL

MOLECULAR PATHOEPIDEMIOLOGY OF CONTRALATERAL BREAST CANCER

DECODING THE INTERACTIONS BETWEEN T CELL RECEPTORS AND PEPTIDE-MHC

STATISTICAL METHODS IN HIV VACCINE EFFICACY TRIALS

EARLY AND REINFECTION IN HIGH RISK WOMEN

TARGETING NRF2 FOR CANCER CHEMOPREVENTION

PROSTATE CANCER ACTIVE SURVEILLANCE STUDY (PASS) COHORT: INFRASTRUCTURE SUPPORT FOR CANCER RESEARCH

MECHANISMS OF TRANSCRIPTIONAL REGULATION AND TRANSCRIPTION FACTOR SPECIFICITY - SUMMARY PRECISE REGULATION OF TRANSCRIPTION IS REQUIRED FOR MANY CELLULAR PROCESSES AND MISREGULATION OF GENE EXPRESSION IS LINKED TO MANY HUMAN DISEASES. IN PRIOR WORK, GREAT PROGRESS HAS BEEN MADE IN IDENTIFYING IMPORTANT MECHANISMS AND PRINCIPLES OF TRANSCRIPTIONAL REGULATION. WITH THIS BACKGROUND, AND USING NEW TECHNOLOGIES AND APPROACHES, THIS IS AN EXCELLENT TIME TO TACKLE THE NEXT SET OF FUNDAMENTAL PROBLEMS IN GENE REGULATION THAT HAVE BEEN DIFFICULT TO ADDRESS IN PRIOR WORK. TWO RELATED AND IMPORTANT QUESTIONS IN THE TRANSCRIPTION FIELD ARE: WHAT ARE THE PRIMARY MECHANISMS OF GENE REGULATION BY SEQUENCE-SPECIFIC TRANSCRIPTION FACTORS? AND, HOW DO THESE FACTORS COOPERATE TO ORCHESTRATE TRANSCRIPTION OF CELLULAR GENES? TO ADDRESS THESE QUESTIONS, WE WILL FOCUS ON THREE AREAS INVOLVING TRANSCRIPTION FACTOR AND COACTIVATOR SPECIFICITY AND THE ACTIVATION MECHANISMS USED AT MANY GENES: (I) MECHANISMS LEADING TO THE GENOME-WIDE SPECIFICITIES OF THE COACTIVATORS TFIID AND SAGA. DIFFERENTIAL USE OF THESE COACTIVATORS DEFINES TWO FUNDAMENTAL GENE CLASSES THAT DICTATE THE MECHANISMS OF PREINITIATION COMPLEX (PIC) ASSEMBLY AND THE RESPONSE TO TRANSCRIPTION FACTORS AND CHROMATIN. (II) THE GENE-SPECIFIC FUNCTIONS OF THE COACTIVATOR MEDIATOR IN TRANSCRIPTIONAL REGULATION. AT LEAST TWO DISTINCT PATHWAYS ARE USED BY TRANSCRIPTION FACTORS TO MODULATE MEDIATOR FUNCTION THAT ARE TRANSCRIPTION FACTOR AND PROMOTER-SPECIFIC, BUT THE MOLECULAR BASIS OF THESE MECHANISMS IS NOT WELL UNDERSTOOD. (III) MECHANISMS OF TRANSCRIPTION ACTIVATOR SPECIFICITY AND FUNCTION. WE WILL BROADEN OUR CURRENT STUDIES ON THE FUNCTION OF ACIDIC ACTIVATION DOMAINS TO EXAMINE MECHANISMS USED BY OTHER WIDELY USED ACTIVATOR TYPES AND TO EXAMINE HOW TRANSCRIPTION FACTORS BOUND AT NATIVE UAS/ENHANCER ELEMENTS COOPERATE. TO ADDRESS THESE FUNDAMENTAL PROBLEMS, AS IN PAST WORK, WE WILL USE A COMBINATION OF METHODS AND TECHNOLOGIES THAT INCLUDE MOLECULAR, BIOCHEMICAL, GENOMIC, COMPUTATIONAL, AND STRUCTURAL APPROACHES. IN COMBINATION WITH OUR STRONG PRELIMINARY RESULTS, THESE NEW APPROACHES AND DIRECTIONS WILL REVEAL IMPORTANT CONSERVED MECHANISMS AND PRINCIPLES THAT ILLUSTRATE HOW TRANSCRIPTION FACTORS, COACTIVATORS, CHROMATIN, AND THE BASAL TRANSCRIPTION MACHINERY WORK TOGETHER TO MODULATE GENOME-WIDE TRANSCRIPTION.

THE ROLE AND MECHANISM OF ALTERNATIVE RNA SPLICE VARIANTS AND GENE FUSIONS AS DRIVERS OF CANCER - ABSTRACT MY LAB HAS BEEN THE LEADER IN THE FIELD OF MOUSE MODELING FOR BRAIN TUMORS OVER THE PAST 15 YEARS. WE HAVE DEVELOPED A SUITE OF GENETICALLY ENGINEERED MOUSE MODELS THAT ARE DEMONSTRABLY REPRESENTATIVE OF HUMAN GLIOMAS AND OTHER TUMOR TYPES. THESE MODELS HAVE BEEN USED TO INFORM TREATMENT OPTIONS FOR CLINICAL AGENTS, AND THIS NOW ENABLES US TO PROPOSE THESE MODELS ARE SUITABLE TESTBEDS FOR TESTING POTENTIAL MAJOR IMPROVEMENTS TO HOW THESE DISEASES ARE TREATED. WE HAVE THREE PROJECTS. 1) WE ARE UNDERSTANDING THE CENTRAL ROLE OF SPECIFIC SPLICE VARIANTS OF TRKB IN EMBRYONIC DEVELOPMENT AND ONCOGENESIS THROUGHOUT THE BODY. THE RCAS MODELING SYSTEM HAS BEEN USED HERE TO SHOW THAT FORCED EXPRESSION OF THE EMBRYONIC SPLICE VARIANT IN ADULT TISSUES LEADS TO CANCER FORMATION BROADLY. IN THIS PROJECT WE WILL INVESTIGATE THE MECHANISMS OF ONCOGENESIS FOR THIS SPLICE VARIANT AND DETERMINE IF IT COULD BE A GOOD DIAGNOSTIC OR THERAPEUTIC TARGET. 2) WE ARE NOW USING THE MODELING SYSTEM DEVELOPED FOR GLIOMA TO ADDRESS THE BIOLOGY OF RARE TUMORS DRIVEN BY GENE FUSIONS. IN THIS GRANT WE PROPOSE TO UNDERSTAND THE MECHANISMS OF ONCOGENESIS FOR YAP1 GENE FUSIONS IN THE RARE TUMORS EPENDYMOMA, POROCARCINOMA AND AGGRESSIVE MENINGIOMA (ALL FOR WHICH WE HAVE YAP1 GENE FUSION DRIVEN MODELS CURRENTLY). 3) AND, WE WILL USE THESE MOUSE MODELS TO STUDY THERAPEUTIC RESPONSE AND IDENTIFY THERAPEUTIC STRATEGIES FOR THESE FUSION DRIVEN TUMORS INCLUDING IDENTIFICATION OF FDA APPROVED DRUGS THAT WOULD INTERVENE DOWNSTREAM OF THE ACTION OF THE GENE FUSION.

