What is FRED HUTCHINSON CANCER CENTER's OSHA violation history?

FRED HUTCHINSON CANCER CENTER has 4 OSHA inspections on record with 4 violations and $14,400 in total penalties.

How does FRED HUTCHINSON CANCER CENTER's safety record compare to its industry?

FRED HUTCHINSON CANCER CENTER operates in the all other outpatient care centers industry. The industry average Total Recordable Incident Rate (TRIR) is 3.5. FRED HUTCHINSON CANCER CENTER's self-reported DART rate is 0.83 compared to an industry average of 1.1.

Establishment profile

FRED HUTCHINSON CANCER CENTER

820 YALE AVE N, SEATTLE, WA, 98109
621498 — All Other Outpatient Care Centers
EIN 911935159

Download as PDF →

OSHA inspections

over 3 years

Violations

$14,400 in penalties

Penalties

$14,400

$3,600 avg

Violations across 3 federal agencies

Enforcement actions from multiple agencies may indicate systemic compliance issues across functions.

Summary

FRED HUTCHINSON CANCER CENTER has accumulated 4 OSHA violations across 4 inspections over 3 years of recorded history, with $14,400 in total assessed penalties.

The establishment sits in the 75th percentile for violations within its industry-state peer group of 135 employers. Inspection frequency runs at the 98th percentile. The most recent enforcement activity was recorded 12 months ago.

Federal records were found in 3 of 15 sources. Sources without matching records returned empty for this establishment.

Agency coverage

FRED HUTCHINSON CANCER CENTER appears in OSHA workplace safety, EPA environmental compliance, NLRB labor relations, OFLC visa and labor certification (historical), and FMCSA motor carrier registration records only. No matching records were found in WHD wage enforcement, MSHA mine safety, SAM.gov federal debarment, CMS nursing home enforcement, UVA Corporate Prosecution Registry, CPSC product recalls, or NHTSA vehicle recalls.

OSHA workplace safety

Inspections

1.3 / yr · last 3 yrs

Violations

1.3 / yr

Penalties

$14,400

$3,600 avg / violation

50% serious50% other

Inspection trigger · complaint

3 of 4

Inspection trigger · referral

1 of 4

50% of inspections at this establishment produced violations,

Most-cited OSHA standards

Top OSHA standards cited at this employer, ranked by citation count. Standards (CFR sections) cluster citations into safety themes -- machine guarding, lockout-tagout, hazard communication, fall protection, process safety, etc. A concentration on one or two sections reveals a pattern that individual citations don’t. 4 distinct standards shown · 4 citations in this view · $14,400 in penalties.

CFR section	Citations	Inspections	Total penalty	First cited	Last cited
296-800-15030	1	1	$4,800	Jun 2023	Jun 2023
296-800-16050	1	1	$4,800	Jun 2023	Jun 2023
296-901-14010(1)(B)	1	1	$4,800	Jun 2023	Jun 2023
296-800-21005	1	1	—	Oct 2025	Oct 2025

Source: OSHA inspection citations (violation_detail). CFR section codes can be looked up at osha.gov/laws-regs for the formal standard text. Per-inspection detail and the specific violation descriptions are available by expanding individual inspections below.

Peer comparison

75th

Above average violations in NAICS 6214 within WA. Peer group: 135 employers. This establishment has 4 OSHA violations; peer median is 1.

Fewer violationsMore violations

Penalty percentile

99th

peer median: $0

Inspection frequency

98th

peer median: 1

Safety self-report (OSHA 300A)

Recordable injury rates the employer filed with OSHA’s Injury Tracking Application. DART covers cases with days away, restricted, or transferred; TRIR is the total recordable case rate.

DART rate

0.8

vs industry

−0.3

TRIR

1.9

vs industry

−1.6

Reported for 2,151 average annual employees at this establishment.

Source: OSHA ITA Form 300A (employer self-reported). Rates are per 100 full-time equivalent workers. Establishments below the ~10-FTE threshold are not required to report.

Industry benchmark

Industry avg TRIR

3.5

BLS SOII 2024

Industry avg DART

1.1

BLS SOII 2024

Self-reported TRIR

1.9

OSHA ITA Form 300A (employer self-reported)

BLS rates reflect industry-wide averages. Self-reported figures come from OSHA’s Injury Tracking Application; absence of self-reported data does not necessarily indicate non-compliance — many establishments fall below the ITA reporting threshold.

Inspection breakdown

Complaint

Referral

Complaint- and accident-triggered inspections are stronger risk signals than routine planned inspections.

OSHA severe injury reports

No severe injury reports (hospitalization, amputation, or loss of an eye) on file under 29 CFR 1904.39 for FRED HUTCHINSON CANCER CENTER. Verify directly with Occupational Safety and Health Administration →

Activity timeline

Data refreshed

Weekly

First OSHA inspection

—

Most recent activity

12 months ago

Most recent federal enforcement activity recorded 12 months ago. Data on this page is refreshed weekly.

Wage & Hour Division (WHD)

No WHD wage, overtime, or child-labor enforcement cases on file for FRED HUTCHINSON CANCER CENTER. Verify directly with Wage and Hour Division →

Mine safety (MSHA)

No MSHA mine safety violations on file for FRED HUTCHINSON CANCER CENTER. Verify directly with Mine Safety and Health Administration →

Labor relations (NLRB)

Company-level in WA — for FRED HUTCHINSON CANCER CENTER, not this location alone

Total cases

Unfair labor practice

Representation (union)

National Labor Relations Board — unfair labor practice charges and union representation cases. The NLRB records cases at the company/regional level (no worksite address), so these are matched by company name and state and may span other FRED HUTCHINSON CANCER CENTER locations in the same state.

NLRB cases

National Labor Relations Board cases involving this employer. Includes unfair labor practice (ULP) filings and representation election proceedings. NLRB enforcement is process-driven; no per-case monetary penalty is assessed (remedies are case-by-case backpay orders, posting requirements, election re-runs, etc.). 4 cases · 3 ULP · 1 representation

Case number	Type	Filed	Closed	Status	Region
19-CA-390074	Unfair labor practice	Jul 2026	Jul 2026	Closed	Region 19, Seattle, Washington
19-RC-387828	Representation election	May 2026	—	Open	Region 19, Seattle, Washington
19-CA-322877	Unfair labor practice	Aug 2023	Jan 2024	Closed	Region 19, Seattle, Washington
19-CA-322235	Unfair labor practice	Jul 2023	Jan 2024	Closed	Region 19, Seattle, Washington

Source: NLRB case files. Rows shown are those the agency has published. Region numbers (1–31) correspond to NLRB's geographic offices.

Visa & labor certification (OFLC) — historical

Total applications

150

Certified

138

Denied

Avg wage ratio

1.43x

H-1B1 SingaporeH-1BE-3 Australian

Office of Foreign Labor Certification — labor condition applications for H-1B, H-2A, H-2B visa programs. Wage ratio = offered / prevailing wage. Historical data only: DOL ended OFLC Performance Data Disclosure publication in 2026, so the figures above reflect filings through the last ingested cycle and are not being refreshed. Treat as a historical snapshot, not a current signal.

Environmental compliance (EPA)

EPA inspections

Quarters non-compliant

EPA Enforcement and Compliance History — Clean Air Act, Clean Water Act, RCRA, Safe Drinking Water Act. Status: No Violation Identified.

EPA-registered facilities

Every EPA ECHO facility associated with this employer, sorted most-significant first. Each row links to EPA’s Detailed Facility Report for the source-of-truth record. Permits column lists active programs (Air = Clean Air Act, Water = Clean Water Act, RCRA = hazardous waste, TRI = Toxics Release Inventory reporting). 1 facility.

Facility	Permits	Status	Inspections	Formal actions	Penalties	Last inspected	ECHO
FRED HUTCHINSON CANCER CENTER 825 EASTLAKE AVE E · SEATTLE, WA, 98109	RCRA	No Violation Identified QNCR 5	1	0	—	Feb 2025	View →

Source: EPA ECHO (Enforcement and Compliance History Online). Compliance status follows EPA’s own labels (“Sig Violation” = significant noncompliance; QNCR = quarters of noncompliance over the recent reporting window). Inactive facilities (struck through) retain historical enforcement records even after operations ceased.

Motor carrier safety (FMCSA)

DOT number

1671571

Operation

Federal Motor Carrier Safety Administration — DOT-regulated carrier registration and fleet data.

Federal criminal prosecution record

No federal criminal prosecutions, plea agreements, or deferred-prosecution agreements on file for FRED HUTCHINSON CANCER CENTER. Verify directly with UVA Corporate Prosecution Registry →

Federal contracts

This location

Obligated (5-yr)

$86.8M

Obligated (all-time)

$87.5M

Awards

Top agency

Department of Health and Human Services

$86.5M

Top agencies by obligation (this location)

Department of Health and Human Services$86.5M

Department of Veterans Affairs$1.1M

Department of Defense$11K

Largest awards (top 50 of 57)