HUMAN PAPILLOMAVIRUS AND POLYOMAVIRUS ASSOCIATED MALIGNANCIES.

PREVENTING GVHD BY INHIBITION OF ALLOANTIGEN PRESENTATION IN THE GUT

MODELING PRECISION INTERVENTIONS FOR PROSTATE CANCER CONTROL

THE MYC TRANSCRIPTION FACTOR NETWORK AND THE PATH TO CANCER

DEVELOPMENT OF INNOVATIVE RESOURCES TO ADVANCE MDS RESEARCH - (PLEASE KEEP IN WORD, DO NOT PDF) ENTER THE TEXT HERE THAT IS THE NEW ABSTRACT INFORMATION FOR YOUR APPLICATION. THIS SECTION MUST BE NO LONGER THAN 30 LINES OF TEXT. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC STEM CELL DISEASES, RESULTING PREDOMINANTLY FROM ACQUISITION OF SOMATIC MUTATIONS IN HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPC), WHICH CAUSE INEFFECTIVE HEMATOPOIESIS, CYTOPENIAS, AND POSSIBLE PROGRESSION TO LEUKEMIA. THE ACQUIRED AND GERMLINE GENOMIC ALTERATIONS IMPACT GENES IN DIVERSE BIOLOGICAL PATHWAYS, GLOBALLY MODIFYING GENE EXPRESSION OR GENOMIC INTEGRITY, INCLUDING EPIGENETIC REGULATION, RNA SPLICING, DNA REPAIR, AND TRANSCRIPTION. AT PRESENT A COMPREHENSIVE UNDERSTANDING OF BIOLOGY PROMOTING THE DEVELOPMENT, PROGRESSION AND MDS RESISTANCE TO THERAPY IS LACKING. ONE MAJOR OBSTACLE FOR ADVANCING OUR UNDERSTANDING OF MDS BIOLOGY HAS BEEN THE PAUCITY OF INFORMATIVE DISEASE MODELS. IN THIS PROPOSAL WE WILL DEVELOP CRITICAL RESOURCES FOR INVESTIGATORS PURSUING MDS RESEARCH INCLUDING A) KEY INFORMATION, A ‘ROADMAP’, OF THE MUTATIONAL ARCHITECTURE OF MDS; B) A REPOSITORY OF INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED MDS HSPC CELL LINES; C) A COMPREHENSIVE RESOURCE CONTAINING MOLECULARLY-DEFINED DRUG SENSITIVITIES FOR MDS LINKED TO KEY CLINICAL DATA; D) A CATALOGUE OF NOVEL ANTIGENIC TARGETS AND MODELS TO ADVANCE ADOPTIVE T CELL IMMUNOTHERAPY FOR MDS PATIENTS. THIS RESEARCH WILL ENABLE A MORE RATIONAL APPROACH TO DEVELOPING SPECIFIC TREATMENT STRATEGIES AND PREDICTING PATIENT OUTCOMES. THE PROPOSED STUDIES WILL USE A UNIQUE, LARGE COHORT OF MDS MARROW SAMPLES FROM A DIVERSE POPULATION OF PATIENTS WITH COMPREHENSIVE CLINICAL AND GENOMIC ANNOTATIONS. IN AIM 1, WE WILL REPROGRAM MDS CELLS INTO IPSC, GENERATING A PANEL OF CELL LINES BASED ON PATIENT GENOTYPES, AND EMPLOY IPSCS AND MOLECULAR DATA TO RECONSTRUCT CLONAL HISTORIES AND ASSESS THE FUNCTIONAL CONSEQUENCE OF MUTATION ORDER. AIM 2 WILL FOCUS ON THE FUNCTIONAL CONSEQUENCES OF MDS MUTATIONS, USING A PLATFORM THAT INTEGRATES MUTATIONS, GENE EXPRESSION, AND HIGH-THROUGHPUT SENSITIVITY SCREENS EMPLOYING A LARGE CUSTOM PANEL OF DRUGS, TARGETED INHIBITORS, AND COMBINATIONS RATIONALLY DESIGNED FOR THIS DISEASE. IN AIM 3, WE WILL USE MDS PRIMARY SAMPLES AND IPSC LINES TO PERFORM PROTEOMIC ANALYSIS, LINKING MUTATIONAL AND PROTEOMIC DATA TO DISCOVER POTENTIAL NEW TARGET ANTIGENS FOR T CELL IMMUNOTHERAPIES, PERMISSIVE FOR NORMAL HEMATOPOIESIS WHILE ERADICATING MDS PROGENITORS. OUR PROPOSED COLLABORATIVE AND SYNERGISTIC STUDIES WILL ADVANCE OUR UNDERSTANDING OF THE PATH FROM MUTATIONAL PERTURBATION TO FUNCTIONAL CONSEQUENCES IN MDS AND CREATE A LIBRARY OF RESOURCES THAT CAN BE SHARED WITH THE GREATER MDS SCIENTIFIC COMMUNITY TO ENABLE FURTHER PROGRESS TOWARD IMPROVED TREATMENT STRATEGIES.