Department of Health and Human Services
WOMEN'S HEALTH INITIATIVE (WHI) - CLINICAL COORDINATING CENTER (CCC) - TASK AREA A
contract · Last action 2025-05-13
$27,789,231
Department of Health and Human Services
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. ,
assistance · Last action 2025-09-22
$18,523,030
Department of Health and Human Services
NATIONAL CANCER INSTITUTE'S CONTACT CENTER
contract · Last action 2025-05-16
$17,000,365
Department of Health and Human Services
THE NATIONAL CANCER INSTITUTE'S (NCI) CANCER INFORMATION SERVICE (CIS) IS AN EXISTING AND ESTABLISHED CRITICAL COMPONENT OF HEALTHCARE DELIVERY, PARTICULARLY IN FACILITATING PUBLIC ACCESS TO CLINICAL TRIALS. ESTABLISHED UNDER THE NATIONAL CANCER
contract · Last action 2026-05-01
$15,149,061
Department of Health and Human Services
IGF::OT::IGF CORE INFRASTRUCTURE SUPPORT FOR SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS (SEER)
contract · Last action 2025-08-27
$13,275,062
Department of Health and Human Services
WOMEN'S HEALTH INITIATIVE (WHI) CLINICAL COORDINATING CENTER - TASK AREA A AND A2
contract · Last action 2026-06-11
$10,225,386
Department of Health and Human Services
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.
assistance · Last action 2026-04-16
$8,735,327
Department of Health and Human Services
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.
assistance · Last action 2026-02-19
$8,239,305
Department of Health and Human Services
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)
assistance · Last action 2025-09-16
$7,696,898
Department of Health and Human Services
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.
assistance · Last action 2025-07-17
$5,128,451
Department of Health and Human Services
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.
assistance · Last action 2026-05-28
$5,031,369
Department of Health and Human Services
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.
assistance · Last action 2025-07-21
$5,025,129
Department of Health and Human Services
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.
assistance · Last action 2026-04-16
$4,974,135
Department of Agriculture
SEATTLE DIETARY BIOMARKER DEVELOPMENT CENTER
assistance · Last action 2025-11-18
$4,969,948
Department of Health and Human Services
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.
assistance · Last action 2025-12-15
$4,722,849
Department of Health and Human Services
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.
assistance · Last action 2025-07-30
$4,661,966
Department of Health and Human Services
IDENTIFYING PLASMA PROTEOMIC PROFILES OF CHRONIC PAIN DEVELOPMENT IN ENDOMETRIOSIS FROM ADOLESCENCE TO ADULTHOOD - ABSTRACT ENDOMETRIOSIS IS A DEBILITATING GYNECOLOGIC DISEASE PRESENTING WITH SEVERE PELVIC PAIN AND IS CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE OF THE UTERUS IMPACTING 10% OF REPRODUCTIVE AGED WOMEN OR AN ESTIMATED 200 MILLION WOMEN AND ADOLESCENTS WORLDWIDE. COMPARED TO WOMEN WITHOUT ENDOMETRIOSIS, WOMEN WITH ENDOMETRIOSIS, ESPECIALLY ADOLESCENTS AND YOUNG ADULTS WITH ENDOMETRIOSIS, ARE AT AN INCREASED RISK OF CHRONIC OPIOID USE, DEPENDENCE, AND OVERDOSE. THEREFORE, OPTIMAL PAIN MANAGEMENT IN ENDOMETRIOSIS PATIENTS, ESPECIALLY STARTING IN ADOLESCENCE, IS CRITICAL AND WILL HAVE SIGNIFICANT POSITIVE IMPACT ON RESOLVING THE OPIOID HEALTH CRISIS. CURRENTLY, PRIMARY TREATMENT OPTIONS FOR ENDOMETRIOSIS FOCUS ON HORMONAL SUPPRESSION AND/OR EXCISION OF THE ENDOMETRIOTIC LESIONS, ALTHOUGH RESPONSE TO THESE CONVENTIONAL TREATMENTS IS VARIABLE AND AS A RESULT, MANY OF THOSE WITH ENDOMETRIOSIS ARE PLAGUED WITH PERSISTENT PELVIC PAIN. EMERGING EVIDENCE SUGGESTS THAT ENDOMETRIOSIS PATIENTS WHO DEVELOP PERSISTENT PELVIC PAIN HAVE DEVELOPED CENTRALIZED PAIN, AND THEREFORE SURGICAL REMOVAL OF ENDOMETRIOTIC TISSUE DOES NOT FULLY IMPROVE THEIR PAIN. SINCE MANY WOMEN WITH DIAGNOSED ENDOMETRIOSIS REPORT THEIR SYMPTOMS STARTED DURING ADOLESCENCE, THIS TRANSITION FROM ACUTE TO CHRONIC PAIN IS LIKELY HAPPENING DURING ADOLESCENCE AND YOUNG ADULTHOOD. THUS, STUDYING ADOLESCENTS AND YOUNG ADULTS WITH ENDOMETRIOSIS, WHO ARE IN THE EARLY STAGES OF THEIR DISEASE TRAJECTORY, IS CRITICAL TO FULLY UNDERSTANDING WHO IS AT HIGHER RISK OF DEVELOPING CHRONIC PAIN. HOWEVER, DATA ON LONGITUDINAL CHANGES IN BIOMARKERS AND ENDOMETRIOSIS- ASSOCIATED PAIN IN ADOLESCENTS IS LACKING, RESULTING IN LOST OPPORTUNITY FOR EARLY INTERVENTIONS. THE OVERARCHING GOAL OF THIS INNOVATIVE APPLICATION IS TO IMPROVE AND OPTIMIZE PAIN MANAGEMENT FOR ENDOMETRIOSIS THROUGH IDENTIFYING PLASMA PROTEIN BIOMARKERS OF CHRONIC PAIN DEVELOPMENT IN ADOLESCENTS AND YOUNG ADULTS WITH ENDOMETRIOSIS. SPECIFICALLY, WE PROPOSE TO CONDUCT A LONGITUDINAL ANALYSIS OF ENDOMETRIOSIS CASES DIAGNOSED IN ADOLESCENCE WITH FOLLOW-UP DATA AND PAIRED BLOOD SAMPLES COLLECTED 10 YEARS APART FROM ADOLESCENCE TO ADULTHOOD AND APPLY A STATE OF THE ART 7000-PLEX PROTEOMICS ASSAY TO IDENTIFY PLASMA PROTEIN BIOMARKERS OF CENTRALIZED, CHRONIC PAIN DEVELOPMENT. IN ADDITION, WE WILL EXAMINE CHANGE IN PLASMA PROTEOMIC BIOMARKERS IN PAIRED BLOOD SAMPLES DRAWN 10 YEARS APART (I.E. AT ADOLESCENCE AND ADULTHOOD), AND TOGETHER THESE UNIQUE RESOURCES WILL ALLOW PROSPECTIVE INVESTIGATION OF PREDICTORS AND BIOLOGICAL FACTORS RELATED TO TRANSITIONING FROM ACUTE TO CHRONIC PAIN OR CHRONIFICATION OF PAIN. RESULTS FROM THIS STUDY WILL GENERATE IMPORTANT NOVEL DATA IDENTIFYING ADOLESCENTS AND YOUNG WOMEN WITH ENDOMETRIOSIS WHO ARE AT GREATER RISK OF DEVELOPING CHRONIC PAIN DESPITE RECEIVING CURRENT STANDARD OF CARE, LEADING TO DEVELOPMENT OF NOVEL PAIN INTERVENTIONS TARGETED TO A YOUNGER POPULATION TO PREVENT CHRONIFICATION OF PAIN, WHICH WILL BE A CRITICAL STEP FORWARD TO RESOLVING THE ONGOING OPIOID CRISIS.
assistance · Last action 2025-12-02
$4,301,233
Department of Health and Human Services
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.
assistance · Last action 2025-09-19
$4,234,248
Department of Health and Human Services
IDENTIFYING VULNERABILITIES IN THE LONG-LIVED HIV RESERVOIR TO ACCELERATE ITS DECAY - PROJECT SUMMARY LATENTLY INFECTED CD4+ T CELLS HARBORING INTEGRATED AND REPLICATION-COMPETENT HIV GENOMES PERSIST DURING ART AND ARE THE MAIN OBSTACLE TO HIV ERADICATION. IN MOST PEOPLE WITH HIV (PWH), THE RESERVOIR IS EXTREMELY STABLE WITH A HALF-LIFE OF OVER 3 YEARS. ALL PRIOR ATTEMPTS TO SIGNIFICANTLY REDUCE ITS SIZE OR ACCELERATE ITS DECAY HAVE FAILED. USING SAMPLES FROM PARTICIPANTS IN THE MERLIN CLADE B PRIMARY HIV INFECTION COHORT (LIMA, PERU), WE OBSERVED 5 TO 10-TIMES FASTER DECAY OF THE HIV RESERVOIR IN INDIVIDUALS INITIATING ART DURING THE FIRST 3 MONTHS OF INFECTION COMPARED TO THOSE RANDOMIZED TO START ART LATER, SUGGESTING THAT HIV-INFECTED CELLS IN PEOPLE TREATED EARLY ARE MORE SUSCEPTIBLE TO ELIMINATION. DIFFERENCES IN THE HALF-LIFE OF THE RESERVOIR, WHICH ARE MAINTAINED DURING AT LEAST THE FIRST 4 YEARS OF ART, OFFER A UNIQUE OPPORTUNITY TO IDENTIFY MECHANISMS THAT COULD BE HARNESSED TO REDUCE THE RESERVOIR IN ALL PWH ON ART. IN THIS PROJECT, WE PROPOSE TO UNRAVEL THE CELLULAR AND VIRAL FEATURES RESPONSIBLE FOR THE RAPID CLEARANCE OR LONG-TERM PERSISTENCE OF INDIVIDUAL HIV RESERVOIR CELLS. WE WILL TEST THE HYPOTHESIS THAT THE CAPACITY OF RESERVOIR CELLS TO PERSIST FOR PROLONGED PERIODS IS DRIVEN BY A COMBINATION OF CELLULAR AND VIRAL FEATURES, WHICH DIFFER BETWEEN EARLY AND LATE TREATED INDIVIDUALS AND RESULT IN DIFFERENTIAL RESERVOIR DECAY. WE WILL TAKE ADVANTAGE OF THE UNIQUE MERLIN COHORT TO STUDY HIV RESERVOIR CELLS IN 12 PARTICIPANTS WHO INITIATED ART LESS THAN 3 MONTHS AFTER HIV ACQUISITION (EARLY ART: RAPID DECAY) AND 12 PARTICIPANTS WHO DEFERRED TREATMENT FOR 6 MONTHS (LATE ART: SLOW DECAY). WE WILL STUDY THE EARLY, INTERMEDIATE AND LATE RESERVOIRS, USING CRYOPRESERVED LEUKAPHERESES (COLLECTED AT 1 & 2-3 YEARS OF ART) AND NEWLY COLLECTED LEUKAPHERESIS FROM THE SAME CONTINUALLY- SUPPRESSED PARTICIPANTS AT >7 YEARS OF ART. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT INTRINSIC CELLULAR FEATURES OF HIV RESERVOIR CELLS UNDERLIE DIFFERENCES IN RESERVOIR DECAY. WE WILL EMPLOY A SINGLE CELL APPROACH TO IDENTIFY PRO-SURVIVAL FACTORS ASSOCIATED WITH RESERVOIR STABILITY (BCL-2, TCF-1, FOXO3A ETC.) OR THAT MAY PROTECT INFECTED CELLS FROM IMMUNE CLEARANCE (LIGANDS OF IMMUNE CHECKPOINT MOLECULES, SERPIN B9, TGF-SS). WE WILL ALSO EVALUATE THE CLONALITY OF THE RESERVOIR WITH THE HYPOTHESIS THAT CLONAL EXPANSIONS OF INTACT GENOMES WILL BE MORE COMMON IN LATE TREATED PARTICIPANTS. IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT SPECIFIC VIRAL CHARACTERISTICS ALSO CONTRIBUTE TO THE PERSISTENCE OF HIV-INFECTED CELLS AND WILL BE GRADUALLY ENRICHED OVER TIME ON ART. TO DETERMINE IF SPECIFIC VIRUSES ARE SELECTED AGAINST DURING THERAPY, WE WILL USE AN ASSAY THAT COUPLES INTEGRATION SITE SEQUENCING WITH HIV TRANSCRIPTION ASSESSMENT, TO DETERMINE THE PROPORTION OF RESERVOIR CELLS THAT ARE TRANSCRIPTIONALLY ACTIVE. WE WILL USE A NOVEL APPROACH TO RECONSTRUCT MOLECULAR VIRAL CLONES FROM THE LATENT RESERVOIR, AND WILL MEASURE THE FITNESS OF THESE VIRUSES AND FUNCTIONALLY ASSESS THEIR HIV PROTEOMES. IN THIS WAY, WE WILL DETERMINE IF THE RESERVOIR IS GRADUALLY ENRICHED IN PROVIRUSES ENCODING FUNCTIONAL NEF AND VPU, WHICH CAUSE ESCAPE OF ANTIGEN PRESENTATION AND IMPEDE CTL-MEDIATED KILLING AS WELL AS NEUTRALIZATION AND ADCC BY AUTOLOGOUS ANTIBODIES. RESULTS FROM THIS STUDY WILL IDENTIFY CELLULAR AND VIRAL MECHANISMS THAT CAN BE TARGETED TO ACCELERATE DECAY OF THE HIV RESERVOIR.
assistance · Last action 2026-06-09
$3,900,655
Department of Health and Human Services
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.
assistance · Last action 2025-08-22
$3,872,365
Department of Health and Human Services
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.
assistance · Last action 2026-02-25
$3,642,526
Department of Health and Human Services
GENETICS, EPIGENETICS, AND RISK PREDICTION FOR ESOPHAGEAL ADENOCARCINOMA - PROJECT SUMMARY/ABSTRACT ESOPHAGEAL ADENOCARCINOMA (EAC) IS ONE OF THE MOST LETHAL CANCERS, WITH A 5-YEAR SURVIVAL RATE LESS THAN 20%. INCIDENCE OF EAC HAS RISEN SHARPLY IN THE U.S. AND OTHER WESTERN COUNTRIES OVER THE PAST FOUR DECADES, LARGELY DUE TO RISING PREVALENCE OF TWO RISK FACTORS – GASTROESOPHAGEAL REFLUX DISEASE AND OBESITY. EAC DEVELOPS FROM BARRETT’S ESOPHAGUS (BE), A CANCER PRECURSOR DEFINED BY A SPECIALIZED COLUMNAR METAPLASIA OF THE DISTAL ESOPHAGUS. ALTHOUGH BE FOLLOWS AN INDOLENT COURSE IN MOST PATIENTS, 5-10% EVENTUALLY PROGRESS TO CANCER, AND A SIZABLE FRACTION OF BE REMAIN UNDETECTED IN THE POPULATION. A CRITICAL UNMET NEED IS TO IDENTIFY INDIVIDUALS WITH HIGH-RISK BE WHO ARE MOST LIKELY TO DEVELOP EAC AND THUS BENEFIT FROM SCREENING AND ENDOSCOPIC SURVEILLANCE. CONVERSELY, IDENTIFYING THE MAJORITY WHO ARE UNLIKELY TO PROGRESS WILL REDUCE RISKS AND COSTS ASSOCIATED WITH UNNECESSARILY FREQUENT SURVEILLANCE. BIOMARKER-ASSISTED RISK STRATIFICATION, HOWEVER, CONTINUES TO BE HINDERED BY OUR LIMITED UNDERSTANDING OF THE MOLECULAR PATHWAYS UNDERLYING EARLY STEPS IN THE DEVELOPMENT OF EAC. IN RECENT YEARS, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED ~20 NOVEL GENETIC SUSCEPTIBILITY LOCI, YET MOST HERITABILITY REMAINS UNEXPLAINED, AND ONLY ONE SNP IS LINKED SPECIFICALLY TO BEEAC PROGRESSION. THE EPIGENOME, AN IMPORTANT INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME, HAS NOT BEEN STUDIED FOR ITS POTENTIAL MEDIATING ROLES IN RELATION TO GENOTYPES, STRONG ENVIRONMENTAL RISK FACTORS AND PROGRESSION TO EAC. TO ADDRESS THESE GAPS, OVERCOME SAMPLE SIZE LIMITATIONS FOR A RARE CANCER, AND INVIGORATE EXISTING RESEARCH EFFORTS, NEWER MOLECULAR AND STATISTICAL APPROACHES ARE NEEDED TO SYSTEMATICALLY INTEGRATE MULTI-OMICS DATA WITH ESTABLISHED DISEASE EXPOSURES. IN THIS PROJECT WE WILL CONDUCT THE MOST COMPREHENSIVE MULTI-OMICS STUDY OF BE, THE KEY CANCER PRECURSOR, PROFILING THE TRANSCRIPTOME AND METHYLOME OF 500 BIOPSIES FROM THE NCI-FUNDED BARRETT’S AND ESOPHAGEAL ADENOCARCINOMA CONSORTIUM AND ROSWELL PARK COMPREHENSIVE CANCER CENTER, AND PERFORM INTEGRATIVE ANALYSES LEVERAGING GENOTYPES AND ENVIRONMENTAL RISK FACTORS ALREADY AVAILABLE THROUGH THE LARGEST GWAS META-ANALYSIS FOR BE/EAC (N˜27,000). THE GOAL IS TO IDENTIFY NEW GENETIC RISK LOCI THROUGH EQTL MAPPING AND TRANSCRIPTOME-WIDE ASSOCIATION STUDY (AIM 1), NEW EPIGENETIC LOCI MEDIATING AND PREDICTING THE RISK OF BE PROGRESSION TO EAC (AIM 2), AND DEVELOP RISK PREDICTION MODELS INTEGRATING GENOME-WIDE POLYGENIC RISK SCORE AND ENVIRONMENTAL EXPOSURES (AIM 3). THE UNIFYING THEME OF THE THREE AIMS IS DEVELOPMENT AND IMPLEMENTATION OF INNOVATIVE ANALYTICAL STRATEGIES, LEVERAGING TRANSCRIPTOME AND METHYLOME DATA. ULTIMATELY, GENETICS, EPIGENETICS, AND ENVIRONMENTAL EXPOSURES WILL BE INCORPORATED TO IDENTIFY HIGH-RISK POPULATIONS FOR TAILORED SCREENING AND SURVEILLANCE, AND PREVENT CANCER DEVELOPMENT.
assistance · Last action 2026-01-15
$3,588,780
Department of Health and Human Services
PROMOTING T CELL RECONSTITUTION AFTER HEMATOPOIETIC CELL TRANSPLANTATION - PROJECT SUMMARY THE THYMUS, WHICH IS THE PRIMARY SITE OF T CELL GENERATION, IS EXTREMELY SENSITIVE TO INJURY; BUT ALSO HAS A REMARKABLE CAPACITY FOR ENDOGENOUS REPAIR. HOWEVER, EVEN THOUGH THERE IS CONTINUAL THYMIC INVOLUTION AND REGENERATION IN RESPONSE TO EVERYDAY INSULTS LIKE STRESS AND INFECTION, PROFOUND THYMIC DAMAGE CAUSED BY COMMON CANCER THERAPIES AND THE CONDITIONING REGIMES FOR HEMATOPOIETIC CELL TRANSPLANTATION (HSCT) LEAD TO PROLONGED T CELL LYMPHOPENIA. FURTHERMORE, IN THE CONTEXT OF ALLOGENEIC HCT, THE THYMUS IS AN EXTREMELY SENSITIVE TARGET TO ALLOREACTIVE T CELLS DURING GRAFT VERSUS HOST DISEASE (GVHD). CONSEQUENTLY, IDENTIFICATION OF THERAPIES THAT CAN BOOST T CELL RECONSTITUTION IN RECIPIENTS OF HSCT IS A CLINICAL PRIORITY. WE HAVE PREVIOUSLY IDENTIFIED TWO DISTINCT PATHWAYS OF ENDOGENOUS THYMIC REGENERATION, CENTERED ON THE PRODUCTION OF THE REGENERATION FACTORS IL-22 BY INNATE LYMPHOID CELLS (ILCS), AND BMP4 BY ENDOTHELIAL CELLS (ECS); BOTH OF WHICH MEDIATE THEIR REGENERATIVE EFFECTS BY TARGETING THYMIC EPITHELIAL CELLS (TECS). MORE RECENTLY WE HAVE FOUND THAT THE TRIGGER FOR THESE DISTINCT REGENERATIVE PATHWAYS HINGE ON THE BALANCE BETWEEN FORMS OF CELL DEATH, WITH IMMUNOLOGICALLY SILENT APOPTOSIS (WHICH IS ABUNDANT IN THYMOCYTES DURING STEADY-STATE) SUPPRESSIVE TO THE REGENERATIVE PROGRAM. ON THE OTHER HAND, AFTER THYMIC DAMAGE CAUSED BY RADIATION INJURY, WE FOUND A SWITCH TOWARD IMMUNOGENIC CELL DEATH, WITH THE RESULTING RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS) SUFFICIENT TO PROMOTE REGENERATION. SPECIFICALLY, WE IDENTIFIED THAT INTRACELLULAR ZN WAS RELEASED AFTER RADIATION INJURY, WHERE IT COULD SIGNAL THROUGH THE G-PROTEIN COUPLED RECEPTOR 39 (GPR39) TO STIMULATE PRODUCTION OF BMP4 AND IL-23, A KEY UPSTREAM REGULATOR OF IL-22 PRODUCTION. SEPARATELY, WE ALSO FOUND THAT THE RELEASE OF THE PROTOTYPICAL DAMP, ATP, WAS ABLE TO SIGNAL DIRECTLY ON THYMIC EPITHELIAL CELLS THROUGH PURINERGIC (P2) RECEPTORS AND PROMOTE THEIR EXPRESSION OF FOXN1, KEY MICROENVIRONMENTAL DRIVERS OF T CELL DEVELOPMENT. IMPORTANTLY, OUR PRELIMINARY DATA ALSO SUGGESTS THAT EACH OF THESE PATHWAYS CAN BE THERAPEUTICALLY TARGETED TO IMPROVE THYMIC RECOVERY IN MOUSE MODELS OF HCT. OUR PRELIMINARY DATA HAS ALSO IDENTIFIED PUTATIVE TEC PRECURSORS THAT ARE IMPORTANT FOR REGENERATING THE EPITHELIAL COMPARTMENT AND THUS PROMOTING REGENERATION, AS WELL AS THE EMERGENCE WITH AGE OF ABERRANT EPITHELIAL CELLS THAT LIMIT THYMIC FUNCTION, INCLUDING IN ITS REPARATIVE CAPACITY AFTER ACUTE DAMAGE. OUR RESEARCH PROGRAM IS THUS EXPLORING SEVERAL KEY QUESTIONS: WHAT ARE THE TRIGGERS AND UPSTREAM REGULATORS OF ENDOGENOUS TISSUE REGENERATION IN THE THYMUS? WHICH CELLS MEDIATE TISSUE REGENERATION IN THE THYMUS AFTER ACUTE INJURY? ARE THERE LIMITATIONS TO ENDOGENOUS REGENERATION AFTER HCT ACROSS SEX AND LIFESPAN? CAN WE EXPLOIT THESE MECHANISMS OF ENDOGENOUS REGENERATION TO DEVELOP THERAPEUTIC STRATEGIES TO BOOST T CELL RECONSTITUTION IN HCT RECIPIENTS? THE STUDIES OUTLINED IN THIS PROPOSAL NOT ONLY HAVE THE POTENTIAL TO DEFINE IMPORTANT PATHWAYS UNDERLYING TISSUE REGENERATION BUT COULD ALSO RESULT IN INNOVATIVE CLINICAL APPROACHES TO ENHANCE THYMIC FUNCTION.
assistance · Last action 2026-03-27
$3,562,727
Department of Health and Human Services
ASSESSING THE EFFECTS OF ORAL PRE-EXPOSURE PROPHYLAXIS ON PHARMACOKINETICS OF MONOCLONAL AND VACCINE-INDUCED ANTIBODIES AMONG WOMEN VULNERABLE TO HIV-1 - ABSTRACT IN THIS PROPOSAL, WE WILL DETERMINE THE INFLUENCE OF ORAL PRE-EXPOSURE PROPHYLAXIS (PREP) ON THE PHARMACOKINETICS (PK) OF PASSIVELY ADMINISTERED MONOCLONAL ANTIBODIES (MABS) AND VACCINE-INDUCED POLYCLONAL ANTIBODIES (ABS) IN FEMALES VULNERABLE TO HIV-1, USING DATA AND SPECIMENS FROM PAST HIV-1 PREVENTION TRIALS. THIS RESEARCH WILL HAVE A SIGNIFICANT IMPACT ON GLOBAL HEALTH BECAUSE ORAL PREP IS CURRENTLY THE MOST ACCESSIBLE PHARMACEUTICAL HIV-1 PREVENTION OPTION, AND ABS ARE CRITICAL FOR IMMUNE PROTECTION AND THERAPEUTIC EFFICACY. AIM 1 FOCUSES ON DETERMINING WHETHER ORAL PREP AFFECTS THE PK OF VRC01, A BROADLY NEUTRALIZING HIV-1 MAB, IN FEMALE PARTICIPANTS FROM THE RECENTLY COMPLETED ANTIBODY MEDIATED PREVENTION (AMP) STUDY. WE WILL IDENTIFY BIOMARKERS OF PREP USE THAT CORRELATE WITH INCREASED MAB CLEARANCE, WITH A SPECIFIC EMPHASIS ON ASSESSING PREP’S EFFECTS ON TWO INTESTINAL AB CLEARANCE MECHANISMS: DISRUPTION OF THE EPITHELIAL BARRIER AND INCREASED FC RECEPTOR (FCR) MEDIATED AB DEGRADATION. AIM 2 EXTENDS THIS INVESTIGATION BY EXAMINING THE IMPACT OF ORAL PREP ON THE MAGNITUDE AND DURABILITY OF HIV-1 VACCINE-INDUCED ANTIBODIES (ABS) IN FEMALE PARTICIPANTS FROM TWO COMPLETED HIV-1 VACCINE EFFICACY TRIALS. TO EXTEND BEYOND HIV-1, WE WILL ALSO ASSESS DURABILITY OF HEPATITIS B (HB) VACCINE-INDUCED ABS IN FEMALE AND MALE PARTICIPANTS FROM AMP AND THE VACCINE TRIALS. CONSISTENT WITH WHAT WAS OBSERVED FOR VRC01 PK IN MALES FROM THE AMP TRIAL, OUR PRELIMINARY DATA IN TWO PRE-EFFICACY VACCINE TRIALS SUGGEST AN ASSOCIATION BETWEEN PREP USE AND FASTER DECAY OF HIV-1 VACCINE-INDUCED ABS. WE PLAN TO IDENTIFY PREP BIOMARKERS ASSOCIATED WITH VACCINE AB KINETICS. IN BIOPSY DONORS, WE WILL ALSO DETERMINE THE ASSOCIATION BETWEEN HB VACCINE AB KINETICS AND IDENTIFIED BIOMARKERS WITH THE TWO POTENTIAL INTESTINAL MECHANISMS OF AB CLEARANCE. CHARACTERIZING ANY PREP EFFECTS ON ABS IS CRUCIAL FOR PEOPLE WHO TAKE ORAL PREP AND RELY ON MAB IMMUNOTHERAPIES AND/OR AB-INDUCING VACCINES FOR PROTECTION AGAINST PATHOGENS. AIM 3 FOCUSES ON DEVELOPING A PHARMACOKINETIC AND STATISTICAL MODELING FRAMEWORK TO RANK AND SELECT MAB REGIMENS FOR EFFICACY TESTING. THIS FRAMEWORK WILL ACCOUNT FOR PREP USE AND MAB PK BIOMARKERS IDENTIFIED IN AIM 1. IT WILL ALSO INCORPORATE MAB LEVELS IN SERUM AND RECTAL TISSUE FROM BOTH MALES AND FEMALES, RECOGNIZING THE IMPORTANCE OF TISSUE LEVELS IN PREDICTING PROTECTION AGAINST HIV-1 AND INTESTINAL PREP EFFECTS ON MAB PK. BY BUILDING AND VALIDATING ADVANCED PK MODELS AND STATISTICAL METHODS FOR BRIDGING DIFFERENCES IN STUDY POPULATIONS, WE SEEK TO ENHANCE THE ACCURACY OF SELECTING THE MOST PROMISING MAB REGIMENS FOR FUTURE CLINICAL TRIALS, ULTIMATELY CONTRIBUTING TO MORE EFFECTIVE HIV-1 PREVENTION STRATEGIES.
assistance · Last action 2025-09-12
$3,554,273
Department of Health and Human Services
DIGITAL SMOKING CESSATION INTERVENTION FOR NATIONALLY-RECRUITED AMERICAN INDIANS AND ALASKA NATIVES: A FULL-SCALE RANDOMIZED CONTROLLED TRIAL - PROJECT SUMMARY/ABSTRACT (DESCRIPTION) SINCE THE EARLY 1980S, AMERICAN INDIANS AND ALASKA NATIVES (AIANS) HAVE MAINTAINED THE HIGHEST RATES OF COMMERCIAL CIGARETTE SMOKING OF ANY RACIAL/ETHNIC GROUP IN THE US. CURRENTLY, 27% OF AIANS SMOKE CIGARETTES. COMPARED TO OTHER RACIAL/ETHNIC GROUPS, THEY HAVE 6 TIMES HIGHER RATES OF DEVELOPING SMOKING-RELATED CANCERS. AIANS ARE ONLY HALF AS LIKELY TO QUIT SMOKING COMPARED TO OTHER RACES/ETHNICITIES. THE RESULT IS THAT COMMERCIAL CIGARETTE SMOKING ACCOUNTS FOR HALF OF ALL DEATHS AMONG AIANS NATIONWIDE. A MAJOR CAUSE OF THESE LONGSTANDING INEQUITIES IS THE LACK OF ACCESS TO EFFICACIOUS SMOKING CESSATION INTERVENTIONS AMONG AIANS. COMPOUNDING THE BARRIER OF LACK OF ACCESS TO SMOKING CESSATION INTERVENTIONS IS THE BARRIER OF LACK OF RESEARCH ON THE EFFICACY OF SMOKING CESSATION INTERVENTIONS FOR AIANS. DESPITE HAVING THE HIGHEST SMOKING PREVALENCE OF ANY RACIAL/ETHNIC GROUP IN THE US FOR OVER 40 YEARS, A MERE 0.3% OF ALL FULL-SCALE SMOKING CESSATION RANDOMIZED CONTROLLED TRIALS (RCTS) HAVE FOCUSED ON AIANS. REGARDING ACCESSIBILITY, A SMARTPHONE APPLICATION (“APP”) HAS THE POTENTIAL TO DELIVER A LOW-COST SMOKING CESSATION INTERVENTION WITH WIDE GEOGRAPHIC REACH TO AIANS AND IN REGIONS OF THE US WITH SMOKING RATES AS HIGH AS 57% IN THIS GROUP (I.E., NORTHERN PLAINS). REGARDING EFFICACY, OUR PRELIMINARY DATA PROVIDES PROMISING EVIDENCE FOR OUR ACCEPTANCE AND COMMITMENT THERAPY (ACT)-BASED SMARTPHONE APP, CALLED ICANQUIT, TO HELP AIANS QUIT SMOKING. WE COMPARED THE ICANQUIT APP WITH THE NCI’S QUITGUIDE APP AMONG THE AIAN SUBSAMPLE (N = 165 RECRUITED FROM 32 US STATES) ENROLLED IN OUR FULL-SCALE RCT. THIS SECONDARY ANALYSIS OF AIANS SHOWED DESCRIPTIVELY HIGHER RATES OF SMOKING CESSATION AT THE 12-MONTH FOLLOW-UP (30% FOR ICANQUIT VS. 18% FOR QUITGUIDE; OR = 1.96; 95% CI = 0.90, 4.26, P = .089). WHILE ENCOURAGING, ANALYSES WERE EXPLORATORY, NON-SIGNIFICANT, AND NOT A SUBSTITUTE FOR A FULL-SCALE EFFICACY TEST. TO ADDRESS WEAKNESSES OF PRIOR RESEARCH, A FULLY-POWERED COMPARATIVE EFFICACY RCT OF ICANQUIT VS. QUITGUIDE FOCUSING NATIONWIDE ON AIANS WHO SMOKE IS NOW NEEDED. THUS, THE GOAL OF THIS PROJECT IS TO CONDUCT A NATIONALLY RECRUITED AND FULLY-POWERED TWO-ARM RCT COMPARING ICANQUIT (N = 388) TO QUITGUIDE (N = 388), IN ORDER TO DETERMINE: (1) THE EFFICACY OF ICANQUIT RELATIVE TO THE QUITGUIDE APP FOR BIOCHEMICALLY VERIFIED 30-DAY POINT PREVALENCE ABSTINENCE (PPA) AT 12 MONTHS POST-RANDOMIZATION AND (2) WHETHER ICANQUIT’S (BUT NOT QUITGUIDE’S) 12-MONTH SMOKING CESSATION OUTCOMES ARE SIGNIFICANTLY MEDIATED BY IMPROVEMENTS IN CORE ACT-BASED PROCESSES. THIS STUDY WILL BE THE FIRST FULL-SCALE RCT OF A DIGITAL INTERVENTION FOR HELPING AIANS NATIONWIDE STOP SMOKING. QUALITATIVE INTERVIEWS WITH (1) A SUBSAMPLE OF ICANQUIT PARTICIPANTS TO THEMATIZE TESTIMONIALS OF THEIR EXPERIENCE WITH ICANQUIT AND (2) AIAN MEMBERS FROM OUR STUDY COMMUNITY ADVISORY BOARD (CAB) WILL GUIDE OUR PLAN FOR BROADLY DISSEMINATING ICANQUIT TO AIAN ADULTS NATIONWIDE. POSITIVE RESULTS WOULD IMPROVE HEALTH EQUITY BY PROVIDING A HIGHLY ACCESSIBLE AND EFFICACIOUS INTERVENTION WITH POTENTIAL FOR SUSTAINABILITY AND BROAD DISSEMINATION FOR AIANS NATIONWIDE.
assistance · Last action 2026-01-20
$3,532,837
Department of Health and Human Services
AN INTEGRATIVE OMICS APPROACH TO INVESTIGATE GENE-ENVIRONMENT INTERACTION IN COLORECTAL CANCER RISK - PROJECT SUMMARY/ABSTRACT COLORECTAL CANCER (CRC) REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS AROUND THE WORLD. MANY ENVIRONMENTAL RISK FACTORS AND OVER 200 GENETIC RISK VARIANTS HAVE BEEN IDENTIFIED FOR THIS COMPLEX, MULTIFACTORIAL DISEASE. HOWEVER, DESPITE THE STRONG BIOLOGICAL RATIONALE FOR THE IMPORTANCE AND ABUNDANCE OF GENE-ENVIRONMENT (GXE) INTERACTIONS, THE EXTENT TO WHICH ENVIRONMENTAL RISK FACTORS (BROADLY DEFINED HERE AS LIFESTYLE, DIET, OBESITY, DRUG USE AND INTERMEDIATE BIOMARKERS) MODULATE GENETIC RISK FACTORS IS POORLY UNDERSTOOD. TO ACHIEVE THE PROMISE OF PRECISION PREVENTION, WE URGENTLY NEED TO GAIN A DEEPER UNDERSTANDING OF GXE INTERACTIONS IN CRC RISK. UNDERSTANDING WHICH MODIFIABLE RISK FACTORS MODULATE GENETIC RISK, WHICH IS FIXED, PROVIDES BIOLOGICAL INSIGHTS AND ACTIONABLE TARGETS FOR NEW PREVENTION INTERVENTION STRATEGIES. TO ACCELERATE THE DISCOVERY OF GXE INTERACTIONS IN CRC RISK AND TO TAKE AN IMPORTANT NEXT STEP TOWARDS TRANSLATION, WE PROPOSE A COMPREHENSIVE INNOVATIVE APPROACH THAT COMBINES SINGLE-CELL MULTI-OMICS DATA, INDIVIDUAL-LEVEL HARMONIZED EPIDEMIOLOGICAL AND CLINICAL DATA, AND GENOME-WIDE DATA FROM LARGE, WELL-CHARACTERIZED, DIVERSE STUDY POPULATIONS, WITH NOVEL COMPUTATIONAL AND STATISTICAL APPROACHES. DRAMATIC IMPROVEMENTS IN SINGLE-CELL MULTIMODAL OMICS TECHNOLOGIES, COMBINED WITH NEW COMPUTATIONAL TOOLS BASED ON POWERFUL DEEP-LEARNING MODELING APPROACHES NOW ALLOW US TO PREDICT THE IMPACT OF GENETIC VARIANTS ON GENE REGULATION IN A CELL-TYPE- SPECIFIC HOLISTIC MANNER. BECAUSE SIMULTANEOUSLY MEASURED SINGLE-CELL GENE EXPRESSION (SCRNA-SEQ) AND CHROMATIN ACCESSIBILITY (SCATAC-SEQ) DATA FOR NORMAL COLORECTAL MUCOSA TISSUE IS LACKING FOR RACIALLY AND ETHNICALLY DIVERSE SAMPLES WITH DETAILED ASSESSMENT OF ENVIRONMENTAL RISK FACTORS, WE PROPOSE IN AIM 1 TO GENERATE SUCH DATA FOR 50 INDIVIDUALS. THIS RESOURCE, TOGETHER WITH OTHER SINGLE CELL MULTI-OMICS COMPENDIA FOR COLORECTAL TISSUE (LIKE HTAN), WILL BE LEVERAGED TO DEVELOP FUNCTIONAL PREDICTION SCORES FOR GENETIC VARIANTS ACROSS THE GENOME. IN AIM 2, WE WILL USE THESE FUNCTIONAL PREDICTION SCORES TO BOOST STATISTICAL POWER FOR DISCOVERY OF NOVEL GXE INTERACTIONS. WE WILL PERFORM GENOME-WIDE GXE SCANS IN OVER 230,000 RACIALLY AND ETHNICALLY DIVERSE CRC CASES AND CONTROLS ACROSS KEY ENVIRONMENTAL RISK FACTORS, INCLUDING OBESITY, DIABETES, SMOKING, ALCOHOL, DRUG USE, DIETARY FACTORS AND INTERMEDIATE BIOMARKERS LINKED TO METABOLIC DYSREGULATION AND CHRONIC INFLAMMATION. TO EXPAND THE NUMBER OF KEY RISK FACTORS WE CAN EVALUATE, WE WILL UTILIZE EXISTING GENETIC INSTRUMENTS. IN AIM 3, WE WILL COMPREHENSIVELY CHARACTERIZE AND TRANSLATE GXE INTERACTIONS. TO DO SO, WE WILL STRATIFY GXE FINDINGS BY CLINICAL FACTORS, INCLUDING AGE OF ONSET, RACIAL AND ETHNIC GROUP, SEX, AND TUMOR SUBTYPES. ADDITIONALLY, WE WILL INCORPORATE GXE INTERACTIONS AND GENETICALLY PREDICTED BIOMARKERS IN A COMPREHENSIVE TRANS-ANCESTRAL RISK PREDICTION MODEL TO IMPROVE PREDICTION AND PROVIDE ACTIONABLE INFORMATION TO REDUCE THE BURDEN OF CRC. OUR COMMUNITY ADVISORS HAVE STRESSED THE IMPORTANCE OF INCLUDING THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN RISK PREDICTION MODELING TO ENHANCE THE ACCEPTANCE OF RISK PREDICTION MODELS IN THE COMMUNITY.