BIOLOGY AND THERAPY OF C11ORF95-RELA FUSION-DRIVEN EPENDYMOMA

CLINICAL TRANSLATION OF A NEXGEN PLATFORM FOR QUANTIFYING PROTEIN NETWORKS IN HUMAN BIOSPECIMENS

CLONAL HEMATOPOIESIS IN THE WOMENS HEALTH INITIATIVE MEMORY STUDY

DEFINING BCR EVOLUTION DURING IMMUNIZATION

DETERMINANTS OF RESPONSE TO CANCER IMMUNOTHERAPY - PROJECT SUMMARY/ABSTRACT WHILE IMMUNOTHERAPY IS TRANSFORMING CANCER TREATMENT, THE MAJORITY OF PATIENTS DO NOT ACHIEVE DURABLE RESPONSES. WE HAVE BEEN STUDYING RESPONSE AND RESISTANCE TO DIFFERENT IMMUNE CHECKPOINT INHIBITORS AND ARE NOW POISED TO PROPOSE MECHANISTIC STUDIES AIMED AT PROVIDING AN UNDERSTANDING OF THE IMMUNE STATES AND PATHWAYS THAT MEDIATE OR INHIBIT RESPONSE TO IMMUNE CHECKPOINT BLOCKADE. USING HIGH-DIMENSIONAL UNBIASED SINGLE-CELL RNA-SEQ (SCRNASEQ), WE CAN IDENTIFY BOTH CANONICAL AND NON-CANONICAL IMMUNE EFFECTORS THAT CAN MEDIATE ANTI-TUMOR RESPONSES. WE BELIEVE THAT NON-CANONICAL EFFECTORS SUCH AS CYTOTOXIC CD4 T CELLS, WHICH WE HAVE RECENTLY DESCRIBED, ARE NOT EFFECTIVELY TRIGGERED BY OUR CURRENT TREATMENTS. USING THE SAME SINGLE-CELL APPROACHES, WE CAN IDENTIFY BOTH KNOWN AND NOVEL CELL TYPES IN CANCER PATIENTS THAT CAN MEDIATE IMMUNE SUPPRESSION. IN OUR FIRST OBJECTIVE, WE WILL DETERMINE WHETHER COMBINATION IMMUNOTHERAPIES THAT INCLUDE DRUG(S) TARGETING SPECIFIC IMMUNOSUPPRESSIVE CELLS CAN ENHANCE THE FUNCTION OF THESE CYTOTOXIC CD4+ T CELLS. BY LEVERAGING NEOADJUVANT CLINICAL TRIALS WHERE PATIENTS RECEIVE IMMUNOTHERAPY PRIOR TO SURGERY, WE WILL USE SINGLE CELL GENOMICS AND PROTEOMICS TO DEFINE WHETHER THESE COMBINATIONS CAN 1) TARGET THE DESIRED IMMUNOSUPPRESSIVE MECHANISMS, AND 2) ENHANCE CANONICAL AND/OR NON-CANONICAL EFFECTORS WITHIN THE RESECTED TUMORS. WE WILL ALSO USE THIS APPROACH TO DETERMINE WHETHER WE CAN MAP THESE SPECIFIC CELL STATES INTO THE CIRCULATING COMPARTMENT. THE SECOND OBJECTIVE IS BASED ON A LONGSTANDING INTEREST IN OUR GROUP TO DEFINE THE DYNAMICS OF ANTIGEN-SPECIFIC RESPONSES. USING SINGLE-CELL T CELL RECEPTOR SEQUENCING, WE CAN IDENTIFY EXPANDED T CELL CLONES AS WELL AS FOLLOW THEIR LOCALIZATION. IN ADDITION TO UNDERSTANDING HOW IMMUNOTHERAPY COMBINATIONS INDUCE AND MODULATE SPECIFIC T CELL CLONOTYPES WITHIN THE TUMOR, WE CAN DETERMINE HOW IMMUNOTHERAPIES CAN INDUCE FUNCTIONAL PLASTICITY TO DESIRED OR UNDESIRED STATES. THE THIRD OBJECTIVE BUILDS ON OUR 20 YEAR EXPERIENCE USING MOUSE MODELS TO DISSECT MECHANISMS UNDERLYING RESPONSE OR RESISTANCE TO IMMUNOTHERAPY. WE WILL DETERMINE THE FUNCTIONAL SIGNIFICANCE OF NON-CANONICAL IMMUNE EFFECTORS USING DEPLETION AND KNOCK-OUT STRATEGIES. WE WILL ALSO DETERMINE HOW COMBINATION IMMUNOTHERAPIES CAN ELICIT BOTH EFFECTIVE OR INEFFECTIVE ANTI- TUMOR IMMUNE RESPONSES, THEREBY GUIDING THE DESIGN OF FUTURE CLINICAL TRIALS. IN CONCLUSION, OUR PROPOSAL IS BASED ON HYPOTHESIS-DRIVEN BENCH-TO-BEDSIDE AND BEDSIDE-TO-BENCH MECHANISTIC STUDIES WITH THE GOAL OF ADVANCING CANCER IMMUNOTHERAPY. WITH OUR DEEP EXPERTISE IN THIS FIELD, EXPERIENCE LEADING MULTI-DISCIPLINARY TEAMS FOCUSED ON TRANSLATIONAL RESEARCH, AND A RICH NETWORK OF BASIC SCIENCE AND CLINICAL COLLABORATORS; WE ARE UNIQUELY POSITIONED TO SUCCEED IN THE RESEARCH PLAN OUTLINED IN THIS PROPOSAL.

CONSORTIUM ON TRANSLATIONAL RESEARCH IN EARLY DETECTION OF LIVER CANCER: DATA MANAGEMENT AND COORDINATING CENTER (DMCC)

FECAL MICROBIOTA TRANSPLANTATION AND FIBER FOR THE TREATMENT OF GRAFT-VERSUS-HOST DISEASE AFTER HEMATOPOIETIC CELL TRANSPLANTATION - PROJECT SUMMARY ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (HCT) IS A LIFE-SAVING TREATMENT FOR HEMATOLOGIC MALIGNANCIES THAT REMAINS THE TREATMENT OF CHOICE FOR CONDITIONS SUCH AS HIGH RISK LEUKEMIAS. GRAFT-VERSUS-HOST DISEASE (GVHD) IS A COMMON COMPLICATION OF ALLOGENEIC HCT, AFFECTING >50% OF PATIENTS. DESPITE DECADES OF PROGRESS IN TRANSPLANTATION BIOLOGY, WE HAVE LIMITED TREATMENT OPTIONS FOR THIS COMMON CONDITION ASSOCIATED WITH SUBSTANTIAL MORBIDITY AND MORTALITY. GVHD HAS BEEN LINKED TO LOSS OF GUT BACTERIAL DIVERSITY AND CHANGES IN BACTERIAL COMMUNITY COMPOSITION AFTER HCT. THERE IS COMPELLING EVIDENCE FROM ANTIBIOTIC INTERVENTION STUDIES IN ANIMALS AND HUMANS THAT MANIPULATION OF THE GUT MICROBIOTA INFLUENCES SUBSEQUENT RISK OF GVHD. OBSERVATIONAL STUDIES OF FECAL MICROBIOTA TRANSPLANTATION (FMT) HAVE GENERATED INTRIGUING DATA SUGGESTING THAT FMT IS A PROMISING INTERVENTION FOR SAFELY REPOPULATING THE GUT MICROBIOTA IN HCT RECIPIENTS WITH GVHD. HOWEVER, THE EFFECT OF FMT DELIVERY ROUTE ON MICROBIAL RECONSTITUTION HAS NOT BEEN INVESTIGATED IN A CONTROLLED MANNER, THE ROLE OF DIETARY SUPPLEMENTATION ON MAINTAINING A BENEFICIAL GUT MICROBIOTA AFTER FMT REMAINS UNEXPLORED IN THIS POPULATION, AND THERE IS LIMITED INSIGHT INTO MECHANISMS FOR HOW THE MICROBIOTA MAY IMPACT CLINICAL OUTCOMES AFTER FMT. FOR EXAMPLE, ADMINISTERING FMT VIA ORAL CAPSULES MAY SEED A LARGER AREA OF THE INTESTINAL TRACT YIELDING MORE DURABLE CHANGES IN GUT MICROBIAL COLONIZATION, BUT CONVERSELY COULD LEAD TO LOSS OF FUNCTIONALLY IMPORTANT BACTERIAL SPECIES THROUGH KILLING BY GASTRIC ACID AND BILE SALTS IN THE UPPER TRACT. SIMILARLY, COLONIZATION EFFICIENCY MAY BE ENHANCED BY PROVIDING BACTERIA WITH KEY NUTRIENTS SUCH AS DIETARY FIBER. IN ADDITION, DIETARY FIBER IS A SUBSTRATE FOR BACTERIAL PRODUCTION OF SHORT CHAIN FATTY ACIDS SUCH AS BUTYRATE LINKED TO IMMUNE MODULATION AND INTESTINAL HEALTH. IT IS UNKNOWN IF DIETARY FIBER SUPPLEMENTATION ENHANCES MICROBIOLOGICAL ENGRAFTMENT AFTER FMT IN THESE PATIENTS OR FOSTERS A METABOLIC ENVIRONMENT THAT PROMOTES HEALING AFTER HCT RELATED GUT INJURY. THERE ARE NO PUBLISHED RANDOMIZED CONTROLLED TRIALS OF FMT FOR TREATMENT OF GVHD. OUR PROPOSED F2 STUDY (FMT X FIBER) IN PATIENTS WITH GUT GVHD WILL INVESTIGATE HOW ROUTE OF FMT (ORAL CAPSULE, UPPER VS. COLONIC INSTILLATION, LOWER) AND DIETARY FIBER SUPPLEMENTATION INFLUENCE RECONSTITUTION OF A BENEFICIAL MICROBIOTA. THIS STUDY WILL FEATURE FREQUENT STOOL SAMPLING, ROBUST ANALYSIS OF BACTERIAL COMMUNITY COMPOSITION AND METAGENOMIC CONTENT IN STOOL, EVALUATION OF THE IMPACT OF THE INTERVENTIONS ON RECOVERY OF T-CELL SUBSETS IN BLOOD WITH KNOWN ASSOCIATIONS WITH GVHD, ASSESSMENT OF METABOLITES SUCH AS SHORT CHAIN FATTY ACIDS PRODUCED BY THE GUT MICROBIOTA THAT MAY AMELIORATE GVHD, AND FOLLOW-UP TO ASSESS RESOLUTION OF GVHD SYMPTOMS, STAGE, AND GRADE. THESE IN-DEPTH LONGITUDINAL MICROBIAL, METABOLIC, NUTRITIONAL, IMMUNOLOGICAL, AND CLINICAL DATA WILL ALLOW A MUCH-NEEDED, MECHANISTIC INVESTIGATION OF HOW A BENEFICIAL GUT MICROBIOME CAN BE OPTIMALLY RESTORED AND MAINTAINED THROUGH FMT FOR TREATMENT OF GVHD.