assistance · Last action 2026-05-28
$3,511,381
Department of Health and Human Services
A COMPASS FOR THOSE WITH RELAPSED LEUKEMIA AFTER TRANSPLANT - ABSTRACT RELAPSE OF LEUKEMIA OCCURS IN NEARLY HALF OF PATIENTS AFTER HEMATOPOIETIC CELL TRANSPLANTATION (HCT). WHILE THERE ARE A GROWING NUMBER OF THERAPEUTIC OPTIONS FOR LEUKEMIC RELAPSE AFTER HCT, WE LACK A CLINICAL ASSAY CAPABLE OF SIMULTANEOUSLY DETECTING DISEASE AND TRIAGING PATIENTS TO TREATMENT WHICH WILL MOST LIKELY BENEFIT THEM. IN THIS APPLICATION, WE PROPOSE TO RIGOROUSLY EVALUATE AND EMPLOY NOVEL SINGLE-CELL GENOMIC METHODS AND THEIR ACCOMPANYING COMPUTATIONAL APPROACHES TO DETECT DISEASE AT LOW LEVELS, INFORM MECHANISMS OF RELAPSE, AND DIRECT FUTURE THERAPY. IN AIM 1, WE WILL OPTIMIZE COMPUTATIONAL METHODS FOR DETECTING NATURAL GENETIC VARIATION BETWEEN DONOR AND RECIPIENT, A DIAGNOSTIC MANEUVER WE BELIEVE WILL IMPROVE THE SENSITIVITY OF DETECTING MALIGNANT CELLS AFTER HCT. WE WILL THEN VALIDATE THESE METHODS USING SAMPLES FROM PATIENTS IN A RETROSPECTIVE FASHION. TO PROVIDE INSIGHT INTO MECHANISMS OF RELAPSE, WE HAVE DEVELOPED A NOVEL MOLECULAR APPROACH FOR IDENTIFYING PERTURBATIONS IN HLA AND RELATED GENES, A COMMON MEANS BY WHICH LEUKEMIA EVADES THE IMMUNE SYSTEM AFTER HCT. IN AIM 2, WE WILL VALIDATE THIS METHOD IN A MANNER THAT EXPLORES THE LOWER LIMIT OF DETECTION FOR HLA- PERTURBED CELLS. FINALLY, IN AIM 3, WE WILL BUILD ON DECADES OF WORK USING FLOW CYTOMETRY TO ASSESS THE HETEROGENEITY OF MYELOID NEOPLASMS BY INTEGRATING OUR SINGLE-CELL MOLECULAR MEASURES WITH CELL-SURFACE IMMUNOPHENOTYPE. USING THIS APPROACH, WE SEEK TO DEFINE COMMON MOLECULAR SIGNATURES IN LEUKEMIA-INITIATING CELLS (LICS), A SUBSET OF CELLS IN MYELOID NEOPLASMS THOUGHT TO BE A CHEMO-RESISTANT RESERVOIR OF LEUKEMIA. THE PROPOSED STUDIES WILL ESTABLISH A NEW METHOD FOR SURVEILLANCE OF RESIDUAL DISEASE AFTER HCT, WHICH WE BELIEVE WILL PROVIDE A DEEPER LEVEL OF CONFIDENCE AND INSIGHT INTO LEUKEMIC RELAPSE POST-TRANSPLANT. WE EXPECT THESE STUDIES TO FORM THE FOUNDATIONAL PRECLINICAL DATA FOR A SINGLE-CELL GENOMICS CLINICAL ASSAY CAPABLE OF RISK-STRATIFYING PATIENTS WITH EARLY EVIDENCE OF LEUKEMIC RELAPSE AFTER HCT.
assistance · Last action 2026-06-19
$3,497,050
Department of Health and Human Services
DEVELOPING DURABLE, ENV-BOOSTED CAR T CELLS FOR HIV CURE - PROJECT SUMMARY/ABSTRACT MODIFICATION OF AUTOLOGOUS T CELLS WITH CHIMERIC ANTIGEN RECEPTOR (CAR) MOLECULES WAS FIRST PROPOSED NEARLY 30 YEARS AGO AS A THERAPY FOR PEOPLE LIVING WITH HIV. SINCE THEN, CAR-T CELLS HAVE EMERGED AS A POTENT AND HIGHLY SUCCESSFUL THERAPY FOR LIQUID TUMORS, WHILE HIV-SPECIFIC CAR-T CELLS HAVE ONLY BEGUN TO SHOW EFFICACY IN LARGE ANIMAL MODELS AND CLINICAL TRIALS. BASED ON OUR LONGSTANDING INTEREST IN CAR-T CELL THERAPIES FOR HIV, WE POSIT THREE PRIMARY BARRIERS THAT LIMIT THE CURATIVE POTENTIAL OF THIS APPROACH. FIRST, LOW LEVELS OF HIV-1 ANTIGEN AT THE CELL SURFACE (NAMELY ENV PROTEIN), ESPECIALLY DURING ANTIRETROVIRAL THERAPY (ART), RENDER LATENTLY INFECTED CELLS NEARLY INVISIBLE TO CAR-T CELLS AND OTHER VIRUS-SPECIFIC IMMUNE EFFECTORS. SECOND, THE WEALTH OF KNOWLEDGE REGARDING CELLULAR TRAFFICKING OF THE VIRAL ENV PROTEIN HAS YET TO BE THOROUGHLY APPLIED IN THE CONTEXT OF ENV- DEPENDENT HIV CURE STRATEGIES. THIRD, CAR-T CELL PERSISTENCE AND FUNCTION WANE OVER TIME, PRIOR TO COMPLETE CLEARANCE OF THE LATENT HIV RESERVOIR. OUR GROUNDBREAKING PRELIMINARY DATA OUTLINES A PATH TO OVERCOME THESE LIMITATIONS. WE RECENTLY REPORTED FINDINGS IN FOUR RHESUS MACAQUES THAT WERE INFECTED WITH AN HIV-LIKE VIRUS, SUPPRESSED BY ART AND THEN INFUSED WITH VIRUS-SPECIFIC CAR-T CELLS CONTAINING THE CD4 EXTRACELLULAR DOMAIN (CD4CAR). TO EXPAND THESE POTENT ANTIVIRAL EFFECTORS IN VIVO, ANIMALS WERE NEXT BOOSTED WITH AN IRRADIATED CELL LINE STABLY EXPRESSING HIV-1 ENV. FOLLOWING ART TREATMENT INTERRUPTION (ATI), VIRAL CONTROL WAS OBSERVED IN 2 OF 4 ANIMALS, CONSISTENT WITH ROBUST AND ENV-DEPENDENT EXPANSION OF CD4CAR-T CELLS. THE CENTRAL GOAL OF THIS PROPOSAL IS TO INCREASE THE POTENCY AND FEASIBILITY OF THIS APPROACH. IN AIM 1, WE WILL TRANSITION OUR ENV BOOSTING STRATEGY FROM AN IMMORTALIZED CELL LINE TO AN FDA-APPROVED MRNA LIPID NANOPARTICLE (MRNA-LNP) PLATFORM, ANALOGOUS TO THE MODERNA AND PFIZER/BIONTECH VACCINES FOR SARS-COV-2. ENV IMMUNOGENS WILL BE OPTIMIZED FOR CD4CAR T CELL INTERACTIONS AND DEVELOPED AS ENV MRNA-LNP VACCINES. IN AIM 2, WE WILL USE CRISPR- CAS9 GENE EDITING TO EXTEND THE DURABILITY AND FUNCTION OF CD4CAR-T CELLS. WE WILL COMPARE A SERIES OF CAR PRODUCTS THAT CARRY INACTIVATED IMMUNE CHECKPOINT ALLELES, WHICH WE HYPOTHESIZE WILL SUPPORT MORE DURABLE FUNCTION AND EFFICIENTLY CLEAR PERSISTENT VIRAL RESERVOIRS. IN AIM 3, WE WILL BENCHMARK ENV MRNA-LNP AND IMMUNE CHECKPOINT GENE EDITING STRATEGIES IN OUR VETTED NONHUMAN PRIMATE (NHP) MODEL OF HIV GENE THERAPY. THESE EXPERIMENTS WILL FEATURE A POWERFUL COMPETITIVE REPOPULATION STUDY DESIGN, PROVIDING CRITICAL INFORMATION ON BASIC CAR BIOLOGY THAT CANNOT BE GATHERED IN CLINICAL STUDIES. TOGETHER, THESE AIMS BUILD ON WHAT WE BELIEVE TO BE THE MOST PROMISING ANTI-HIV CELL AND GENE THERAPY APPROACH REPORTED TO DATE. OUR UNIQUE AND HIGHLY INFORMATIVE NHP MODEL OF HIV PERSISTENCE AND CAR-T CELL THERAPY WILL FILL IN CRITICAL GAPS IN KNOWLEDGE REGARDING CAR-T CELL SAFETY AND FUNCTION IN LIMITED ANTIGEN ENVIRONMENTS, AND FACILITATE CLINICAL TRANSLATION BOTH IN DEVELOPED AND DEVELOPING NATIONS. THE LESSONS WE LEARN FROM THESE STUDIES WILL BE APPLICABLE NOT ONLY AS A CURATIVE THERAPY FOR HIV-1, BUT FOR A RANGE OF DISEASES SUCH AS SOLID TUMORS WHERE CAR-T CELL THERAPIES MUST BE SIMILARLY AUGMENTED.
assistance · Last action 2025-11-27
$3,377,416
Department of Health and Human Services
MOLECULAR BASIS AND PROTECTIVE EFFICACY OF CROSS-NEUTRALIZING ANTIBODIES AGAINST FOUR MAJOR RESPIRATORY VIRUSES - PROJECT SUMMARY/ABSTRACT TENS OF THOUSANDS OF OTHERWISE DEADLY CANCERS ARE CURED WORLDWIDE EACH YEAR BY HEMATOPOIETIC STEM CELL TRANSPLANTATION (HCT), BUT UNFORTUNATELY OVER ONE IN TEN PATIENTS WILL DEVELOP A VIRAL LOWER RESPIRATORY TRACT INFECTION, WITH ALMOST HALF OF THESE PATIENTS SUCCUMBING TO THE INFECTION. WITHOUT AN INTACT IMMUNE SYSTEM IN THE FIRST FEW MONTHS AFTER TRANSPLANT, THESE LIFE-THREATENING INFECTIONS OFFSET THE BENEFIT DERIVED FROM POTENTIALLY LIFE- SAVING TRANSPLANT. OVER HALF OF THESE INFECTIONS ARE CAUSED BY FOUR VIRUSES: RSV, HMPV, HPIV3, AND HPIV1, NONE OF WHICH CURRENTLY HAVE ANY PHARMACOLOGIC INTERVENTIONS FOR TREATMENT OR PREVENTION AFTER HCT. ALTHOUGH ADULTS ARE UNIVERSALLY INFECTED WITH THESE VIRUSES IN CHILDHOOD, HCT RECIPIENTS LOSE THEIR IMMUNITY, MAKING THEM VULNERABLE TO SEVERE COMPLICATIONS. PASSIVE IMMUNIZATION WITH MONOCLONAL ANTIBODIES (MABS) REPRESENTS A STRATEGY TO REDUCE THE RISK OF THESE INFECTIONS. WHILE SEVERAL ANTI-RSV MAB CANDIDATES HAVE PROGRESSED THROUGH CLINICAL TRIALS, THEIR USE IS LIMITED TO INFANTS IN WHOM RSV IS RESPONSIBLE FOR VIRTUALLY ALL CASES OF LUNG INFECTION. HOWEVER, THE CLINICAL EFFICACY OF THESE MABS IS EXPECTED TO BE SUBSTANTIALLY LOWER IN HCT PATIENTS BECAUSE OTHER IMPORTANT VIRUSES LIKE HMPV, HPIV3, AND HPIV1 CONTRIBUTE SIGNIFICANTLY TO DISEASE. TO FILL THIS CLINICAL GAP FOR HCT PATIENTS, WE HAVE DISCOVERED TWO CROSS-NEUTRALIZING MABS: ONE THAT TARGETS BOTH RSV AND HMPV AND ANOTHER THAT TARGETS BOTH HPIV3 AND HPIV1. TOGETHER, THESE MABS COULD BE COMBINED TO SIMULTANEOUSLY PROTECT AGAINST THE FOUR VIRUSES THAT CAUSE MOST LUNG INFECTIONS AFTER HCT. TO TEST EFFICACY, WE WILL ADMINISTER THESE MABS PROPHYLACTICALLY AND THERAPEUTICALLY TO IMMUNOCOMPETENT AND IMMUNOCOMPROMISED ANIMALS. WE WILL ALSO TEST THE PHARMACOKINETICS OF THESE MABS WITH MODIFICATIONS DESIGNED FOR INCREASED HALF-LIFE AND LUNG BIOAVAILABILITY, SUCH THAT A SINGLE DOSE COULD BRIDGE THE ENTIRE PERIOD OF VULNERABILITY AFTER TRANSPLANT. ANOTHER OFTEN NEGLECTED PITFALL IN BRINGING NOVEL ANTIBODY THERAPIES TO THE BEDSIDE IS THE POTENTIAL FOR RESISTANCE. RECENT FAILED CLINICAL TRIALS OF ANTI-RSV MABS HAVE SHOWN THAT THE EMERGENCE OF ESCAPE VARIANTS CAN CRIPPLE CLINICAL DEVELOPMENT. HOW TO PREDICT SUCCESS OR FAILURE DURING THE PRECLINICAL PHASE BEFORE CANDIDATES PROGRESS INTO CLINICAL TRIALS IS AN IMPORTANT QUESTION, AND THE ANSWERS COULD SAVE MASSIVE AMOUNTS OF RESOURCES, EFFORT, AND TIME. TO FILL THIS KNOWLEDGE GAP, WE HAVE DEVELOPED AN INNOVATIVE APPROACH CALLED DEEP MUTATIONAL SCANNING THAT PROVIDES A COMPREHENSIVE PICTURE OF THE VIRAL MUTATIONAL LANDSCAPE, ALLOWING AN UNPRECEDENTED PRECLINICAL EVALUATION OF RESISTANCE. SINCE THE TWO CROSS-NEUTRALIZING MABS DESCRIBED IN THIS PROPOSAL BIND TO CONSERVED EPITOPES, THESE AND SIMILAR MABS MAY HAVE A HIGH BARRIER OF RESISTANCE. TO PREPARE FOR AND COUNTER RESISTANCE BY FUTURE VIRAL VARIANTS, WE WILL LEVERAGE PREDICTIONS FROM OUR COMPLETE MUTATIONAL MAPS TO IDENTIFY NEXT- GENERATION MABS, ALLOWING US TO STAY A FEW STEPS AHEAD OF VIRAL EVOLUTION. THESE NOVEL CROSS-NEUTRALIZING MABS AND THE INNOVATIVE AND RIGOROUS APPROACHES WE HAVE DEVELOPED TO VET THEM COULD PROVIDE A NEW STANDARD OF CARE FOR HCT PATIENTS AND INFORM THE DESIGN AND TESTING OF OTHER CANDIDATES WITH THE GREATEST CHANCE FOR SUCCESS.
assistance · Last action 2026-03-09
$3,195,963
Department of Health and Human Services
DEEPLY ANALYZING MHC CLASS I-RESTRICTED PEPTIDE PRESENTATION MECHANISTICS ACROSS ALLELES, PATHWAYS, AND DISEASE COUPLED WITH TCR DISCOVERY/CHARACTERIZATION - PROJECT ABSTRACT/SUMMARY - OUR FRAMING HYPOTHESIS IS THAT THE COMBINED CONSTRAINTS OF PEPTIDE PROCESSING, HLA ALLELIC SPECIFICITY, AND PEPTIDE EDITING GENERATE A SIGNIFICANT “FUNNEL EFFECT”, WHERE THE PEPTIDOME CONSTITUTES ONLY A TINY PERCENTAGE OF ALL POSSIBLE PEPTIDES OBTAINABLE FROM A CELL’S PROTEOME AND THE LIGANDOME CONSTITUTES ONLY A SMALL PERCENTAGE OF ALL PEPTIDES FROM A CELL’S PEPTIDOME. OUR RESEARCH FOCUS IS UNDERSTANDING HOW THE INTERPLAY OF DIFFERENTIAL SEQUENCE RECOGNITION AT EACH STEP ULTIMATELY INFORMS FUNCTIONAL PRESENTATION OF A HIGHLY RESTRICTED SUBSET OF ALL POSSIBLE PROTEOME-DERIVED PEPTIDES – AND HOW TO IDENTIFY THE MOST “TRANSLATABLE” PHLA TARGETS FROM LIGANDOMES. - WE WILL RIGOROUSLY TEST THIS HYPOTHESIS USING OUR ALLELE-SPECIFIC MASS-SPEC PLATFORM FOR PEPTIDE DISCOVERY, ARTEMIS, TO IDENTIFY RELEVANT, HLA-RESTRICTED PEPTIDES FROM MESOTHELIN AND HIGH-RISK HPV E6/E7 ONCOPROTEINS. IDENTIFIED PEPTIDES WILL BE VALIDATED AND CHARACTERIZED BIOCHEMICALLY. CELL-SURFACE DISPLAYED PEPTIDE ARRAYS FROM E6/E7 AND MESOTHELIN WILL BE USED TO DETERMINE THE MAGNITUDE OF THE “FUNNEL EFFECT” OF PEPTIDE PROCESSING ON PEPTIDOME COMPOSITION. PATIENT T CELL RESPONSES TO IDENTIFIED MESOTHELIN PEPTIDES WILL BE MAPPED USING STATE- OF-THE-ART METHODOLOGIES. UNUSUAL PEPTIDES AND ALTERNATE BINDING CONFORMATIONS WILL BE CHARACTERIZED CRYSTALLO- GRAPHICALLY. WE WILL ASSESS VIRAL IMMUNOEVASION MECHANISMS, HLA-G PRESENTATION AND RECEPTOR INTERACTIONS, AND THE PRESENTATION OF GLYCOSYLATED PEPTIDES. DELIVERABLES INCLUDE MAPPING THE FULL MESOTHELIN AND E6/E7 PRESENTOMES ACROSS MULTIPLE ALLELES AND PRESENTATION MODALITIES, RANKED FOR FUTURE CLINICAL EXPLOITATION AS IMMU- NOTHERAPY TARGETS. - SIGNIFICANCE: FROM A BASIC SCIENCE PERSPECTIVE, ASSAYING CELLULAR PEPTIDOMES AND LIGANDOMES IS FUNDAMENTAL FOR UNDERSTANDING HOW THE IMMUNE SYSTEM RESPONDS TO INFECTIONS AND CANCER, IMMUNOEVASION MECHANISMS, THE RECOGNITION RULES OF MHC PROTEINS, THE MECHANISTICS OF ANTIGEN PROCESSING/EDITING, AND HOW SELF IS DEFINED. FROM A TRANSLATIONAL PERSPECTIVE, VALIDATED HLA-RESTRICTED PEPTIDES REPRESENT TARGETS FOR DIAGNOSIS AND THERAPY, THROUGH THERAPEUTIC VACCINATION, ENGINEERED T CELL-BASED ADOPTIVE IMMUNOTHERAPIES, AND ANTIBODY-BASED RECOG- NITION OF SPECIFIC, DISEASE-ASSOCIATED PEPTIDE/HLA COMPLEXES OUR PROPOSED STUDIES ADVANCE BOTH OBJECTIVES BY ELUCIDATING THE UNDERLYING MOLECULAR PRINCIPLES GOVERNING PEPTIDE PROCESSING AND PRESENTATION THROUGH INTE- GRATED STUDIES OF AN EXTENDED SET OF CLASSICAL AND NON-CLASSICAL HUMAN HLA CLASS I PROTEINS AND, IN THE PROCESS, IDENTIFY SPECIFIC PHLAS USEFUL FOR FUTURE CLINICAL APPLICATIONS.
assistance · Last action 2026-01-17
$3,192,698
Department of Health and Human Services
A PATIENT-CENTRIC APPROACH TO ADVANCE FUNCTIONAL PRECISION ONCOLOGY - PROJECT SUMMARY/ABSTRACT THE DEVELOPMENT OF DRUG RESISTANCE IS A MAJOR CAUSE OF CANCER TREATMENT FAILURE AND MORTALITY. ALTHOUGH MUCH IS KNOWN ABOUT THE MECHANISMS BY WHICH TUMOR CELLS CAN BECOME RESISTANT TO A GIVEN DRUG, TRANSLATING THIS INTO EFFECTIVE THERAPEUTIC SOLUTIONS REMAINS AN UNMET CLINICAL NEED. HERE WE PROPOSE TO PIONEER THE USE OF PATIENT DERIVED TUMOR ORGANOIDS (PDTOS) AS A PLATFORM TO IDENTIFY AND VALIDATE NOVEL TARGETS AND EFFECTIVE DRUGS TO OVERCOME DRUG RESISTANCE IN OVARIAN CANCER, PANCREATIC CANCER, AND OTHER TUMOR TYPES. IN OUR PRELIMINARY STUDIES, WE SHOW THAT PDTOS GENETICALLY AND PHENOTYPICALLY MATCH THE TUMOR FROM WHICH THEY WERE DERIVED AND CAN BE USED TO STUDY THE PHENOTYPIC CONSEQUENCES OF TUMOR HETEROGENEITY, TUMOR EVOLUTION, AND DRUG RESISTANCE. USING A CLINICAL LABORATORY IMPROVEMENT AMENDMENTS (CLIA) APPROVED HIGH COMPLEXITY ASSAY, WE SHOW THAT PDTO DRUG SENSITIVITIES ARE HIGHLY CONCORDANT WITH KNOWN GENETIC BIOMARKERS, RETROSPECTIVE TREATMENT HISTORY AND PROSPECTIVE PATIENT RESPONSES. TUMOR ORGANOIDS DERIVED FROM PATIENTS WHO DEVELOPED IN SITU DRUG RESISTANCE DEMONSTRATE EX VIVO RESISTANCE TO THOSE SAME DRUGS BUT ALSO DEMONSTRATE SENSITIVITY TO OTHER ALTERNATIVE ONCOLOGY DRUGS. ADDITIONAL PRELIMINARY STUDIES SHOW STABLE DISEASE OR TUMOR REGRESSION IN PATIENTS TREATED WITH DRUGS IDENTIFIED FROM ORGANOID DRUG SCREENS. HERE, WE PROPOSE TO COMBINE DRUG SCREENING AND MOLECULAR PROFILING OF PDTOS DERIVED FROM A GIVEN PATIENT FROM DIFFERENT ANATOMIC TUMOR SITES AND BEFORE AND AFTER THERAPY TO ELUCIDATE THE MECHANISTIC BASIS FOR DRUG SENSITIVITY OR RESISTANCE AND TO IDENTIFY NOVEL TARGETS AND EFFECTIVE DRUGS TO TREAT METASTATIC, DRUG RESISTANT CANCERS. ACCOMPANYING COMPUTATIONAL PREDICTION MODELS THAT INTEGRATE LARGE PUBLIC DATASETS AS WELL AS INNOVATIVE METHODS OF MECHANISTIC TARGET VALIDATION INCLUDING CRISPR, TARGETED PROTEIN DEGRADATION TECHNOLOGIES, AND EPIGENETIC PROFILING, WILL BE USED TO PRIORITIZE AND ADVANCE TARGETS AND ASSOCIATED BIOMARKERS WITH GREATEST CLINICAL POTENTIAL. THE RATIONALE BEHIND OUR APPROACH IS THAT IDENTIFYING TARGETS AND EFFECTIVE DRUGS DIRECTLY IN PATIENT DERIVED SAMPLES WITH KNOWN CLINICAL HISTORY AND OUTCOMES WILL SIGNIFICANTLY ENHANCE TRANSLATION OF OUR FINDINGS. THIS PROPOSAL IS SIGNIFICANT BECAUSE IT WILL DEMONSTRATE THE UTILITY OF PDTOS AS BOTH A RESEARCH TOOL FOR TARGET DISCOVERY AND VALIDATION BUT ALSO AS A CLINICALLY USEFUL PLATFORM TO GUIDE FUNCTIONAL PRECISION MEDICINE. THE FINDINGS AND METHODS DEVELOPED CAN BE READILY APPLIED TO OTHER CANCER TYPES AND CLINICAL CHALLENGES, WILL ACCELERATE PRECLINICAL DRUG AND DRUG TARGET DEVELOPMENT, AND WILL TRANSLATE TO CLINICAL STUDIES. THE MODELS, APPROACHES, AND EXPECTED OUTCOMES OF THIS PROPOSAL ARE HIGHLY RESPONSIVE TO THE REQUIREMENTS OF PAR-21-274.
assistance · Last action 2026-04-10
$3,167,628
Department of Health and Human Services
PAR-4 REGULATION OF ACTOMYOSIN CONTRACTILITY AS A TUMOR SUPPRESSIVE MECHANISM IN BREAST CANCER - PROJECT SUMMARY/ABSTRACT TUMOR PROGRESSION – INCLUDING RESISTANCE TO THERAPY, METASTASIS, AND RECURRENCE – IS RESPONSIBLE FOR THE MAJORITY OF CANCER DEATHS. UNDERSTANDING HOW CANCER CELLS SURVIVE TREATMENT, SPREAD TO DISTANT SITES, PERSIST AS DORMANT RESIDUAL CELLS, AND EVENTUALLY RECUR IS ESSENTIAL TO IMPROVING THE TREATMENT OF THIS DISEASE. THE LONG-TERM GOAL OF MY RESEARCH GROUP IS TO IDENTIFY THE PATHWAYS THAT REGULATE THESE PROCESSES IN ORDER TO PREVENT OR TREAT TUMOR RECURRENCE. TO ACHIEVE, THIS WE ARE USING CONDITIONAL GENETICALLY ENGINEERED MOUSE (GEM) MODELS OF BREAST CANCER THAT ALLOW FOR THE MECHANISTIC DISSECTION OF THE PROCESSES OF DORMANCY AND RECURRENCE. USING THESE MODELS, WE HAVE IDENTIFIED A FUNCTIONAL ROLE FOR THE TUMOR SUPPRESSOR PAR-4 IN REGULATING SURVIVAL AND RECURRENCE OF BREAST CANCER CELLS AFTER THERAPY. PAR-4 IS DOWNREGULATED IN RECURRENT TUMORS FROM THREE GEM MODELS, AND THIS DOWNREGULATION IS BOTH NECESSARY AND SUFFICIENT FOR TUMOR RECURRENCE. SIMILARLY, IN WOMEN WITH BREAST CANCER, LOW PAR-4 EXPRESSION IS ASSOCIATED WITH A POOR RESPONSE TO NEOADJUVANT THERAPY AND AN INCREASED RISK OF RECURRENCE. WE HAVE CHARACTERIZED THE UPSTREAM PATHWAYS THAT REGULATE PAR-4 EXPRESSION AND FUNCTION DURING DORMANCY AND RECURRENCE, AS WELL AS THE DOWNSTREAM PATHWAYS THAT PAR-4 REGULATES TO INHIBIT DORMANT CELL SURVIVAL AND RECURRENCE. THIS PROPOSAL WILL BUILD ON THIS WORK TO FURTHER EXPLORE THE MECHANISM BY WHICH PAR-4 ACTS AS A TUMOR SUPPRESSOR. THE OVERARCHING HYPOTHESIS OF THE PROPOSAL IS THAT PAR-4 PROMOTES CELL DEATH IN PART THROUGH INDUCING ACTOMYOSIN CONTRACTILITY, AND THIS CONTRIBUTES TO ITS TUMOR SUPPRESSIVE FUNCTIONS. WE WILL EXPLORE THIS HYPOTHESIS IN THE CONTEXT OF PAR-4’S ROLE IN RESIDUAL CELL SURVIVAL AND THE SURVIVAL OF INVASIVE LOBULAR CANCER CELLS. OUR WORK WILL REVEAL NEW INFORMATION ON HOW PAR-4 FUNCTIONS TO REGULATE DORMANT RESIDUAL CELL SURVIVAL AND MAY UNCOVER NOVEL OPPORTUNITIES FOR THERAPEUTIC INTERVENTION IN ELIMINATING RESIDUAL CELLS AND PREVENTING RECURRENCE.
assistance · Last action 2026-06-11
$3,037,398
Department of Health and Human Services
MODULATION OF SIGNALING FROM DAMAGE-ASSOCIATED MOLECULAR PATTERNS TO IMPROVE RADIATION-INDUCED THYMIC DYSFUNCTION - PROJECT SUMMARY THE THYMUS, WHICH IS THE PRIMARY SITE OF T CELL GENERATION, IS EXTREMELY SENSITIVE TO INSULT, BUT ALSO HAS A REMARKABLE CAPACITY FOR ENDOGENOUS REPAIR. EVEN THOUGH THERE IS LIKELY CONTINUAL THYMIC INVOLUTION AND REGENERATION IN RESPONSE TO EVERYDAY INSULTS LIKE STRESS AND INFECTION, PROFOUND THYMIC DAMAGE CAUSED BY RADIATION INJURY LEADS TO PROLONGED T CELL LYMPHOPENIA. CONSEQUENTLY, IDENTIFICATION OF THERAPIES THAT CAN BOOST T CELL RECONSTITUTION IN RECIPIENTS AFTER A DOSE OF RADIATION IS A CLEAR PRIORITY. WE HAVE PREVIOUSLY IDENTIFIED TWO DISTINCT PATHWAYS OF ENDOGENOUS THYMIC REGENERATION, CENTERED ON THE PRODUCTION OF THE REGENERATION FACTORS IL-22 BY INNATE LYMPHOID CELLS (ILCS), AND BMP4 BY ENDOTHELIAL CELLS (ECS); BOTH OF WHICH MEDIATE THEIR REGENERATIVE EFFECTS BY TARGETING THYMIC EPITHELIAL CELLS. MORE RECENTLY WE HAVE FOUND THAT THE TRIGGER FOR THESE DISTINCT REGENERATIVE PATHWAYS HINGE ON THE BALANCE BETWEEN FORMS OF CELL DEATH, WITH IMMUNOLOGICALLY SILENT APOPTOSIS (WHICH IS ABUNDANT IN THYMOCYTES DURING STEADY-STATE) SUPPRESSIVE TO THE REGENERATIVE PROGRAM. ON THE OTHER HAND, AFTER THYMIC DAMAGE CAUSED BY RADIATION INJURY, WE FOUND A SWITCH TOWARD IMMUNOGENIC CELL DEATH, WITH THE RESULTING RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS) SUFFICIENT TO PROMOTE REGENERATION. SPECIFICALLY, WE IDENTIFIED THAT INTRACELLULAR ZN WAS RELEASED AFTER RADIATION INJURY, WHERE IT COULD SIGNAL THROUGH THE G-PROTEIN COUPLED RECEPTOR 39 (GPR39) TO STIMULATE PRODUCTION OF BMP4 AND IL-23, A KEY UPSTREAM REGULATOR OF IL-22 PRODUCTION. SEPARATELY, WE ALSO FOUND THAT THE RELEASE OF THE PROTOTYPICAL DAMP, ATP, WAS ABLE TO SIGNAL DIRECTLY ON THYMIC EPITHELIAL CELLS THROUGH PURINERGIC (P2) RECEPTORS AND PROMOTE THEIR EXPRESSION OF FOXN1, KEY MICROENVIRONMENTAL DRIVERS OF T CELL DEVELOPMENT. IMPORTANTLY, OUR PRELIMINARY DATA ALSO SUGGESTS THAT EACH OF THESE PATHWAYS CAN BE THERAPEUTICALLY TARGETED TO IMPROVE THYMIC RECOVERY FOLLOWING RADIATION DAMAGE IN YOUNG MICE. BASED ON OUR PRELIMINARY DATA, WE HYPOTHESIZE THAT MODULATION OF PATHWAYS ASSOCIATED WITH THESE DAMPS CAN BE USED AS A COUNTERMEASURE TO IMPROVE IMMUNE FUNCTION AFTER RADIATION INJURY BY STIMULATING THE GENERATION OF NEW T CELLS IN THE THYMUS. SPECIFICALLY, OUR PROPOSAL HAS THE FOLLOWING AIMS: (1) TO VALIDATE AND OPTIMIZE THE TARGETING OF GPR39 OR P2 RECEPTORS TO IMPROVE THE PRODUCTION OF NEW T CELLS AND IMMUNE FUNCTION AFTER RADIATION INJURY; (2) TO EXAMINE THE ABILITY OF THE THYMUS TO RESPOND TO REGENERATIVE SIGNALS ACROSS MOUSE LIFESPAN AND SEX; AND (3) TO COMPREHENSIVELY EVALUATE THE POTENTIAL FOR TARGETING GPR39 OR P2 RECEPTORS TO IMPROVE THYMIC FUNCTION AFTER RADIATION DAMAGE ACROSS MOUSE LIFESPAN AND SEX. THE STUDIES OUTLINED IN THIS PROPOSAL NOT ONLY HAVE THE POTENTIAL TO DEFINE IMPORTANT PATHWAYS UNDERLYING TISSUE REGENERATION ACROSS LIFESPAN BUT COULD ALSO RESULT IN INNOVATIVE APPROACHES TO ENHANCE T CELL RECOVERY AFTER RADIATION DAMAGE.
assistance · Last action 2026-05-26
$3,024,848
Department of Health and Human Services
DEFINING PROTECTIVE CMV IMMUNITY AFTER TRANSPLANTATION - PROJECT SUMMARY/ABSTRACT CYTOMEGALOVIRUS (CMV) INFECTION IS A FREQUENT AND LIFE-THREATENING COMPLICATION THAT SIGNIFICANTLY LIMITS THE SUCCESSFUL OUTCOME OF ALLOGENEIC HEMATOPOIETIC STEM CELL OR BONE MARROW TRANSPLANTATION (REFERRED TO HEREAFTER AT BMT). WE HAVE RECENTLY DEVELOPED LONG-DESIRED PRECLINICAL (MURINE) MODELS OF CMV REACTIVATION AFTER BMT AND SHOW FOR THE FIRST TIME, THAT HUMORAL IMMUNITY IS CRITICAL TO PREVENT VIRAL RECRUDESCENCE. WE NOW DEMONSTRATE THAT EITHER THE TRANSFER OF IMMUNE T CELLS OR STRAIN-SPECIFIC SERA (CONTAINING IGG ANTIBODY) PREVENTS VIRAL REACTIVATION, VIREMIA, END-ORGAN VIRAL REPLICATION AND CMV DISEASE DURING GRAFT-VERSUS-HOST DISEASE (GVHD). WE PLAN TO UTILIZE OUR UNIQUE, BUT WELL-ESTABLISHED PRECLINICAL MODELS TO DEFINE THE IMPACT OF PROTECTIVE ANTIBODY ON THE TEMPORAL AND SPATIAL CHARACTERISTICS OF CMV REACTIVATION, DISSEMINATION AND ANTIGEN PRESENTATION. SUBSEQUENTLY WE WILL DEFINE THE INTERPLAY OF T CELL AND HUMORAL RESPONSES THAT ARE REQUIRED FOR THE DURABLE CONTROL OF CMV REACTIVATION AFTER BMT. FINALLY, WE WILL DEVELOP CLINICALLY TRACTABLE PATHWAYS TO ENHANCE CMV IMMUNITY WHILST PREVENTING GVHD AND ASSOCIATED INFLAMMATION, TARGETING IL-6 INHIBITION. OUR PROPOSED STUDIES WILL PROVIDE CRITICAL INSIGHTS INTO THE IMMUNE REQUIREMENTS FOR EFFECTIVE AND LONG-TERM CONTROL OF CMV IN RECIPIENTS WITH GVHD AND/OR CLINICALLY RELEVANT IMMUNE SUPPRESSION AND INFLAMMATION THAT WILL ALLOW US TO OPTIMIZE CMV IMMUNITY IN CLINICAL BMT TO IMPROVE PATIENT OUTCOMES.
assistance · Last action 2026-02-24
$3,018,159
Department of Health and Human Services
NRF2 SUPPRESSION OF INFLAMMATORY SIGNALING AND ITS ROLE IN TUMOR PROGRESSION - PROJECT SUMMARY/ABSTRACT TUMOR METASTASIS IS RESPONSIBLE FOR THE VAST MAJORITY OF DEATHS FROM EPITHELIAL CANCERS, INCLUDING BREAST CANCER. UNDERSTANDING HOW CANCER CELLS SPREAD TO DISTANT SITES, PERSIST AS DORMANT DISSEMINATED TUMOR CELLS (DTCS), AND EVENTUALLY RECUR IS ESSENTIAL TO IMPROVING THE TREATMENT OF THIS DISEASE. THE LONG-TERM GOAL OF MY RESEARCH GROUP IS TO IDENTIFY PATHWAYS THAT REGULATE THESE PROCESSES TO ENABLE THE DEVELOPMENT OF THERAPIES THAT CAN PREVENT OR TREAT METASTATIC RECURRENCES. WE RECENTLY IDENTIFIED A ROLE FOR THE ANTIOXIDANT STRESS RESPONSE TRANSCRIPTION FACTOR NRF2 IN PROMOTING THE SURVIVAL AND LOCAL RECURRENCE OF MAMMARY TUMORS FOLLOWING TARGETED THERAPY. WE FOUND THAT NRF2 IS ACTIVATED FOLLOWING DIVERSE TARGETED THERAPIES AS A CONSEQUENCE OF METABOLIC AND OXIDATIVE STRESS. NRF2 REMAINS CONSTITUTIVELY ACTIVATED IN RECURRENT TUMORS, WHERE IT FUNCTIONS TO PROMOTE RECURRENCE THROUGH REGULATING REDOX HOMEOSTASIS AND NUCLEOTIDE METABOLISM. WHILE THESE RESULTS IDENTIFY A FUNCTION FOR NRF2 IN LOCAL RECURRENCE, A ROLE FOR NRF2 IN PROMOTING METASTATIC DISSEMINATION REMAINS RELATIVELY UNEXPLORED. EMERGING EVIDENCE SUGGESTS THAT METASTATIC DISSEMINATION IS ASSOCIATED WITH METABOLIC AND OXIDATIVE STRESS. CONSISTENT WITH THIS, WE RECENTLY FOUND THAT THE NRF2 TRANSCRIPTIONAL PROGRAM IS ELEVATED IN METASTATIC TUMORS FROM PATIENTS WITH BREAST CANCER. HOWEVER, A THOROUGH UNDERSTANDING OF NRF2 REGULATION DURING METASTATIC DISSEMINATION, AND HOW NRF2 ACTIVATION FUNCTIONALLY AFFECTS METASTASIS, REMAINS UNKNOWN. THIS PROPOSAL WILL BUILD ON THIS WORK TO DEFINE THE REGULATION AND FUNCTION OF NRF2 DURING METASTASIS IN BREAST CANCER. IN NEW PRELIMINARY DATA, WE FOUND THAT NRF2 SUPPRESSES PRO-INFLAMMATORY SIGNALING IN BREAST CANCER. CONSISTENT WITH THIS, NRF2 KNOCKDOWN LEADS TO INFILTRATION OF IMMUNE CELLS INTO THE TUMOR MICROENVIRONMENT. BASED UPON THESE FINDINGS, THE CENTRAL HYPOTHESIS FOR THIS PROPOSAL IS THAT NRF2 PROMOTES BREAST CANCER PROGRESSION BY INHIBITING PRO-INFLAMMATORY SIGNALING BETWEEN CANCER CELLS AND THE TUMOR IMMUNE MICROENVIRONMENT. WE WILL TEST THIS HYPOTHESIS THROUGH THREE SPECIFIC AIMS. IN AIM 1, WE WILL DEFINE THE MECHANISM AND FUNCTION OF NRF2 REGULATION OF THE TUMOR IMMUNE MICROENVIRONMENT. IN AIM 2, WE WILL DETERMINE THE ROLE OF NRF2 SUPPRESSION OF INFLAMMATORY SIGNALING IN PROMOTING THE OUTGROWTH OF DISSEMINATED TUMOR CELLS. IN AIM 3 WE WILL TEST WHETHER TARGETING METABOLIC PATHWAYS CAN PREVENT THE GROWTH OF NRF2-HIGH TUMORS. OUR WORK WILL REVEAL NEW INFORMATION ON HOW NRF2 FUNCTIONS TO REGULATE TUMOR PROGRESSION AND MAY UNCOVER NOVEL THERAPEUTIC OPPORTUNITIES TO PREVENT METASTATIC RECURRENCE.
assistance · Last action 2026-06-19
$2,964,873
Department of Health and Human Services