COORDINATING CENTER FOR POPULATION-BASED RESEARCH TO OPTIMIZE CANCER SCREENING (PROSPR) (U24)

IMMUNO AND EPIGENETICS OF HEMATOPOIETIC CELL TRANSPLANTATION

PROTEOGENOMIC STUDIES TO UNDERSTAND MECHANISMS AND DRIVERS OF RESISTANCE TO IMMUNOTHERAPIES - PROJECT SUMMARY/ABSTRACT MELANOMA IS THE DEADLIEST FORM OF SKIN CANCER. ITS INCIDENCE IS ON THE RISE WITH 106,000 NEW CASES EXPECTED IN THE U.S. IN 2021. IMMUNE CHECKPOINT INHIBITORS (ICIS) HAVE REVOLUTIONIZED THE TREATMENT OF EARLY AND ADVANCED MELANOMA, WITH CONCURRENT ANTI-CTLA-4 AND ANTI-PD-1 MONOCLONAL ANTIBODIES DEMONSTRATING A RESPONSE IN ~50% OF PATIENTS, INCLUDING HIGHLY DURABLE RESPONSES. UNFORTUNATELY, THERE ARE NO ADEQUATE BIOMARKERS TO PREDICT RESPONSE TO SINGLE AGENT OR COMBINATION ICI, AND DUAL CHECKPOINT BLOCKADE IS ASSOCIATED WITH SIGNIFICANT GRADE 3/4 IMMUNE-RELATED ADVERSE EVENTS (IRAES) IN ~55% OF PATIENTS. THE GOALS OF OUR PTRC ARE DESIGNED TO ADDRESS TWO UNMET CLINICAL NEEDS: (I) IMPROVE OUR UNDERSTANDING OF MECHANISMS OF RESISTANCE TO ICIS TO DESIGN MORE EFFECTIVE IMMUNOTHERAPIES AND COMBINATIONS, AND (II) IDENTIFY POTENTIAL BIOMARKERS TO SELECT PATIENTS APPROPRIATELY FOR SINGLE AGENT VS COMBINATION IMMUNOTHERAPIES AND TO PREDICT AND MONITOR IRAES. IN OUR PRECLINICAL ARM, WE WILL PERFORM INTEGRATED PROTEOGENOMIC ANALYSIS OF CLINICALLY ANNOTATED, PRE-TREATMENT BIOPSIES FROM MELANOMA PATIENTS WHO RECEIVED ICI. THE DATA WILL BE ANALYZED IN THE CONTEXT OF CLINICAL ANNOTATIONS TO REFINE AN EXISTING SIGNATURE OF MELANOMA ICI RESPONSE IDENTIFIED BY OUR TEAM AND TO FURTHER ELUCIDATE MECHANISMS OF ICI RESPONSE/RESISTANCE AND SIGNATURES ASSOCIATED WITH IRAES. IN OUR CLINICAL ARM, WE WILL ANALYZE CLINICAL TRIAL BIOSPECIMENS USING MRM-BASED ASSAYS TO CONFIRM & EXTEND FINDINGS GENERATED IN THE PRECLINICAL ARM.

REGULATION OF CHROMOSOME SEGREGATION

PCPT AND SELECT COHORTS: CORE INFRASTRUCTURE SUPPORT FOR CANCER RESEARCH

PEDIARIC ONCOLOGY RESEARCH TRAINING PROGRAM

URBAN NATIVE ELDERS (URBANE2): RISK AND PROTECTIVE FACTORS FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS – LONGITUDINAL FOLLOW-UP - PROJECT SUMMARY/ABSTRACT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) DISPROPORTIONATELY AFFECT AMERICAN INDIAN AND ALASKA NATIVE (AI/AN) ELDERS, YET AI/AN ELDERS REMAIN LARGELY ABSENT FROM DEMENTIA RESEARCH AND NATIONAL COHORTS. MOST AI/AN PEOPLE LIVE IN URBAN AREAS WHERE RISK, RESILIENCE, AND HEALTHCARE ACCESS DIFFER MARKEDLY, BUT ALMOST NO ADRD STUDIES HAVE INCLUDED THIS POPULATION. TO ADDRESS THIS GAP, OUR TEAM LAUNCHED THE URBAN NATIVE ELDERS (URBANE) STUDY, WHICH SUCCESSFULLY ENROLLED 1,001 PARTICIPANTS ACROSS FIVE CITIES, DEMONSTRATED FEASIBILITY OF NEUROIMAGING AND COGNITIVE TESTING, AND REVEALED DISTINCT RISK AND PROTECTIVE PROFILES. BUILDING DIRECTLY ON THIS FOUNDATION, URBANE 2 WILL RE-ENGAGE THE ORIGINAL COHORT AND EXPAND THE TOTAL SAMPLE TO 1,350 AI/AN MEN AND WOMEN AGED 55 AND OLDER FROM SEATTLE, WA; ANCHORAGE, AK; SAN BERNARDINO, CA; PHOENIX, AZ; AND OKLAHOMA CITY, OK. UNLIKE URBANE 1, THIS FOLLOW-UP STUDY WILL INCLUDE LONGITUDINAL FOLLOW-UP TO CAPTURE TRAJECTORIES OF COGNITIVE CHANGE AND RESILIENCE OVER TIME. AIM 1: WE WILL ESTIMATE THE PREVALENCE OF MILD COGNITIVE IMPAIRMENT (MCI) AND DEMENTIA, AS WELL AS UNDERLYING ETIOLOGIC CONDITIONS, THROUGH BIOMARKER-INFORMED CLINICAL PROFILING AND REPEATED COGNITIVE ASSESSMENTS. WE EXPECT LONGITUDINAL DATA TO REVEAL MORE PROBABLE ADRD CASES THAN CROSS-SECTIONAL ESTIMATES. AIM 2: WE WILL QUANTIFY THE CONTRIBUTIONS OF MRI-DEFINED VASCULAR BRAIN INJURY (VBI), WHITE MATTER INTEGRITY, AND RESTING-STATE FUNCTIONAL CONNECTIVITY TO CORTICAL AND HIPPOCAMPAL VOLUMETRIC CHANGES AND MARKERS OF GLYMPHATIC FUNCTION. WE ANTICIPATE THAT VBI, REDUCED INTEGRITY, AND DECREASED CONNECTIVITY WILL BE ASSOCIATED WITH CORTICAL VOLUME LOSS AND POOR GLYMPHATIC FUNCTION. AIM 3: WE WILL DESCRIBE ASSOCIATIONS BETWEEN SLEEP QUALITY AND PHYSICAL ACTIVITY WITH BRAIN VOLUME, GLYMPHATIC FUNCTION, AND COGNITIVE DECLINE OR RESILIENCE. WE HYPOTHESIZE THAT BETTER SLEEP AND HIGHER ACTIVITY WILL CORRELATE WITH LESS ATROPHY AND GREATER COGNITIVE RESERVE. AIM 4: WE WILL EVALUATE THE RELATIONSHIP OF SEX WITH AT(N) BIOMARKERS, PREVALENCE OF MCI, PROBABLE ADRD, AND RELATED RISK AND PROTECTIVE FACTORS. URBANE 2 IS INNOVATIVE IN ITS INTEGRATION OF ADVANCED MRI, BIOMARKER PROFILING, SLEEP AND PHYSICAL ACTIVITY MEASURES, AND LONGITUDINAL COGNITIVE ASSESSMENT IN AN EXCLUSIVELY URBAN AI/AN ELDER COHORT. THE STUDY WILL GENERATE THE FIRST COMPREHENSIVE, GENERALIZABLE ESTIMATES OF ADRD AND VBI IN THIS POPULATION, CLARIFY MODIFIABLE AND NON-MODIFIABLE RISK AND RESILIENCE FACTORS, AND ESTABLISH A COHORT FOR FUTURE LONGITUDINAL AND INTERVENTIONAL STUDIES. FINDINGS WILL HAVE IMMEDIATE IMPLICATIONS FOR CLINICAL CARE AND COMMUNITY-BASED PREVENTION, WHILE ADVANCING EXCELLENCE IN DEMENTIA SCIENCE AND STRENGTHENING PARTNERSHIPS WITH NATIVE COMMUNITIES NATIONWIDE.

DEFINING HUMAN CORRELATES OF SUPER-EVASIVE DISSEMINATED TUMOR CELLS, THEIR PATHOLOGICAL RELEVANCE AND HOW TO ERADICATE THEM

GENETIC CONFLICT SHAPES CENTROMERES AND HETEROCHROMATIN

CHROMOSOME METABOLISM AND CANCER TRAINING GRANT

INFLAMMATION-DRIVEN T CELL RESPONSES AND THEIR DICHOTOMOUS EFFECT ON HOST IMMUNITY

CHARACTERIZING THE BROAD ANTIBODY RESPONSE TO HIV SUPERINFECTION

STATISTICS AND DATA MANAGEMENT CENTER (SDMC) FOR THE NCI CANCER SCREENING RESEARCH NETWORK (CSRN) - MULTI-CANCER DETECTION ASSAYS OFFER NEW OPPORTUNITIES TO SCREEN FOR MANY DIFFERENT CANCERS THAT CURRENTLY HAVE LIMITED OPTIONS FOR EARLY DETECTION. THE CANCER SCREENING RESEARCH NETWORK (CSRN) WILL CONDUCT DEFINITIVE CLINICAL TRIALS AND STUDIES TO EVALUATE THESE ASSAYS. DESIGN AND IMPLEMENTATION OF SCREENING TRIALS INVOLVE MANY CHALLENGES. CANCER INCIDENCE AND DEATH ARE RARE EVENTS IN AN AVERAGE RISK POPULATION.TRIAL DESIGNS MUST BALANCE SCREENING FREQUENCY, TRIAL DURATION, AND SAMPLE SIZE TO ACHIEVE TRIAL OBJECTIVES IN A COST-EFFICIENT MANNER. IMPLEMENTATION MUST ANTICIPATE ISSUES SUCH AS NON-ADHERENCE, NON-COMPLIANCE, AND CONTAMINATION. ANALYSIS MUST ACCOMMODATE THE DESIGN WHILE ADAPTING TO THE CIRCUMSTANCES OF IMPLEMENTATION. THE STATISTICS AND DATA MANAGEMENT CENTER (SDMC) OF THE CSRN WILL OFFER A RIGOROUS SYSTEM FOR CSRN TRIAL DESIGN, MANAGEMENT AND ANALYSIS SO THAT THE INFORMATION GENERATED BY CSRN TRIALS FORMS A SOUND BASIS FOR NATIONAL CANCER SCREENING POLICY. OUR TEAM BRINGS TOGETHER STATISTICAL LEADERS AND CLINICAL TRIAL MANAGEMENT EXPERTS WITH EXPERIENCE IN MAJOR CLINICAL TRIALS NETWORKS, INCLUDING THE WOMEN’S HEALTH INITIATIVE CLINICAL COORDINATING CENTER, THE SWOG STATISTICS AND DATA MANAGEMENT CENTER AND THE EARLY DETECTION RESEARCH NETWORK DATA MANAGEMENT AND COORDINATING CENTER. WE HAVE EXPERTLY DESIGNED, IMPLEMENTED, ANALYZED AND REPORTED CANCER SCREENING, PREVENTION, AND TREATMENT TRIALS. THIS WORK HAS REQUIRED DEVELOPING PROCEDURES AND PROCESSES FOR EXPERT EXECUTION OF TRIALS AND PRODUCTION OF RELIABLE RESULTS. IT HAS NECESSITATED CREATING CLOSE COLLABORATIONS WITH CLINICIANS, SCIENTISTS, PATIENT ADVOCATES, AND SUBJECT MATTER EXPERTS. AND, PARTICULARLY IN THE CASE OF SCREENING TRIALS, IT HAS INSPIRED DEVELOPMENT OF NOVEL STATISTICAL METHODS THAT HAVE BECOME ESTABLISHED IN THE FIELD. OUR GOAL IS TO PROMOTE EXCELLENCE IN ALL ASPECTS OF STATISTICAL AND DATA MANAGEMENT FOR THE CSRN. TO ADDRESS THE CRITICAL QUESTIONS REGARDING POTENTIAL BENEFITS AND RISKS OF NEW CANCER SCREENING METHODOLOGIES, THE CSRN CLINICAL TRIALS MUST BE DESIGNED AND IMPLEMENTED WITH GREAT INTEGRITY AND EFFICIENCY TO PRODUCE THE MOST KNOWLEDGE POSSIBLE WITHIN REALISTIC CONSTRAINTS OF TIME AND RESOURCES. TO ATTAIN THESE GOALS, THE SDMC FOR THE CSRN HAS FOUR SPECIFIC AIMS: (1) INTEGRATE THE SDMC WITH THE OTHER CSRN COMPONENTS. (2) PROVIDE RIGOROUS AND HIGH-QUALITY DESIGNS AND ANALYSIS FOR CSRN STUDIES. (3) BUILD A STATE-OF-THE-ART DATA SYSTEM TO ENSURE DATA QUALITY AND INTEGRITY FOR CSRN TRIALS. (4) DEVELOP STATISTICAL AND DATA MANAGEMENT APPROACHES TO A LARGE CSRN SCREENING CLINICAL TRIAL THAT WOULD BUILD UPON THE VANGUARD STUDY. MCD TESTING REPRESENTS A POTENTIAL PARADIGM SHIFT FOR CANCER EARLY DETECTION. SUCCESSFUL EXECUTION OF THESE AIMS WILL ENSURE THAT THE CSRN PRODUCES VALID AND RELIABLE QUANTITATIVE RESULTS CONCERNING THE EFFICACY AND BENEFIT-HARM TRADEOFFS OF CANDIDATE PRODUCTS TO SUPPORT EVIDENCE-BASED POLICIES CONCERNING THEIR USE.