BREAST-CANCER FOCUSED BIOMARKER CHARACTERIZATION CENTER EMPLOYING TARGETED MASS SPEC ASSAYS IN A CLIA ENVIRONMENT - PROJECT SUMMARY/ABSTRACT (OVERALL COMPONENT, RFA-CA-22-040) WE PROPOSE TO DEVELOP A BLOOD-BASED TEST WHOSE INDICATED USE IS TO COMPLEMENT MAMMOGRAPHY IN THE EARLY DETECTION OF BREAST CANCERS. ALTHOUGH MAMMOGRAPHY SAVES LIVES THROUGH EARLY DETECTION, IT IS IMPERFECT. APPROXIMATELY ONE IN SEVEN BREAST CANCERS GOES UNDETECTED DESPITE SCREENING MAMMOGRAPHY, AND INTERVAL CANCERS THAT MANIFEST WITHIN A YEAR OF A NORMAL MAMMOGRAM REMAIN A VEXING PROBLEM, ESPECIALLY (ALTHOUGH NOT EXCLUSIVELY) FOR THE >27 MILLION WOMEN IN THE UNITED STATES WITH HETEROGENEOUSLY OR EXTREMELY DENSE BREASTS AT HIGH RISK FOR INTERVAL CANCERS. WE PROPOSE TO DEVELOP A BLOOD TEST THAT COULD BE USED AS AN ADJUNCT TO MAMMOGRAPHY TO IMPROVE EARLY DETECTION BY IMPROVING SENSITIVITY AND/OR SPECIFICITY OF MAMMOGRAPHY. USING A NOVEL BIOMARKER DISCOVERY APPROACH LEVERAGING HUMAN-IN-MOUSE BREAST CANCER PATIENT-DERIVED XENOGRAFT MODELS AND STATE-OF-THE-ART MASS SPECTROMETRY METHODS, WE PRIORITIZED 162 CANDIDATE BREAST CANCER PROTEIN BIOMARKERS FOR VALIDATION STUDIES. OUR BCC WILL PERFORM EDRN PHASE 2 BIOMARKER VALIDATION STUDIES OF OUR PRIORITIZED 162 CANDIDATE PLASMA PROTEIN BIOMARKERS OF BREAST CANCER. WE HAVE AN EXPERIENCED MULTIDISCIPLINARY TEAM (INCLUDING TWO JUNIOR INVESTIGATORS) WITH A STRONG TRACK RECORD OF PRODUCTIVE COLLABORATION AND REPRESENTING EXPERTISE IN CLINICAL ONCOLOGY, CANCER BIOMARKERS, PATHOLOGY, CLIA/CAP/GLP ASSAYS, EPIDEMIOLOGY, RADIOLOGY/BREAST IMAGING, CANCER SCREENING, ‘OMICS DATA GENERATION, AND BIOSTATISTICS. OUR TEAM INCLUDES 2 INDUSTRY PARTNERS, ENCOMPASSES 3 CLIA LABORATORIES, AND CAN PROVIDE EXPERTISE AND ACCESS TO MULTIPLE QUANTITATIVE PLATFORMS IN A CLIA/CAP/GLP ENVIRONMENT TO SUPPORT EDRN NETWORK COLLABORATIONS FOR BIOMARKER VALIDATION STUDIES WITH OTHER BCCS. THE BIOMARKER DEVELOPMENT LABORATORY WILL CONTRIBUTE TO THE BIOMARKER VALIDATION STUDIES BY: (I) DEVELOPING QUALIFIED REAGENTS & METHODS FOR QUANTIFYING 162 CANDIDATE PROTEIN BIOMARKERS, (II) PROCURING PLASMA BIOSPECIMENS (COMPLIANT WITH EDRN PROBE STUDY DESIGN) FOR PHASE 2 BIOMARKER VALIDATION STUDIES, (III) DELIVERING PLASMA ALIQUOTS TO OUR BRL CLIA LABS IN A BLINDED FASHION, AND (IV) ANALYZING EDRN PHASE 2 VALIDATION DATA GENERATED BY THE BRL, PROVIDING STATISTICAL, EPIDEMIOLOGICAL, AND BREAST IMAGING EXPERTISE TO SET AND EVALUATE PERFORMANCE METRICS TO ENSURE BIOMARKERS ARE ADEQUATE TO PROVIDE CLINICAL UTILITY FOR EARLY DETECTION. THE BIOMARKER REFERENCE LABORATORY WILL CONTRIBUTE TO THE PROPOSED VALIDATION STUDIES BY: (I) VALIDATING A CLIA- COMPLIANT STANDARD OPERATING PROCEDURE FOR AN IMMUNO-MRM ASSAY TO QUANTIFY UP TO 162 CANDIDATE PROTEIN BIOMARKERS OF EARLY-STAGE BREAST CANCER THAT WILL SERVE AS THE BASIS FOR OUR BIOMARKER VALIDATION STUDIES, (II) PERFORMING PHASE 2 BIOMARKER VALIDATION STUDIES, AND (III) PROVIDING REFERENCE LABORATORY SUPPORT FOR THE EDRN NETWORK (E.G., MASS SPECTROMETRIC ANALYSES, FLOW CYTOMETRY, NEXTGEN SEQUENCING AND ELISA ASSAYS. THE ADMINISTRATIVE CORE WILL SUPPORT ALL ASPECTS OF THE BCC, INCLUDING MANAGING ALL ADMINISTRATIVE AND PROJECT MANAGEMENT ASPECTS OF THE BCC AS WELL AS MANAGING ALL CENTER LOGISTICS AND COMMUNICATION.
assistance · Last action 2025-12-02
$2,860,531
Department of Health and Human Services
TRANSLATING THE TUMOR REGULOME FROM CELL-FREE DNA FOR PRECISION ONCOLOGY - PROJECT SUMMARY/ABSTRACT AN ACCURATE TUMOR CLASSIFICATION IS PIVOTAL TO CLINICAL CANCER CARE AND PRECISION ONCOLOGY. TREATMENT OPTIONS ARE OFTEN INFORMED BY THE PATHOLOGY OR DIAGNOSTIC FROM THE TUMOR TISSUE. A MAJOR CHALLENGE FOR PATIENTS WITH METASTATIC CANCER IS THE LIMITED ACCESS TO TUMOR TISSUE BECAUSE SURGICAL BIOPSIES ARE NOT ROUTINELY NOR REPEATEDLY COLLECTED THROUGHOUT THE COURSE OF THERAPY. HOWEVER, TUMORS CAN UNDERGO DRASTIC MOLECULAR CHANGES DURING METASTATIC PROGRESSION AND RESISTANCE TO THERAPIES. CIRCULATING TUMOR DNA (CTDNA) RELEASED FROM TUMOR CELLS INTO THE BLOOD IS A NON-INVASIVE SOLUTION FOR ADDRESSING CHALLENGES IN TISSUE ACCESSIBILITY. CURRENT RESEARCH AND CLINICAL EFFORTS HAVE FOCUSED ON DETECTING GENOME ALTERATIONS IN CTDNA, BUT THEY DO NOT ALWAYS EXPLAIN TREATMENT FAILURE. TREATMENT-RESISTANT PHENOTYPES ARE DEFINED BY DISTINCT CHANGES IN THE GENETIC AND EPIGENETIC REGULATORY LANDSCAPE, WHICH COLLECTIVELY FORM THE TUMOR REGULOME. CURRENTLY, IT IS NOT POSSIBLE TO COMPREHENSIVELY PORTRAY THE TUMOR REGULOME IN PATIENTS DURING THE COURSE OF THERAPY. WE PROPOSE TO OVERCOME THESE LIMITATIONS BY DEVELOPING INNOVATIVE COMPUTATIONAL METHODS AND EPIGENETIC ASSAYS THAT WILL BE EMPLOYED TO PROFILE THE TUMOR REGULOME AND SURVEY THE REGULATION OF RESISTANT PHENOTYPES DIRECTLY FROM CTDNA. OUR METHODS WILL INTEGRATE THE ANALYSIS OF GENOME ALTERATIONS, CHROMATIN ACCESSIBILITY, TRANSCRIPTIONAL REGULATION, AND DNA METHYLATION FROM THE SAME CTDNA SAMPLE. THIS COST-EFFECTIVE STRATEGY PROVIDES A TEMPORAL WINDOW INTO THE PATIENT’S DISEASE BY MONITORING THE TUMOR EPIGENETIC REGULATION AND ITS CLINICAL PHENOTYPE. THE INNOVATIVE ASPECTS OF THIS PROJECT INCLUDE THE DEVELOPMENT OF DEEP NEURAL NETWORKS AND MACHINE LEARNING METHODS TO INTEGRATE THE MULTI-OMIC DATA EXTRACTED FROM A SINGLE CTDNA ASSAY. WE WILL EMPLOY UNIQUE SYSTEMS AND RESOURCES TO DEVELOP OUR METHODS AND ADVANCE OUR UNDERSTANDING OF TUMOR MOLECULAR HETEROGENEITY AND TREATMENT RESPONSE. (1) FROM RAPID AUTOPSY STUDIES, WE WILL ASSESS THE CONTRIBUTION OF DNA FROM MULTIPLE METASTATIC LESIONS TO DETERMINE THE KEY SOURCE OF CTDNA. (2) FROM PATIENT-DERIVED XENOGRAFT (PDX) MOUSE MODELS, WE WILL ESTABLISH A REPOSITORY OF HUMAN CTDNA FROM MOUSE PLASMA TO SUPPORT DEVELOPMENT ACTIVITIES AND STUDIES UNDER PDX TREATMENT CONDITIONS USING NOVEL THERAPIES. THIS FRAMEWORK IS GENERALIZABLE TO ADDRESS RESEARCH QUESTIONS RELATED TO TUMOR BIOLOGY AND TREATMENT RESPONSE, INCLUDING MONITORING CANCER-ASSOCIATED PATHWAYS AND THE EFFECTIVENESS OF TARGETED THERAPIES. SUCCESSFUL INNOVATIONS MADE IN THIS PROJECT WILL ESTABLISH A PARADIGM SHIFT IN CANCER RESEARCH AND ACCELERATE TRANSLATION OF NEW CLINICAL APPLICATIONS TO ADVANCE PRECISION ONCOLOGY.
assistance · Last action 2026-03-05
$2,812,871
Department of Health and Human Services
DEEP MOLECULAR AND CELLULAR PROFILING OF COLORECTAL CANCER TUMOR AND IMMUNE MICROENVIRONMENT IN ALASKA NATIVE PEOPLE - PROJECT SUMMARY ALASKA NATIVE PEOPLE HAVE THE HIGHEST INCIDENCE AND MORTALITY RATES OF COLORECTAL CANCER (CRC) GLOBALLY, WITH RATES THAT ARE MORE THAN DOUBLE THOSE OBSERVED IN THE GENERAL U.S. POPULATION (INCIDENCE: 89.0 VS. 38.6/100,000; MORTALITY: 39.6/100,000 VS. 13.8/100,000). THESE HIGH RATES CANNOT BE EXPLAINED BY ACCESS TO SCREENING, AS DEDICATED EFFORTS TO INCREASE CRC SCREENING HAVE RESULTED IN SCREENING RATES IN ALASKA NATIVE PEOPLE THAT ARE COMPARABLE TO THE US AVERAGE. THESE DISPARITIES HAVE PERSISTED FOR OVER 40 YEARS AND ARE OF NOTED CONCERN TO COMMUNITY MEMBERS AND TRIBAL HEALTH LEADERS ALIKE, MAKING THIS A PRIORITY RESEARCH AREA FOR ALASKA NATIVE PEOPLE. A KEY KNOWLEDGE GAP IS THE LACK OF SIZABLE AND COMPREHENSIVE STUDIES CHARACTERIZING THE MOLECULAR FEATURES OF COLORECTAL TUMORS IN ALASKA NATIVE PATIENTS. ACCORDINGLY, WE PROPOSE AN INTEGRATIVE APPROACH TO BETTER UNDERSTAND CRC TUMORIGENESIS AND MOLECULAR SUBTYPES IN THIS HIGH-RISK POPULATION, AND TO EVALUATE WHETHER VARIOUS TUMOR AND TUMOR MICROENVIRONMENT FEATURES CONTRIBUTE TO DISEASE PROGRESSION. SPECIFICALLY, WE AIM TO DEEPLY CHARACTERIZE THE MUTATIONAL, TRANSCRIPTIONAL, AND CELLULAR LANDSCAPES OF CRC TUMORS AND THEIR IMMUNE MICROENVIRONMENTS IN 500 ALASKA NATIVE PATIENTS AND LINK THESE CHARACTERISTICS TO CRC-SPECIFIC MORTALITY. WE WILL BUILD ON OUR EXISTING COLLABORATION BETWEEN THE ALASKA NATIVE TRIBAL HEALTH CONSORTIUM (ANTHC) AND THE FRED HUTCHINSON CANCER CENTER. WE WILL CAPITALIZE ON ANTHC’S UNIQUE BIOREPOSITORY (LINKABLE TO COMPREHENSIVE MEDICAL RECORDS) THAT CONTAINS TUMOR TISSUE SAMPLES OF THE MAJORITY OF ALASKA NATIVE CRC PATIENTS DIAGNOSED IN ALASKA. PILOT DATA GENERATED USING BIOSPECIMENS FROM THIS RESOURCE AND UTILIZING THE SAME PLATFORMS AS PROPOSED HERE DEMONSTRATE HIGH-QUALITY DATA AND ENSURE THAT IRB AND TRIBAL APPROVALS ARE IN PLACE TO ENABLE RAPID EXECUTION OF THE PROPOSED WORK. TO IDENTIFY CLINICALLY MEANINGFUL POPULATION DIFFERENCES, WE WILL COMPARE MOLECULAR PROFILES WITH THOSE FROM NON-HISPANIC WHITE CRC PATIENTS USING AVAILABLE DATA. IN AIM 1, WE WILL PERFORM WHOLE-EXOME SEQUENCING OF CRC TUMORS AND PAIRED NORMAL SAMPLES TO IDENTIFY DRIVER GENES AND CLINICALLY ACTIONABLE MUTATIONS PARTICULARLY RELEVANT TO THE ALASKA NATIVE POPULATION. TO GAIN ETIOLOGICAL INSIGHT, WE WILL ANALYZE MUTATIONAL SIGNATURES THAT MAY BE LINKED TO ENVIRONMENTAL EXPOSURES AND IDENTIFY GERMLINE MUTATIONS IN HIGH-PENETRANCE CRC RISK GENES TO INVESTIGATE THEIR ROLE IN THE INCREASED CRC RISK IN ALASKA NATIVE PEOPLE. IN AIM 2, WE WILL APPLY TWO COMPLEMENTARY CUTTING-EDGE SPATIAL PROFILING TECHNOLOGIES TO FULLY CHARACTERIZE THE TUMORAL IMMUNE RESPONSE AND DISCOVER MECHANISMS OF IMMUNE EVASION. WE WILL PERFORM SPATIAL WHOLE TRANSCRIPTOME PROFILING OF CRC TUMORS USING NANOSTRING’S GEOMX DIGITAL SPATIAL PROFILING TECHNOLOGY. WE WILL USE AKOYA BIOSCIENCES’ PHENOCYCLER PLATFORM FOR SPATIALLY RESOLVED SINGLE IMMUNE CELL PHENOTYPING. WE EXPECT THAT INSIGHTS GAINED THROUGH THIS WORK CAN INFORM THE DEVELOPMENT OF HIGH-VALUE, NOVEL THERAPEUTIC STRATEGIES. IN AIM 3, WE WILL LEVERAGE THESE MOLECULAR DATA TO DEVELOP NOVEL PREDICTORS OF CRC-SPECIFIC MORTALITY THAT COULD HELP GUIDE CLINICAL DECISION MAKING, IMPROVE OUTCOMES, AND REDUCE LONG-STANDING DISPARITIES.
assistance · Last action 2026-04-13
$2,772,021
Department of Health and Human Services
IMMUNOGLOBULIN REPLACEMENT THERAPY AND INFECTIOUS COMPLICATIONS AFTER CD19-TARGETED CAR-T-CELL THERAPY - PROJECT SUMMARY/ABSTRACT CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY (CARTX) HAS TRANSFORMED TREATMENT FOR B CELL MALIGNANCIES. HOWEVER, THE EFFECTS OF CARTX ON HUMORAL IMMUNITY AND INFECTION RISK ARE INCOMPLETELY UNDERSTOOD. THE HIGH PREVALENCE OF HYPOGAMMAGLOBULINEMIA IN CARTX RECIPIENTS HAS DRIVEN FREQUENT USE OF PROPHYLACTIC IMMUNOGLOBULIN G (IGG) REPLACEMENT THERAPY (IGRT) TO PREVENT INFECTIONS IN THIS PATIENT POPULATION. HOWEVER, LIMITED DATA EXIST TO SUPPORT THIS PRACTICE, AND SHORTAGES, SIDE EFFECTS, AND COST NECESSITATE CAREFUL STEWARDSHIP OF IGRT. EMERGING DATA INDICATE THAT PATHOGEN-SPECIFIC ANTIBODIES OFTEN PERSIST AFTER CD19-CARTX, POTENTIALLY CONTESTING THE NEED FOR IGRT. WELL CONTROLLED STUDIES ARE NEEDED TO ASCERTAIN THE CLINICAL UTILITY OF IGRT IN CARTX RECIPIENTS. WITHIN THIS CLINICAL CONTEXT, OTHER IMPORTANT AND CONNECTED QUESTIONS REMAIN ABOUT HOW IGRT AFFECTS CAR-T CELL FUNCTION, IN ADDITION TO THE POSSIBLE COSTS VERSUS BENEFITS OF THE EFFECT OF IGRT ON HEALTHCARE RESOURCE UTILIZATION. THIS TIMELY AND UNIQUE PROPOSAL WILL BE THE FIRST RANDOMIZED, CONTROLLED TRIAL OF IGRT USE IN CARTX RECIPIENTS AND PROVIDE CRITICAL INSIGHTS INTO THE POTENTIAL RISKS AND BENEFITS OF IGRT IN THIS PATIENT POPULATION. THE KEY OBJECTIVES OF THIS STUDY ARE TO EVALUATE WHETHER IGRT IN CARTX RECIPIENTS REDUCES INFECTION RATES COMPARED TO PLACEBO, AND TO UNDERSTAND THE IMPACT OF IGRT ON PREVIOUSLY UNEXPLORED OUTCOMES SUCH AS CAR-T CELL EXPANSION, CAR- T CELL PERSISTENCE, CAR-T CELL FUNCTION, AND HEALTHCARE RESOURCE UTILIZATION. FOR THE PROPOSED STUDY, WE HAVE ASSEMBLED AN INTERDISCIPLINARY GROUP OF PHYSICIANS AND SCIENTISTS FROM HIGH-VOLUME CARTX CENTERS WHO WILL LEVERAGE OUR EXPERTISE IN IMMUNO-ONCOLOGY, INFECTIOUS DISEASES, AND CANCER OUTCOMES RESEARCH. WE PROPOSE A RANDOMIZED TRIAL OF IGRT VERSUS PLACEBO IN 150 ADULTS WITH SERUM TOTAL IGG =400 MG/DL PRIOR TO CD19-CARTX. PARTICIPANTS WILL BE RANDOMIZED 1:1 TO RECEIVE IGRT OR PLACEBO WITHIN 14 DAYS PRIOR TO CARTX AND AT 28-DAY INTERVALS AFTER CARTX FOR 4 MONTHS. AIM 1 WILL COMPARE BETWEEN STUDY ARMS THE INCIDENCE RATE OF INFECTIONS THROUGH 6 MONTHS AFTER CD19-CARTX; WE WILL ALSO LONGITUDINALLY CHARACTERIZE AND COMPARE TOTAL AND PATHOGEN-SPECIFIC IGG LEVELS AND THEIR ASSOCIATION WITH INFECTIONS. AIM 2 WILL EXPLORE THE ASSOCIATION OF IGRT WITH HEALTHCARE RESOURCE UTILIZATION, CYTOKINE RELEASE SYNDROME, AND CARTX-ASSOCIATED NEUROTOXICITY. AIM 3 WILL CHARACTERIZE THE IMPACT OF IGRT ON CAR-T CELL EXPANSION, PERSISTENCE, AND FUNCTION. THIS WILL BE THE FIRST RANDOMIZED CONTROLLED STUDY OF IGRT AFTER CARTX AND WILL PROVIDE FOUNDATIONAL DATA TO ESTABLISH EVIDENCE-BASED ESTIMATES OF THE CLINICAL EFFICACY AND RISK-BENEFIT OF IGRT IN CD19-CARTX RECIPIENTS. IN PARALLEL, THIS STUDY WILL EXPLORE OTHER POTENTIAL EFFECTS OF IGRT ON CAR-T CELL DYNAMICS AND HEALTHCARE RESOURCE UTILIZATION. THE DATA GENERATED BY THIS PROPOSAL WILL PROVIDE THE GROUNDWORK FOR FUTURE STUDIES TO REFINE INFECTION PREVENTION STRATEGIES IN THE GROWING POPULATION OF CARTX RECIPIENTS.
assistance · Last action 2025-08-14
$2,766,158
Department of Health and Human Services