SEATTLE DIETARY BIOMARKER DEVELOPMENT CENTER

IMMUNOPROTECTIVE PROPERTIES OF TISSUE-RESIDENT MEMORY T CELLS IN MICE AND HUMANS WITHIN MUCOSAL SITES

MODELING AND ANALYTICS FOR CANCER DIAGNOSTICS: TRAVERSING THE DATA-EVIDENCE DIVIDE - THE FIELD OF CANCER DIAGNOSTICS IS IN A RAPIDLY EXPANDING GROWTH PHASE THAT GOES HAND IN GLOVE WITH THE PRECISION MEDICINE REVOLUTION. HOWEVER, THE RAPID PACE AT WHICH NEW TECHNOLOGIES ARE ENTERING THE MARKETPLACE MAKES RIGOROUS EVALUATION VIA CONTROLLED STUDIES INFEASIBLE FOR ALL BUT A RELATIVE FEW. THIS MEANS THAT WHILE WE TYPICALLY HAVE SOME DATA ABOUT DIAGNOSTIC TEST PERFORMANCE, WE FREQUENTLY LACK EVIDENCE REGARDING THE OUTCOMES THAT DRIVE CLINICAL AND POLICY DECISIONS. THE RESEARCH PROGRAM OUTLINED IN THIS APPLICATION WILL TACKLE THIS DATA- EVIDENCE DIVIDE USING THE TOOLS OF MODELING AND ANALYTICS. MODELING IS AN INCREASINGLY ACCEPTED DISCIPLINE FOR INTEGRATING KNOWLEDGE ABOUT THE PROCESS BY WHICH DIAGNOSTIC PERFORMANCE DRIVES OUTCOMES. ANALYTICS IS THE USE OF STATISTICAL LEARNING TECHNIQUES TO FILL IN THE KNOWLEDGE GAPS AND TO PROPAGATE UNCERTAINTY FROM MODEL INPUTS TO OUTCOMES. THE PRINCIPAL INVESTIGATOR HAS BUILT A LEADING RESEARCH PROGRAM IN MODELING AND ANALYTICS FOR EVIDENCE GENERATION IN CANCER POLICY. AMONG MANY METHODOLOGIC AND SUBSTANTIVE CONTRIBUTIONS, HER WORK HAS INFORMED PROSTATE CANCER SCREENING GUIDELINES FROM NATIONAL POLICY PANELS, ESTABLISHED BEST PRACTICES FOR ESTIMATION OF OVERDIAGNOSIS, AND PRODUCED SPECIFIC DIRECTIONS FOR SCREENING HIGH-RISK POPULATIONS INCLUDING BLACK MEN. THE RESEARCH PROGRAM OUTLINED IN THIS APPLICATION WILL HARNESS THE MODELING AND ANALYTICS SKILLSET DEVELOPED BY THE PRINCIPAL INVESTIGATOR OVER NEARLY THREE DECADES TO BUILD A FRAMEWORK AND TOOLS FOR EVIDENCE GENERATION AROUND CANCER DIAGNOSTICS. THE APPLICATION DETAILS A SEQUENCE OF PROJECTS FOR TWO TECHNOLOGIES THAT ARE GENERATING INTENSE CURRENT INTEREST WITH WIDE-RANGING PRACTICE IMPLICATIONS AND SERIOUS EVIDENCE GAPS: MULTI-CANCER EARLY DETECTION TESTING, AND PSMA-PET/CT FOR NEWLY DIAGNOSED AND RECURRENT PROSTATE CANCER. THE MCED WORK WILL DEEPEN OUR UNDERSTANDING OF PERFORMANCE CHARACTERISTICS, PROVIDE GUIDANCE REGARDING A DEFENSIBLE TEST CONFIRMATION STRATEGY, PROJECT BENEFITS AND HARMS OF DIFFERENT MCED STRATEGIES AND OFFER NEW IDEAS FOR SHORTCUTTING THE TYPICALLY LENGTHY PROCESS OF CANCER SCREENING TRIALS. THE PSMA-PET/CT WORK WILL DEVELOP AN APPROACH FOR UPDATING TREATMENT BENEFIT ESTIMATED DERIVED FROM TRIALS THAT INCLUDED A MIXTURE OF PATIENTS WITH UNKNOWN PSMA STATUS AND WILL PROJECT LIVES SAVED OF TREATMENT REALLOCATION ON THE BASIS OF PSMA-PET.CT RESULT. THE TOOLS AND PROCESSES DEVELOPED FOR MODELING THESE TECHNOLOGIES WILL BE APPLICABLE TO OTHER NEW DIAGNOSTICS THAT EMERGE DURING THE LIFETIME OF THE RESEARCH PROGRAM. THE MODELING WORK WILL BE ACCOMPANIED BY A SEQUENCE OF REAL-WORLD ANALYTICS PROJECTS TO ASSESS DISSEMINATION OF AND DISPARITIES IN UPTAKE OF NOVEL DIAGNOSTICS AND THEIR CONSEQUENCES FOR HEALTHCARE UTILIZATION AND COSTS. THIS WORK WILL ESTABLISH COLLABORATIONS WITH NEW REAL-WORLD DATA PARTNERS AND MATERIALLY EXPAND THE PRINCIPAL INVESTIGATOR’S SKILLSET TO ENCOMPASS A GREATER COMPETENCY IN MEDICAL INFORMATICS. THE SUCCESSFUL EXECUTION OF THE RESEARCH PROGRAM WILL IMPROVE OUR UNDERSTANDING OF HOW NOVEL CANCER DIAGNOSTICS IMPACT CLINICAL AND POLICY RELEVANT OUTCOMES SO THAT THESE TECHNOLOGIES CAN BE USED WISELY AND EQUITABLY TO IMPROVE CARE FOR ALL CANCER PATIENTS.

THE SYNGENICDNA AND ?POET PLATFORM: OVERCOMING INNATE BARRIERS TO GENETIC ENGINEERING IN BACTERIA.

MOLECULAR AND CELLULAR MECHANISMS OF WOUND REPAIR

DEFINING THE PROTECTIVE EFFICACY OF ANTIBODIES AGAINST THE EBV GH/GL GLYCOPROTEIN COMPLEX

COMBINING TARGETED RIT AND SYNERGISTIC NOVEL AGENTS TO ERADICATE AML

STATISTICAL METHODS FOR RNA-SEQ DATA ANALYSIS

MOLECULAR MECHANISMS AND FUNCTIONS OF GLOBAL CHROMATIN CONTROL - PROJECT SUMMARY/ABSTRACT THE LONG TERM GOAL OF THE PROPOSED STUDY IS TO DETERMINE, AT THE MOLECULAR LEVEL, MECHANISMS AND FUNCTIONS OF CHROMATIN REGULATION AT A GLOBAL LEVEL. CHROMATIN REGULATION PROFOUNDLY AFFECTS A WIDE VARIETY OF DNA-DEPENDENT PROCESSES, INCLUDING TRANSCRIPTION, DNA REPLICATION, RECOMBINATION, DNA REPAIR, AND DNA DAMAGE RESPONSE. THEREFORE, ELUCIDATING THE MECHANISMS OF CHROMATIN REGULATION IS A NECESSARY PREREQUISITE FOR UNDERSTANDING HOW THESE ESSENTIAL PROCESSES ARE CONTROLLED. ONE OF THE MAJOR CHALLENGES THE CHROMATIN FIELD IS TO ELUCIDATE HOW CHROMATIN IS GLOBALLY REPROGRAMMED DURING PROCESSES LIKE CELL FATE DETERMINATION, DEVELOPMENT AND CELL-CYCLE CONTROL. THIS IS A PARTICULARLY IMPORTANT CHALLENGE, BECAUSE IT WAS RECENTLY DETERMINED THAT MUTATIONS IN CHROMATIN REGULATORS REPRESENT ONE MAJOR CLASS OF SO CALLED CANCER DRIVER MUTATIONS, YET HOW THESE MUTATIONS DRIVE CANCER REMAINS UNKNOWN. THEREFORE, ELUCIDATING THE MECHANISMS OF CHROMATIN REGULATION IMPACTS NOT ONLY THE RESEARCHERS WHO STUDY FUNDAMENTAL PRINCIPLES OF DNA-DEPENDENT PROCESSES, BUT ALSO CANCER BIOLOGISTS. WE HAVE PREVIOUSLY ELUCIDATED HOW CHROMATIN REGULATION AFFECTS TRANSCRIPTION, DNA REPLICATION, S PHASE CHECKPOINT AND RECOMBINATION USING BUDDING YEAST AS A MODEL ORGANISM. LIKE MOST STUDIES IN THE FIELD, WE DID OUR WORK DURING THE MITOTIC CELL-CYCLE. HOWEVER, YEAST CELLS IN THE WILD, LIKE OTHER EUKARYOTIC CELLS, SPEND MOST OF THEIR TIME IN QUIESCENCE. QUIESCENCE IS ASSOCIATED WITH MASSIVE CHROMATIN REPROGRAMMING FOR GLOBAL CONDENSATION. BECAUSE THE VAST MAJORITY OF WORK ON CHROMATIN REGULATION HAS BEEN DONE DURING MITOTIC CELL-CYCLE, WE HAVE LITTLE IDEA OF HOW CHROMATIN IS REGULATED DURING THE TIME CELLS SPEND MOST OF THEIR TIME. IN ORDER TO UNDERSTAND THE WHOLE PICTURE OF CHROMATIN REGULATION IN VIVO, IT IS ESSENTIAL TO UNDERSTAND MECHANISMS AND FUNCTIONS OF CHROMATIN REGULATION DURING QUIESCENCE. IN THE NEXT FUNDING PERIOD, WE WILL ASK THE FOLLOWING QUESTIONS IN QUIESCENT STATE: 1) HOW IS CHROMATIN GLOBALLY REPROGRAMMED BY ATP-DEPENDENT CHROMATIN REMODELING FACTORS? 2) HOW ARE CHROMATIN DOMAINS AND NUCLEOSOME ARRAY FOLDING REGULATED? 3) HOW IS GENE EXPRESSION REGULATED POST-TRANSCRIPTIONALLY AT A GLOBAL SCALE? WE WILL USE THE COMBINATION OF GENOMICS, MOLECULAR GENETICS, EM, MODELING AND BIOCHEMISTRY TO IDENTIFY NOVEL MECHANISMS BY WHICH HIGHLY CONSERVED CHROMATIN REGULATORS FUNCTION TO MASSIVELY REPROGRAM CHROMATIN IN A GENOME-WIDE SCALE. IN THE LONG RUN, THESE STUDIES WILL ALLOW US TO COMPARE AND INTEGRATE THE PRINCIPLES OF CHROMATIN REGULATION THROUGHOUT THE MITOTIC CELL-CYCLE AND QUIESCENCE, SUCH THAT WE CAN OBTAIN THE FULL PICTURE OF CHROMATIN REGULATION.

THERAPEUTIC USE OF HPV L1 VACCINE IN ANOGENITAL NEOPLASIA: VIVA TRIAL

PATHWAYS TO CANCER RESEARCH

INVESTIGATING HOW CELLULAR MECHANISMS INTERFACE TO MAINTAIN ENERGY BALANCE

TARGETING A NOVEL HEMATOPOIETIC STEM CELL POPULATION IN NON-HUMAN PRIMATES FOR EFFECTIVE AND SUSTAINED GENE THERAPY

SMCHD1 PATHWAYS AS CANDIDATE TARGETS FOR FSHD

BIOMARKERS FOR OPTIMIZING RISK PREDICTION AND EARLY DETECTION OF CANCERS OF THE COLON AND ESOPHAGUS - PROJECT SUMMARY GASTROINTESTINAL (GI) CANCERS ARE A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THE U.S. AND THEIR TREATMENT USES A SUBSTANTIAL PROPORTION OF HEALTHCARE RESOURCES. OF THE GI CANCERS, COLORECTAL CANCER (CRC) AND ESOPHAGEAL CANCER (EAC) ACCOUNT FOR A MAJORITY OF THE CANCER RELATED DEATHS, AND BOTH ARE PREVENTABLE BY SCREENING AND SURVEILLANCE. THE CURRENT SCREENING TESTS ARE SUBOPTIMAL AND HAVE VARIABLE SUCCESS. A MAJOR GOAL OF CRC SCREENING TESTS IS TO IDENTIFY ADVANCED TUBULAR AND SERRATED ADENOMAS, WHICH ARE HIGH-RISK FOR BECOMING CRC, AS WELL AS EARLY STAGE CRC. THE RISK FOR CRC IS VARIABLE WITH SOME PEOPLE BEING AT HIGH RISK BECAUSE OF FAMILY HISTORIES OF CRC, HEREDITARY CANCER SYNDROMES, OR A PERSONAL HISTORY OF ADENOMAS. HIGH RISK PEOPLE ARE PLACED ON AGGRESSIVE COLONOSCOPY BASED SURVEILLANCE PROGRAMS AND LOW-RISK PEOPLE ARE PLACED ON MINIMAL SURVEILLANCE PROGRAMS. UNFORTUNATELY, OUR CURRENT SYSTEM FOR IDENTIFYING HIGH AND LOW CRC RISK IS SUBOPTIMAL RESULTING IN UNDER AND OVER SURVEILLANCE AND PREVENTABLE INTERVAL CRCS. BETTER RISK MARKERS FOR CRC TO ARE NEEDED TO PREVENT INTERVAL CRCS AND IMPROVE THE OVERALL EFFECTIVENESS OF CRC SCREENING. ANALOGOUS TO CRC, EAC ARISES FROM A PRECANCEROUS CONDITION OF THE ESOPHAGUS CALLED BARRETTS ESOPHAGUS (BE), WHICH IS A SPECIALIZED INTESTINAL METAPLASIA OF THE ESOPHAGUS AND THE HIGHEST RISK FACTOR FOR EAC. IT IS PRESENT IN 5% OF THE US POPULATION. BE PROGRESSES TO EAC THROUGH SUCCESSIVE HISTOLOGIC STEPS OF LOW GRADE DYSPLASIA (LGD), HIGH GRADE DYSPLASIA (HGD) AND THEN EAC. SCREENING AND SURVEILLANCE FOR BE IS RECOMMENDED USING SERIAL UPPER ENDOSCOPY, WHICH IS CONTROVERSIAL IN ITS EFFECTIVENESS FOR PREVENTING DEATHS FROM EAC. THIS IS IN PART BECAUSE, AS WITH CRC, BE PATIENTS HAVE VARIABLE RISK OF EAC AND ARE PLACED ON HIGH- RISK AND LOW-RISK SCREENING PROGRAMS. HOWEVER, THE CURRENT SYSTEM FOR ASSIGNING RISK IS NOT ACCURATE AND THE CURRENT SCREENING TEST IS EXPENSIVE. MORE COST EFFECTIVE AND ACCURATE EAC AND HGD SCREENING/SURVEILLANCE ASSAYS AND ACCURATE BE RISK BIOMARKERS ARE NEEDED. WE PROPOSE TO DEVELOP AN EDRN BCC THAT IS INTEGRATED INTO THE EDRN CONSORTIUM AND, THROUGH COLLABORATIONS WITHIN AND OUTSIDE THE EDRN, WILL DEVELOP EFFECTIVE GI CANCER SCREENING BIOMARKERS. WE PROPOSE TO IDENTIFY, VALIDATE, AND DEVELOP ACCURATE CLIA COMPLIANT RISK BIOMARKERS FOR CRC AND FOR EAC IN ORDER TO PREVENT EAC AND CRC MISSED UNDER CURRENT SCREENING PROTOCOLS. MOREOVER, THE ACCURATE RISK STRATIFICATION OF PATIENTS FOR CRC AND EAC WILL REDUCE THE FINANCIAL IMPACT OF CURRENT CRC AND EAC PREVENTION PROGRAMS. WE ALSO PROPOSE TO IDENTIFY AND VALIDATE ACCURATE CLIA COMPLIANT EARLY DETECTION MARKERS FOR HGD AND EARLY STAGE EAC THAT CAN BE USED IN AN INEXPENSIVE, NON-ENDOSCOPIC SURVEILLANCE TEST.