BASE-EDITED HEMATOPOIETIC STEM AND PROGENITOR CELLS TO ENABLE SAFE USE OF HIGHLY POTENT CD33-TARGETED RADIOIMMUNOTHERAPY - ABSTRACT ANTIGEN-SPECIFIC THERAPIES HAVE LONG BEEN PURSUED TO IMPROVE OUTCOMES IN ACUTE MYELOID LEUKEMIA (AML). SO FAR MOST EXPLOITED ARE MONOCLONAL ANTIBODIES (MABS) TARGETING CD33, A GLYCOPROTEIN DISPLAYED ON THE CELL SURFACE OF LEUKEMIC BLASTS IN ALMOST ALL CASES AND POSSIBLY LEUKEMIA STEM CELLS IN SOME. LONGER SURVIVAL OF SOME PATIENTS TREATED WITH THE CD33 ANTIBODY-DRUG CONJUGATE GEMTUZUMAB OZOGAMICIN (GO) VALIDATES THIS APPROACH, BUT GO IS OFTEN INEFFECTIVE, PROMPTING EFFORTS TO DEVELOP IMPROVED, MORE POTENT CD33-DIRECTED THERAPEUTICS. BECAUSE AML CELLS ARE EXQUISITELY SENSITIVE TO RADIATION IN A DOSE-DEPENDENT FASHION, RADIONUCLIDES ARE IDEAL TO ARM ANTI- CD33 MABS. INDEED, EARLY PHASE CLINICAL TRIALS DEMONSTRATED SUBSTANTIAL ANTI-AML EFFICACY OF THE ANTI-CD33 MAB LINTUZUMAB (HUM195, SGN-33) WHEN COUPLED WITH THE A-EMITTER ACTINIUM-225 (225AC). A-EMITTERS DELIVER A VERY HIGH AMOUNT OF RADIATION OVER JUST A FEW CELL DIAMETERS, THEREBY ENABLING PRECISE AND EFFICIENT TARGET CELL KILL, RENDERING THEM PARTICULARLY INTERESTING FOR SPECIFIC TARGETING OF AML WITH RADIOIMMUNOCONJUGATES (“RIT”). HOWEVER, EVEN WITH 225AC-LINTUZUMAB, AN IMPORTANT SHORTCOMING IS CD33 EXPRESSION ON NORMAL MYELOID CELLS, WHICH LEADS TO “ON-TARGET, OFF-TUMOR CELL” TOXICITIES THAT MANIFEST AS SEVERE AND PROLONGED MYELOSUPPRESSION WITH LIFE-THREATENING SEQUELAE (E.G. INFECTION). THUS, CLINICAL USE OF CD33-DIRECTED RIT WITHOUT IMMEDIATE STEM CELL RESCUE IS CURRENTLY LIMITED TO SUBOPTIMAL DRUG DOSES. WE HAVE RECENTLY DEMONSTRATED IN MICE AND NONHUMAN PRIMATES THAT CRISPR/CAS9 NUCLEASE-BASED EDITING OF CD33 RESULTS IN FUNCTIONALLY NORMAL HEMATOPOIESIS THAT EXPRESSES REDUCED LEVELS OF CD33 AND IS PROTECTED FROM GO AND CD33-DIRECTED T CELL-ENGAGING THERAPEUTICS. WE HYPOTHESIZE CD33-EDITED NORMAL HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) WILL RESIST CD33-DIRECTED RIT WITH A-PARTICLE-EMITTING RADIONUCLIDES AND ENABLE THEIR SAFE USE AT MAXIMALLY EFFECTIVE DRUG DOSES. HOWEVER, THE CRISPR/CAS9-BASED CD33 GENE EDITING STRATEGY SUFFERS FROM SIGNIFICANT OFF-TARGET ACTIVITY, AND DNA DOUBLE STRAND BREAKS (DSBS) CAN GENERATE LARGER DELETIONS AND COMPLEX CHROMOSOMAL REARRANGEMENTS AND CAUSE TP53-DEPENDENT DNA DAMAGE RESPONSE AND CELL CYCLE ARREST. TO ADDRESS THIS LIMITATION, WE WILL OPTIMIZE AND CHARACTERIZE A NOVEL GENE-EDITING STRATEGY TO PROTECT NORMAL HEMATOPOIESIS FROM HIGHLY POTENT CD33-DIRECTED RIT BY UTILIZING THE RECENTLY DESCRIBED BASE EDITOR (BE) TECHNOLOGY. BES INDUCE PRECISE NUCLEOTIDE MODIFICATIONS WITHOUT INTENTIONAL INTRODUCTION OF DSBS, MAKING THEM AN ATTRACTIVE STRATEGY TO GENERATE CD33NULL “NORMAL” HEMATOPOIETIC CELLS. WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM OF INVESTIGATORS WITH COMPLEMENTARY EXPERTISE IN CD33-DIRECTED THERAPIES, PRECLINICAL OPTIMIZATION OF RIT, AND RADIOPHARMACEUTICS TO CONDUCT WELL-CONTROLLED PRECLINICAL IND-ENABLING STUDIES TO DEVELOP BE-BASED CD33 ENGINEERING OF NORMAL HUMAN HSPCS FOR CLINICAL USE WITH A-EMITTER CD33-DIRECTED RIT FOR PATIENTS WITH AML AND OTHER CD33-EXPRESSING DISORDERS.
assistance · Last action 2025-06-12
$2,758,516
Department of Health and Human Services
BREASTMILK ANTIBODIES REGULATE NEONATAL IMMUNITY TO THE MICROBIOTA - PROJECT SUMMARY TO MAINTAIN HEALTH, THE HOST MUST AVOID GENERATING INFLAMMATORY RESPONSES TO BENEFICIAL GUT BACTERIA, WHILE RETAINING THE ABILITY TO RESPOND TO PATHOGENS. MAINTAINING THIS BALANCE IS PARTICULARLY COMPLICATED IN EARLY LIFE AS MANY OF THE MECHANISMS THAT SERVE TO PROMOTE TOLERANCE TO RESIDENT COMMENSAL MICROBES IN ADULTS ARE EITHER ABSENT OR NOT YET ESTABLISHED DURING THIS PERIOD. WE RECENTLY IDENTIFIED MATERNAL ANTIBODIES AS KEY REGULATORS OF HOST-MICROBIOTA MUTUALISM IN NEONATES. SPECIFICALLY, WE FOUND THAT IN ADDITION TO IGA, HEALTHY MOTHERS GENERATE MICROBIOTA-REACTIVE IGG ANTIBODIES, WHICH ARE TRANSMITTED VIA BREASTMILK AND COAT BACTERIA IN THE NEONATAL GUT. IN COMPARISON WITH CONTROL OFFSPRING, NEONATES THAT DO NOT RECEIVE THESE MATERNAL ISOTYPES HARBOR INCREASED NUMBERS OF COMMENSAL BACTERIA IN GUT DRAINING LYMPH NODES, MOUNT INAPPROPRIATE, MICROBIOTA-DRIVEN CD4 T- DEPENDENT IMMUNE RESPONSES, AND SUFFER INCREASED MORBIDITY WHEN SUBJECTED TO A CHEMICAL FORM OF COLITIS. BUILDING FROM THESE EXCITING FINDINGS, THIS PROPOSAL SEEKS TO UNDERSTAND THE MECHANISMS BY WHICH MATERNAL ANTIBODIES REGULATE NASCENT HOST-MICROBIOTA INTERACTIONS IN NEONATES. SPECIFICALLY, WE WILL DETERMINE THE ANTIGEN SPECIFICITIES AND THE EFFECTOR MECHANISMS (E.G., COMPLEMENT ACTIVATION OR FC RECEPTOR LIGATION) REQUIRED FOR DISTINCT MATERNAL IGG ISOTYPES TO RESTRAIN NEONATAL ADAPTIVE IMMUNE RESPONSES TO BENEFICIAL GUT BACTERIA. ADDITIONALLY, WE WILL DEFINE THE SIGNALING PATHWAYS AND CELL TYPES REQUIRED TO TRIGGER DYSREGULATED ADAPTIVE IMMUNE RESPONSES IN OFFSPRING THAT DO NOT RECEIVE BREASTMILK ANTIBODIES. WE WILL EMPLOY INNOVATIVE APPROACHES TO ACHIEVE THESE GOALS BY LEVERAGING FOSTERING AND OPTIMIZED INFANT FEEDING APPROACHES WITH TRANSGENIC MOUSE MODELS AND MULTI-PARAMETER FLOW CYTOMETRY. THESE STUDIES ARE SIGNIFICANT BECAUSE THEY ADDRESS KEY GAPS IN OUR KNOWLEDGE REGARDING HOW FAVORABLE RELATIONSHIPS BETWEEN THE HOST AND RESIDENT MICROBIOTA ARE ESTABLISHED IN EARLY LIFE. ADDITIONALLY, OUR WORK WILL ALSO ADVANCE OUR UNDERSTANDING OF THE MECHANISMS BY WHICH BREASTFEEDING PROMOTES HEALTH. WE EXPECT THAT THE INSIGHT GAINED FROM THIS RESEARCH WILL SIGNIFICANTLY AID IN OUR ABILITY TO MANIPULATE HOST-MICROBIOTA INTERACTIONS AND MUCOSAL IMMUNITY DURING EARLY LIFE, REGARDLESS OF MODE OF NUTRITION.
assistance · Last action 2026-01-24
$2,697,997
Department of Health and Human Services
ROLE OF LOCAL ANTIBODIES IN CONTROL OF CHRONIC GENITAL HERPES - PROJECT SUMMARY/ABSTRACT INFECTION WITH HERPES SIMPLEX VIRUS 2 (HSV-2) FOR WHICH THERE IS NO VACCINE IS A SIGNIFICANT CAUSE OF HUMAN MORBIDITY BOTH IN THE UNITED STATES AND WORLDWIDE. CURRENT UNDERSTANDING OF HUMORAL IMMUNITY TO HSV-2 IS BASED ON BULK METRICS OF ANTIBODIES CIRCULATING IN BLOODSTREAM, HOWEVER EVERYDAY BATTLE BETWEEN VIRUS AND HOST OCCURS IN MICROSCOPIC TISSUE MICROENVIRONMENT WHICH REPRESENT A UNIQUE IMMUNOLOGICAL NICHE. OUR PREMISE IS THAT STUDY OF LOCAL HUMORAL RESPONSES WILL REVEAL CRITICAL, CURRENTLY UNIDENTIFIED MEDIATORS AND MECHANISMS FOR IMMUNE CONTROL OF HSV-2. AFTER PRIMARY INFECTION, HSV-2 ESTABLISHES LATENCY IN SENSORY NEURONS. CLEARANCE AND SUBSEQUENT CONTROL OF CONSTANTLY REACTIVATING HSV-2 IN TISSUE ARE BELIEVED TO DEPEND ON T CELLS, BUT CLINICAL OBSERVATIONS AND MATHEMATICAL MODELS PRESENT EVIDENCE CONSISTENT WITH ESSENTIAL ROLE FOR LOCAL HUMORAL RESPONSES REQUIRED TO ACHIEVE EFFICIENT VIRUS CONTROL, OUR PRELIMINARY DATA HAS SHOWN THAT ANTIBODY SECRETING CELLS (ASCS) ARE ACTIVELY PRESENT IN GENITAL SKIN DURING HSV-2 REACTIVATION AND LONG AFTER VIRUS OUTBREAK IS CONTAINED. USING THE POWER OF HAVING SEQUENTIAL SAMPLES IN INDIVIDUAL TISSUE BIOPSIES OVER TIME COMBINED WITH RECENT ADVANCEMENTS IN SINGLE-CELL RNA SEQUENCING WE DEMONSTRATED THAT THESE CLONALLY EXPANDED CELLS COMMIT TO THE LONG-LIVED PLASMA CELL LINEAGE IMPLYING POSSIBLE TISSUE RESIDENCY, ISOLATION OF ANTIBODIES FROM THESE UNIQUE CELLS HAS SHOWN THEY RECOGNIZE HSV-2 SUGGESTING THEY MAY BE DIRECTED TO AS YET UNIDENTIFIED HSV-2 ANTIGENS AND/OR PROVIDE FUNCTIONS IMPORTANT FOR VIRUS CONTROL IN THE TISSUE. THEREFORE, THE GOAL OF THIS PROJECT IS TO THOROUGHLY DEFINE THE IMMUNOPROTECTIVE ROLE OF SKIN ANTIBODY-SECRETING CELLS (ASCS) AGAINST REACTIVATING HSV-2. UNDERLYING OUR PROPOSED EXPERIMENTS IS THE IDEA THAT TISSUE RESIDENT ASCS HAVE THE ABILITY TO CONTAIN THE VIRUS OVER LONG TIMEFRAMES VIA SECRETING HSV-2 SPECIFIC ANTIBODIES THAT ARE ESSENTIAL FOR VIRUS CONTROL DUE TO THEIR SPECIFICITY AND/OR EFFECTOR FUNCTIONS. THEREFORE, WE FOCUS ON CRITICAL FEATURES OF ASCS SUCH AS ANTIGENIC SPECIFICITY, GENE EXPRESSION PROFILE, CLONAL STRUCTURE AND FUNCTIONAL ACTIVITY OF COGNATE ANTIBODIES DURING SYMPTOMATIC HSV-2 REACTIVATION AND AT MULTIPLE TIME POINTS FOLLOWING CLEARANCE OF A GENITAL SKIN VIRUS WITHIN MICROSCOPIC SITES OF INFECTION. WE WILL ALSO EVALUATE FREQUENCY OF ESSENTIAL CLONES OF SKIN ASCS AMONG CIRCULATING B CELLS THAT HAVE DIRECT IMPLICATION FOR RATIONAL VACCINE DESIGN ALLOWING TARGETED VACCINATION STRATEGIES. ULTIMATELY, OUR GOAL IS TO USE THE GAINED INSIGHTS TO DEVELOP STRATEGIES THAT WILL ALLOW FOR NOVEL APPROACHES TO DESIGN SUCCESSFUL HERPES VACCINE AND DEVELOPMENT OF IMMUNOTHERAPEUTIC APPROACHES TO TREAT CHRONIC HSV-2 INFECTION.
assistance · Last action 2026-01-03
$2,592,849
Department of Health and Human Services
ADIPOCYTE-DERIVED LIPID AND MITOCHONDRIAL SIGNALS IN NEUROPROTECTIONAND BRAIN SENESCENCE - PROJECT SUMMARY THE LONG-TERM OBJECTIVE IS TO ELUCIDATE THE MECHANISMS OF ADIPOCYTE-BRAIN COMMUNICATION AND THEIR IMPACT ON GLIAL FUNCTION, NEUROPROTECTION, AND BRAIN AGING, WITH POTENTIAL IMPLICATIONS FOR PREVENTING DEMENTIA AND AGE- RELATED COGNITIVE DECLINE. WE WILL DO THIS MY EXECUTING TWO SPECIFIC AIMS: I) INVESTIGATE THE ROLE OF ADIPOCYTE- DERIVED LIPOPROTEINS IN GLIAL PHAGOCYTOSIS, NEUROPROTECTION, AND SENESCENCE. II) EXAMINE HOW ADIPOCYTE MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION IMPACTS GLIAL FUNCTION AND SENESCENCE. TO ACHIEVE THESE AIMS, USING DROSOPHILA AS A MODEL ORGANISM, WE WILL EXPLORE HOW ADIPOCYTE-DERIVED SIGNALS INFLUENCE GLIAL CELL FUNCTION, PARTICULARLY PHAGOCYTIC ACTIVITY. WE WILL FOCUS ON TWO KEY ADIPOCYTE-DERIVED SIGNALS: LIPOPROTEINS AND MITOCHONDRIAL COMPONENTS. FOR AIM 1, WE WILL INVESTIGATE HOW LIPOPROTEINS AND THEIR RECEPTORS MODULATE GLIAL PHAGOCYTIC ACTIVITY THROUGH VARIOUS MOLECULAR AND CELLULAR APPROACHES, INCLUDING KNOCKDOWN STUDIES, SIGNALING PATHWAY ANALYSES, AND LIPIDOMICS. FOR AIM 2, WE WILL EXAMINE THE IMPACT OF ADIPOCYTE MITOCHONDRIAL FUNCTION ON GLIAL CELLS USING SIMILAR TECHNIQUES, AS WELL AS TARGETED PROTEOMICS AND TRANSLATING RIBOSOME AFFINITY PURIFICATION (TRAP). OUR RESEARCH WILL EMPLOY GENETIC MANIPULATION, CONFOCAL MICROSCOPY, BIOCHEMICAL ASSAYS, AND HIGH-THROUGHPUT SEQUENCING TO ANALYZE GLIAL FUNCTION, LIPID METABOLISM, AND GENE EXPRESSION CHANGES IN RESPONSE TO ALTERED ADIPOCYTE SIGNALING. WE WILL ASSESS THE EFFECTS OF THESE SIGNALS ON GLIAL SENESCENCE, LIPID ACCUMULATION, AND NEUROPROTECTIVE CAPABILITIES UNDER VARIOUS METABOLIC CONDITIONS AND DURING AGING. THIS STUDY AIMS TO UNCOVER NOVEL MECHANISMS OF ADIPOCYTE-BRAIN COMMUNICATION AND THEIR ROLES IN NEUROPROTECTION AND AGE-RELATED COGNITIVE DECLINE. THE HIGH DEGREE OF EVOLUTIONARY CONSERVATION BETWEEN DROSOPHILA AND MAMMALS IN ADIPOCYTE-BRAIN SIGNALING AND GLIAL BIOLOGY SUGGESTS THAT OUR FINDINGS MAY HAVE BROAD TRANSLATABLE IMPLICATIONS FOR HUMAN HEALTH, POTENTIALLY LEADING TO NEW THERAPEUTIC STRATEGIES FOR IMPROVING AGE-RELATED CONDITIONS IMPACTED BY DIET-INDUCED OBESITY.
assistance · Last action 2025-09-11
$2,586,818
Department of Health and Human Services
SMARTCORE TECHNOLOGY: USING AI AND PATIENT TISSUE TO IDENTIFY POTENTIAL CANCER THERAPIES FOR ULTRA-RARE CANCERS - PROJECT SUMMARY OUR PROPOSAL PRESENTS A NEW APPROACH, CALLED SMARTCORE, TO TACKLE THE CHALLENGE OF FINDING PRACTICAL SOLUTIONS FOR ULTRA-RARE CANCERS. WE AIM TO USE AN AI-DRIVEN DRUG SCREENING PLATFORM DESIGNED TO TEST PRIMARY HUMAN TUMOR TISSUE. OUR STRATEGY IS TO IDENTIFY AND REPURPOSE DRUGS THAT EXHIBIT ACTIVITY AGAINST THE CANCER OF INTEREST. WE CIRCUMVENT THE LATENCY OF DEVELOPING ORGANOIDS OR PATIENT-DERIVED XENOGRAFT MODELS FOR DRUG SCREENING BY UTILIZING INTACT TUMORS AS ORGANOTYPIC CULTURES. USING A MACHINE-LEARNING ALGORITHM, WE CAN PREDICT TUMOR SENSITIVITY TO A PANEL OF ~4,000 DRUGS, INCLUDING ~1800 FDA-APPROVED DRUGS, BY INPUTTING RESPONSES TO A SET OF COMPUTATIONALLY SELECTED 254 COMPOUNDS. OUR LONG-TERM GOAL IS TO CREATE A ROBUST DRUG AND TARGET DISCOVERY METHOD FOR INDIVIDUAL CANCERS, IRRESPECTIVE OF RARITY, THAT DIRECTLY LINKS TO CLINICAL APPLICATION, THEREBY ADDRESSING A CRITICAL ‘BENCH-TO-BEDSIDE’ GAP IN PERSONALIZED AND PRECISION ONCOLOGY. TO REALIZE OUR GOAL, WE INTEND TO EXPAND THE CAPABILITY OF OUR PLATFORM TO MAKE USE OF CLINICAL NEEDLE BIOPSIES. THIS WILL VASTLY INCREASE THE UTILITY OF OUR SMARTCORE TECHNOLOGY TO ANALYZE BIOPSY SAMPLES FROM ANY TUMOR THAT CAN BE SHIPPED TO OUR PROCESSING FACILITY WITHIN 24 HRS. THIS PROPOSAL WILL DEMONSTRATE THE PROOF-OF-CONCEPT OF OUR SMARTCORE PLATFORM IN AN ULTRA-RARE CONDITION, FIBROLAMELLAR CANCER OF THE LIVER, WITH TWO SPECIFIC AIMS. AIM 1 IS TO DISCOVER THERAPEUTICS FOR FIBROLAMELLAR CANCER USING AI-BASED CHEMICAL SCREENING. HERE, WE WILL ESTABLISH TECHNICAL PARAMETERS FOR OPTIMAL PERFORMANCE OF OUR AI-BASED SCREENING PLATFORM USING INDEPENDENT FLC COHORTS OBTAINED FROM MULTIPLE SOURCES, VALIDATE THE TOP ‘HITS’ USING ESTABLISHED PATIENT-DERIVED XENOGRAFT MODELS FROM THREE INDEPENDENT HUMAN FLCS, AND DEDUCE SIGNALING NETWORKS AND PROTEINS TARGETED BY THE CANDIDATE DRUGS, HIGHLIGHTING MOLECULAR PATHWAYS IMPORTANT FOR THE SURVIVAL OF FLC. AIM 2 IS TO DEVELOP AN AI-BASED CHEMICAL SCREENING APPROACH USING NEEDLE BIOPSIES. TO BROADEN THE IMPACT OF OUR TECHNOLOGY, WE WILL MODIFY OUR AI-BASED SCREENING TO ACCOMMODATE 18- GAUGE CORE NEEDLE BIOPSIES ROUTINELY PERFORMED IN CLINICAL PRACTICE. WE WILL CURATE A SET OF <40 DRUGS FOR FLC- SPECIFIC TESTING AS THE BASIS FOR DRUG PREDICTION USING OUR DEEP NEURAL NETWORK ALGORITHM, TEST THE ACCURACY OF THIS APPROACH BY COMPARING NEEDLE BIOPSIES WITH LARGER TISSUE SLICES IN OUR FLC POPULATION AND OPTIMIZE PRE-ANALYTIC CONDITIONS TO YIELD REPRODUCIBLE RESULTS. IF SUCCESSFUL, OUR TECHNOLOGY WILL MAKE USE OF NEEDLE CORE BIOPSIES, BE AGNOSTIC TO THE UNDERLYING MOLECULAR DERANGEMENT, SCREEN A LARGE COLLECTION OF COMPOUNDS USING DEEP NEURAL NETWORK ALGORITHMS, AND REQUIRE A SHORT TURNAROUND TIME OF ONE WEEK FROM START TO FINISH; ALL OF WHICH ARE ATTRIBUTES OF AN IDEAL TEST THAT OVERCOMES THE ACHILLES HEEL OF PERSONALIZED ONCOLOGY.
assistance · Last action 2024-01-09
$2,500,000
Department of Health and Human Services