STATISTICAL METHODS FOR ANALYZING OBJECTIVELY MEASURED PHYSICAL ACTIVITY DATA

NOVEL APPROACHES TO CD33-DIRECTED RADIOIMMUNOTHERAPY

COMPREHENSIVE CHARACTERIZATION OF THE T-CELL RESPONSE TO KSHV TO ENABLE SPECIFIC IMMUNE THERAPY - PROJECT SUMMARY KAPOSI SARCOMA HERPESVIRUS (KSHV) IS THE ETIOLOGIC AGENT OF KAPOSI SARCOMA (KS), PRIMARY EFFUSION LYMPHOMA, AND MULTICENTRIC CASTLEMAN’S DISEASE. KS CAUSES SIGNIFICANT MORBIDITY AND MORTALITY WORLDWIDE, PARTICULARLY IN PEOPLE LIVING WITH HIV (PLWH) AND IN SUB-SAHARAN AFRICA (SSA) WHERE KSHV SEROPREVALENCE IS HIGH. IT IS ESTIMATED THAT 80% OF THE KS BURDEN IN SSA, WHERE THE IMPACT OF KS IS HEAVIEST, IS ATTRIBUTABLE TO HIV INFECTION. KS MOST OFTEN DEVELOPS IN THE SETTING OF T-CELL DEFICIENCY OR DYSFUNCTION, SUCH AS IN KSHV-SEROPOSITIVE INDIVIDUALS WITH HIV INFECTION OR KSHV-SEROPOSITIVE RECIPIENTS OF SOLID ORGAN OR ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTS. IN THESE SETTINGS KS CAN REMIT FOLLOWING INITIATION OF ANTIRETROVIRAL THERAPY (ART) OR WITHDRAWAL OF IMMUNE SUPPRESSION. IN SSA, PRIMARY INFECTION WITH KSHV IS THOUGHT TO OCCUR IN CHILDHOOD, BUT MOST CASES OF KS AND OTHER KSHV-ASSOCIATED DISEASE IN BOTH PLWH AND PEOPLE WITHOUT HIV INFECTION DEVELOP MANY YEARS, OFTEN SEVERAL DECADES, LATER. THESE OBSERVATIONS SUGGEST THAT LOSS OR IMPAIRMENT OF A T-CELL COMPONENT OF PRE- EXISTING KSHV-SPECIFIC IMMUNITY UNDERLIE THE DEVELOPMENT OF THESE DISEASES. STRATEGIES THAT PRESERVE OR RESTORE THE T-CELL COMPONENT OF KSHV-SPECIFIC IMMUNITY IN PLWH AND OTHERS AT RISK SHOULD, THEREFORE, HAVE POTENTIAL FOR THE PREVENTION OR TREATMENT OF KSHV-ASSOCIATED DISEASE. OUR STUDIES OF TUMOR BIOPSIES AND BLOOD SAMPLES FROM PEOPLE IN UGANDA LIVING WITH HIV AND KS (EPIDEMIC KS) AS WELL AS ADULTS WITH KS BUT NO CONCURRENT HIV INFECTION (ENDEMIC KS) HAVE IDENTIFIED A LARGE REPERTOIRE OF T- CELLS THAT ARE LIKELY TO BE SPECIFIC FOR KSHV. WE HAVE BEGUN TO IDENTIFY THE ANTIGENIC TARGETS OF THESE PUTATIVE KSHV-SPECIFIC T-CELLS AND FIND THAT THEY DEMONSTRATE HIGH AVIDITY FOR KSHV-ENCODED PEPTIDES, RECOGNIZE KSHV- INFECTED CELLS, ARE DETECTABLE IN KS TUMORS, CIRCULATE IN BLOOD, AND PERSIST ACROSS TIME. ADDITIONAL PRELIMINARY DATA FROM WHOLE EXOME SEQUENCING AND TRANSCRIPTIONAL PROFILING OF KS TUMORS REVEAL A SPARSE MUTATIONAL LANDSCAPE BUT CONSISTENT EXPRESSION OF LATENT AND LYTIC CYCLE KSHV GENES, SUPPORTING THE CONCEPT THAT IMMUNE INTERVENTIONS THAT PRESERVE, ENHANCE, OR RESTORE THE T-CELL RESPONSE TO KSHV COULD PROVE EFFECTIVE FOR THE PREVENTION OR TREATMENT OF KS, PARTICULARLY IN PLWH WHO ARE AT GREATEST RISK. COMPREHENSIVE DEFINITION OF THE TARGETS OF THE KSHV-SPECIFIC T-CELL RESPONSE IN KSHV-SEROPOSITIVE INDIVIDUALS AND OF HOW THAT T-CELL RESPONSE IS IMPAIRED OR DISABLED IN INDIVIDUALS WHO DEVELOP KS WILL PROVIDE THE BLUEPRINT FOR SUCH IMMUNE INTERVENTIONS. THE STUDIES IN THIS APPLICATION WILL LAY THE FOUNDATION FOR SPECIFIC IMMUNE THERAPY FOR KS BY IDENTIFYING THE MAJOR TARGETS OF THE T-CELL RESPONSE TO KSHV, IDENTIFYING THOSE THAT ARE NATURALLY PRESENTED BY KSHV-INFECTED CELLS, AND DEFINING MECHANISMS BY WHICH KSHV ATTEMPTS TO EVADE THAT RESPONSE.