DEEP LEARNING-BASED PROTEIN DESIGN OF HIV-1 ENV GP120 CORE IMMUNOGENS FOR CD4 BINDING SITE GERMLINE TARGETING - PROJECT SUMMARY/ABSTRACT THIS RESEARCH PROPOSAL AIMS TO DEVELOP NEW IMMUNOGENS FOR AN HIV-1 VACCINE BY UTILIZING ADVANCED PROTEIN DESIGN TECHNIQUES AND DEEP LEARNING METHODS. CONVENTIONAL STRUCTURE-GUIDED APPROACHES HAVE LIMITATIONS IN ACHIEVING DESIRED STRUCTURAL CHARACTERISTICS. THEREFORE, THIS STUDY PROPOSES USING RFDIFFUSION, PROTEINMPNN, AND ALPHAFOLD2, TO GENERATE NEW GERMLINE-TARGETING GP120 CORES BASED ON THE PRE-FUSION NATIVE-LIKE STRUCTURE OF THE HIV-1 STRAIN 426C. THE DESIGNED IMMUNOGENS PRIORITIZE MAINTAINING THE STRUCTURAL INTEGRITY OF THE PRE-FUSION GP120 WHILE REMOVING THE BRIDGING SHEET AND RE-DESIGNING SPECIFIC REGIONS TO MAINTAIN THE PRE-FUSION NATIVE-LIKE BACKBONE STRUCTURE. IN ADDITION, PARTICULAR ATTENTION IS DIRECTED TOWARDS MASKING OFF-TARGET EPITOPES. IN VITRO CHARACTERIZATION WILL BE PERFORMED TO EVALUATE THE BINDING CHARACTERISTICS OF THESE IMMUNOGENS WITH GERMLINE, BROADLY NEUTRALIZING, AND NON-NEUTRALIZING ANTIBODIES. SUBSEQUENTLY, TRANSGENIC MICE EXPRESSING HUMAN GERMLINE VRC01-CLASS BCRS WILL BE UTILIZED TO ASSESS THE IMMUNOGENICITY OF SELECTED IMMUNOGENS PRESENTED ON NANOPARTICLES AND ANALYZE THEIR IMPACT ON GERMINAL CENTER B CELL RESPONSES AND MEMORY B CELL REPERTOIRE. MONOCLONAL ANTIBODIES (MABS) OBTAINED FROM IMMUNIZED ANIMALS WILL BE STRUCTURALLY CHARACTERIZED, SHEDDING LIGHT ON ANTIBODY MATURATION PATHWAYS INFLUENCED BY THE IMMUNOGEN STRUCTURE. ADDITIONALLY, THIS RESEARCH PLAN AIMS TO EXPAND THE IMMUNOGEN REPERTOIRE BY DESIGNING GP120 CORES BASED FROM DIVERSE HIV-1 CLADES/STRAINS. FURTHERMORE, TO ENHANCE IMMUNOGENICITY, MEMBRANE-BOUND AND NANOPARTICLES DELIVERY THROUGH SELF-AMPLIFYING MRNA WILL BE EXPLORED. THE ULTIMATE OBJECTIVE OF THIS RESEARCH IS TO GAIN VALUABLE INSIGHTS INTO NOVEL ANTIGEN DESIGN TECHNIQUES AND THEIR APPLICATION IN HIV-1 VACCINE STRATEGIES FOR BROADLY NEUTRALIZING ANTIBODIES DEVELOPMENT. THE FINDINGS FROM THIS STUDY WILL CONTRIBUTE TO THE DEVELOPMENT OF IMMUNOGENS THAT CLOSELY RESEMBLE THE PRE-FUSION GP120 STATE, POTENTIALLY LEADING TO ENHANCED B-CELL RESPONSES CAPABLE OF GENERATING BROADLY NEUTRALIZING ANTIBODY LINEAGES. BY ADDRESSING THE COMPLEX FEATURES OF THE HIV-1 ENV PROTEIN AND ADVANCING IMMUNOGEN DESIGN STRATEGIES, THIS RESEARCH AIMS TO MAKE SIGNIFICANT CONTRIBUTIONS TOWARDS THE DEVELOPMENT OF AN EFFECTIVE HIV-1 VACCINE.
assistance · Last action 2026-02-24
$2,446,322
Department of Health and Human Services
EXPERIMENTAL-DATA-BASED IN-SILICO DATA GENERATION PLATFORM TO IMPROVE THE ACCURACY AND RELIABILITY OF SINGLE-CELL AND SPATIAL OMICS DATA ANALYSIS - PROJECT SUMMARY THIS PROJECT AIMS TO DEVELOP A SUITE OF ADVANCED YET PRACTICAL STATISTICAL TOOLS WITH USER-FRIENDLY INTERFACES TO ENHANCE THE RELIABILITY AND POWER OF SINGLE-CELL AND SPATIAL OMICS DATA ANALYSIS THROUGH EXPERIMENTAL-DATA- BASED IN SILICO DATA GENERATION. AIM 1 FOCUSES ON DEVELOPING STATISTICAL METHODS TO GENERATE IN SILICO DATA THAT SERVE AS NEGATIVE CONTROLS AND PSEUDO-REPLICATES OF EXPERIMENTAL DATA. THESE DIGITAL ALTERNATIVES WILL HELP UNCOVER POTENTIAL BIASES AND VARIABILITY IN ANALYSIS RESULTS, WHICH HAVE BECOME MORE COMMON GIVEN THE INCREASING COMPLEXITY OF SINGLE-CELL AND SPATIAL OMICS DATA ANALYSIS. IN SILICO NEGATIVE CONTROLS AND PSEUDO- REPLICATES WILL ENABLE SANITY CHECKS, BIAS CORRECTION, AND VARIABILITY ANALYSIS, ADDRESSING CHALLENGES SUCH AS DOUBLE DIPPING, SMALL SAMPLE SIZES, AND DATA SPARSITY. AIM 2 INVOLVES CREATING A POWER ANALYSIS SUITE LEVERAGING EXPERIMENTAL-DATA-BASED IN SILICO DATA GENERATION, COVERING MULTI-CONDITION COMPARISONS, TEMPORAL DATA ANALYSIS, AND POPULATION-SCALE MOLECULAR QUANTITATIVE TRAIT LOCI ANALYSIS, WITH THE GOAL OF ASSISTING EXPERIMENTAL DESIGN CONSIDERING THE HIGH COST OF SINGLE-CELL AND SPATIAL OMICS TECHNOLOGIES. AIM 3 WILL DEVELOP INTERACTIVE, MODULARIZED SOFTWARE PACKAGES WITH A WEBSITE INTERFACE FOR THE SINGLE-CELL AND SPATIAL OMICS COMMUNITY TO PERFORM EXPERIMENTAL-DATA-BASED IN SILICO DATA GENERATION. THE SOFTWARE WILL INTEGRATE WITH STATE- OF-THE-ART PIPELINES LIKE R'S SEURAT AND PYTHON'S SCANPY, ENABLING RESEARCHERS TO EASILY GENERATE IN SILICO DATA FROM EXPERIMENTAL DATA AND ENHANCE THE REPRODUCIBILITY OF COMMON ANALYSIS TASKS IN SINGLE-CELL AND SPATIAL OMICS STUDIES. OVERALL, THIS PROJECT WILL PROVIDE A NEW ANGLE TO EXTEND THE CAPABILITIES OF COMPUTATIONAL GENOMIC RESEARCH, FOSTERING MORE ACCURATE AND REPRODUCIBLE DATA-DRIVEN DISCOVERIES.
assistance · Last action 2025-09-19
$2,409,233
Department of Health and Human Services
USING A SMART DESIGN TO EVALUATE REMOTELY DELIVERED, CULTURALLY TAILORED WEIGHT LOSS INTERVENTIONS AMONG LATINA BREAST CANCER SURVIVORS - PROJECT SUMMARY / ABSTRACT BREAST CANCER (BC) IS THE LEADING CAUSE OF CANCER DEATH AMONG US LATINAS. LATINAS ARE AT HIGH RISK OF OBESITY AND OBESITY-RELATED DISEASES, WHICH ARE ASSOCIATED WITH POORER CANCER OUTCOMES. THERE IS A SIGNIFICANT LACK OF AN EFFECTIVE INTERVENTION TO ADDRESS THE DIVERSE NEEDS OF LATINA BC SURVIVORS TO ACHIEVE A HEALTHY WEIGHT. WE HAVE DEVELOPED AND TESTED MULTI-COMPONENT WEIGHT LOSS, DIETARY CHANGE, AND PHYSICAL ACTIVITY (PA) INTERVENTIONS AMONG BC SURVIVORS, WITH A FOCUS ON EXPERIENTIAL LEARNING (EL) AMONG LATINAS. AS THE NEXT STEP, WE PROPOSE A SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMIZED TRIAL (SMART) TESTING 12 MONTH ADAPTIVE CULTURALLY- TAILORED WEIGHT LOSS INTERVENTIONS IN A GEOGRAPHICALLY DIVERSE GROUP OF LATINA BC SURVIVORS. THE ADAPTIVE INTERVENTIONS WILL USE THE CDC’S DIABETES PREVENTION PROGRAM (DPP), AN EVIDENCE-BASED WEIGHT LOSS PROGRAM, AS THE CENTRAL EDUCATIONAL COMPONENT. BASED ON OUR PRIOR WORK, WE WILL ADAPT THE DPP TO BE REMOTELY DELIVERED, INCLUDE INFORMATION SPECIFIC TO BC SURVIVORS, AND BE CULTURALLY-TAILORED TO LATINAS. WOMEN WILL BE RECRUITED VIA 3 WEST COAST SEER REGISTRIES. INCLUSION CRITERIA: DIAGNOSIS OF STAGE I-III BC WITHIN 5 YEARS, NO EVIDENCE OF RECURRENT DISEASE, >60 DAYS POST-TREATMENT, AND BODY MASS INDEX (BMI) 30 KG/M2. BASELINE, 1, 3, 6, AND 12 MONTH ASSESSMENTS WILL INCLUDE QUESTIONNAIRES ON MEDICAL HISTORY, DIET, AND PATIENT-REPORTED PSYCHOSOCIAL/QUALITY OF LIFE OUTCOMES; OBJECTIVELY MEASURED WEIGHT; ACCELEROMETER MEASURED PA; AND DRIED BLOOD SPOTS TO MEASURE INFLAMMATORY/CARDIOMETABOLIC BIOMARKERS. QUALITATIVE INTERVIEWS WITH A SUBSET OF PARTICIPANTS WILL TAKE PLACE AT 1 AND 12 MONTHS. THE GOAL OF THE 12 MONTH ¡VIDA! (LIFE!) PROGRAM IS TO ACHIEVE 7% WEIGHT LOSS. FOLLOWING BASELINE ASSESSMENTS, PARTICIPANTS (N=410) WILL BE RANDOMIZED TO ¡VIDA! OR ¡VIDA! + EL. AT 1 MONTH, RESPONDERS (2% WEIGHT LOSS) WILL CONTINUE WITH THEIR INTERVENTION AND NON-RESPONDERS (<2% WEIGHT LOSS) WILL BE RE-RANDOMIZED TO RECEIVE AUGMENTED BEHAVIORAL SUPPORT (I.E., COMBINATIONS OF EL, INDIVIDUALIZED HEALTH COACHING, AND DELIVERED GROCERIES). AIM 1) TO COMPARE THE EFFECTIVENESS OF FOUR ADAPTIVE INTERVENTIONS FOR WEIGHT LOSS IN LATINA BC SURVIVORS, BEGINNING WITH ¡VIDA! OR ¡VIDA! + EL (STAGE 1) FOLLOWED BY AUGMENTED BEHAVIORAL SUPPORT FOR 11 MONTHS FOR NON-RESPONDERS (STAGE 2). AIM 2) TO USE A NOVEL DATA-DRIVEN APPROACH TO DETERMINE WHETHER KEY INDIVIDUAL BASELINE CHARACTERISTICS MODERATE THE EFFECT OF THE ADAPTIVE INTERVENTIONS ON WEIGHT LOSS, AND THUS LAY THE GROUNDWORK FOR MORE PERSONALIZED ADAPTIVE WEIGHT LOSS STRATEGIES. EXPLORATORY AIMS WILL I) ASSESS WHETHER INTERVENTION ENGAGEMENT MODERATES THE EFFECT OF THE ADAPTIVE INTERVENTIONS ON WEIGHT LOSS; II) COMPARE THE EFFECTS OF ADAPTIVE INTERVENTIONS ON CHANGES IN INFLAMMATORY AND CARDIOMETABOLIC BIOMARKERS, DIET QUALITY, AND PA; III) QUANTITATIVELY ASSESS BIOPSYCHOSOCIAL PREDICTORS/MEDIATORS OF BEHAVIOR CHANGE; AND IV) QUALITATIVELY ASSESS THE PARTICIPANT EXPERIENCE TO UNDERSTAND FACTORS THAT CONTRIBUTE TO STUDY OUTCOMES. THE TRIAL WILL GENERATE EVIDENCE ON THE BEST STRATEGIES FOR AN EFFECTIVE, SCALABLE WEIGHT LOSS PROGRAM TO PROMOTE HEALTHY CANCER SURVIVORSHIP AMONG LATINA BC SURVIVORS.
assistance · Last action 2025-07-14
$2,377,399
Department of Health and Human Services
TRANSLATING AUTOANTIBODIES INTO CHIMERIC ANTIGEN RECEPTOR-T CELL THERAPY FOR SMALL CELL LUNG CANCER - ABSTRACT FOR THE LAST 30 YEARS, THE 5-YEAR SURVIVAL RATE OF SMALL CELL LUNG CANCER (SCLC) HAS BEEN LESS THAN 7% DESPITE THE ADDITION OF IMMUNE CHECKPOINT INHIBITORS AS TREATMENT OPTIONS. THERAPIES LIKE IMMUNE CHECKPOINT INHIBITORS THAT AIM TO REENGAGE AN IMMUNE RESPONSE MAY NOT SUCCEED FOR SCLC AS PREVIOUS STUDIES HAVE SHOWN DOWNREGULATION OF MHC MOLECULES, LOW PD-L1 EXPRESSION AND LIMITED IMMUNE INFILTRATION. HOWEVER, SCLC IS OFTEN ASSOCIATED WITH AUTOANTIBODY-DRIVEN PARANEOPLASTIC SYNDROMES, PROVIDING EVIDENCE FOR THE IMMUNOGENICITY OF SCLC. WE PROPOSE THAT CHIMERIC ANTIGEN RECEPTOR T CELLS (CAR-TS) AS A NOVEL APPROACH FOR SCLC IMMUNOTHERAPY THAT OVERCOMES IMPEDIMENTS TO ENDOGENOUS IMMUNITY. CAR-TS ARE SYNTHETICALLY ENGINEERED TO FUSE ANTIBODY LIGAND BINDING DOMAINS WITH COSTIMULATORY COMPONENTS THAT ACTIVATE T CELLS AFTER ENGAGEMENT OF CELL SURFACE ANTIGENS, AND HAVE HAD CONSIDERABLE SUCCESS IN LEUKEMIA, LYMPHOMA, AND MULTIPLE MYELOMA. THE MICROENVIRONMENT OF SCLC IS PHENOTYPICALLY CLOSER TO CAR-T RESPONSIVE LYMPHOMA THAN MANY SOLID TUMORS WHERE CAR-TS HAVE THUS FAR HAD LIMITED SUCCESS. A CHALLENGE FOR CAR-T CELLS IN MANY SOLID TUMORS IS THE IDENTIFICATION OF TARGET ANTIGENS THAT ARE TUMOR-SPECIFIC. WE HAVE IDENTIFIED 13 NOVEL CELL SURFACE ANTIGEN AND HERE WILL PRIORITIZE 3 WITH HIGH PREVALENCE IN SCLC. EACH OF THESE ANTIGENS HAVE POST-TRANSLATIONAL MODIFICATIONS THAT ACT AS NEOANTIGENS AND LEAD TO AUTOANTIBODY PRODUCTION IN A HIGH PERCENTAGE OF SCLC CASES. WE WILL CAPTURE THESE NEOANTIGEN-AUTOANTIBODIES FROM SCLC PATIENT-DERIVED B CELLS, SEQUENCE THE TUMOR SPECIFIC BINDING SEQUENCES, AND DESIGN AND TEST CARS CONSTRUCTED FROM THE SINGLE CHAIN VARIABLE FRAGMENTS (SCFVS). THE BENEFIT OF ISOLATING AUTOANTIBODIES FROM SCLC PATIENTS TO DETECT TUMOR-SPECIFIC NEOANTIGENS IS THREE-FOLD: 1. THE ANTIGENS IDENTIFIED HAVE ALREADY PROVEN TO BE IMMUNOGENIC; 2. THE VARIABLE REGIONS OF THESE HUMAN AUTOANTIBODIES CAN BE DIRECTLY ENGINEERED INTO LIGAND BINDING DOMAINS OF CAR-T CELLS; AND 3. AUTOANTIBODIES CAN BE DETECTED IN THE BLOOD OF PATIENTS AND SERVE AS TISSUE SURROGATE BIOMARKERS TO GUIDE CAR-T CELL TARGET SELECTION. THE CAR-T CELLS WE DEVELOP WILL BE RIGOROUSLY TESTED IN MULTIPLE PRECLINICAL MODELS THAT ADDRESS COMPLEMENTARY BUT NON-OVERLAPPING THERAPEUTIC BARRIERS. THESE INCLUDE TESTING CAR-T CELL TUMOR INFILTRATION, EFFICACY AND TOXICITY IN A LIBRARY OF GENETICALLY DIVERSE SCLC PATIENT DERIVED XENOGRAFTS AND IDENTIFYING, THEN OVERCOMING, IMMUNOSUPPRESSIVE MECHANISMS IN THE IMMUNE COMPETENT RB/P53 GENETICALLY ENGINEERED MOUSE MODEL. OUR TEAM OF EXPERTS IN LUNG CANCER, AUTOANTIBODY BIOMARKERS, IMMUNOLOGY AND CAR-T CELLS IS WELL EQUIPPED TO EXECUTE THE DEVELOPMENT OF NOVEL IMMUNOTHERAPIES THAT ARE DESPERATELY NEEDED IN SCLC.
assistance · Last action 2025-08-13
$2,357,606
Department of Health and Human Services
PRECOMPETITIVE COLLABORATION ON LIQUID BIOPSY FOR EARLY CANCER ASSESSMENT: DATA MANAGEMENT AND COORDINATING UNIT - PROJECT SUMMARY LIQUID BIOPSY IS A CLINICAL TEST THAT INVOLVES THE ANALYSIS OF VARIOUS BIOMARKERS PRESENT IN THE BLOOD OR OTHER TYPES OF BODY FLUIDS. IT ENABLES THE DETECTION OF CANCER AT AN EARLIER STAGE THAN TRADITIONAL IMAGING OR TISSUE BIOPSY METHODS, AND THUS CAN LEAD TO REDUCTION OF CANCER MOBILITY AND MORTALITY. AS ONE OF THE MOST PROMISING SOLUTIONS FOR CANCER EARLY DETECTION, LIQUID BIOPSY HAS THE POTENTIAL TO REVOLUTIONIZE CANCER DIAGNOSIS, PROVIDING PATIENTS WITH MORE EFFECTIVE AND LESS INVASIVE CARE. THE LIQUID BIOPSY ANALYTES INCLUDE CIRCULATING TUMOR CELLS (CTCS), CIRCULATING TUMOR DNA, WHICH IS PART OF CELL-FREE DNA (CFDNA), EXTRACELLULAR VESICLES, AS WELL OTHER TUMOR ASSOCIATED RNAS, PROTEINS AND METABOLITES. THESE ANALYTES TYPICALLY HAVE VERY LOW LEVELS IN BLOOD OR OTHER TYPES OF BODY FLUID OF EARLY-STAGE CANCER PATIENTS, LEADING TO DIFFICULTIES IN OBTAINING REPRODUCIBLE RESULTS AND LOW SENSITIVITY AND SPECIFICITY FOR CANCER EARLY DETECTION. WHILE MANY NEW ASSAYS AND TECHNIQUES HAVE BEEN DEVELOPED TO TACKLE THESE CHALLENGES, VALIDATION OF THESE ASSAYS/TECHNIQUES IN DIFFERENT POPULATIONS AND/OR CANCER TYPES POSES MANY CHALLENGES, AND THESE ARE THE MAIN AREAS OF RESEARCH SUPPORTED BY THE LIQUID BIOPSY CONSORTIUM (LBC). AS DATA MANAGEMENT AND COORDINATING UNIT (DMCU) OF LBC, WE WILL SUPPORT STATE- OF-THE-ART STATISTICAL METHODS FOR STUDY DESIGN AND DATA ANALYSIS, THE COORDINATION, IMPLEMENTATION, AND CONDUCT OF COLLABORATIVE STUDIES ACROSS THE CONSORTIUM AND WORK CLOSELY WITH LBC INVESTIGATORS ON DATA ANALYSIS BY STATISTICAL METHODS, MACHINE LEARNING MODELING AND ARTIFICIAL INTELLIGENCE. WE WILL ALSO SUPPORT CONSORTIUM COORDINATION AND DATA MANAGEMENT, INCLUDING IDENTIFICATION AND ADOPTION OF STANDARD DATA ELEMENTS FOR LIQUID BIOPSY STUDIES. WE SEEK TO ESTABLISH THE DMCU AS A LEADING CENTER FOR INNOVATION AND RESOURCES IN LIQUID BIOPSY RESEARCH, AND TO ENHANCE, IMPROVE AND MAINTAIN LBC NETWORK INTEGRATION AND COORDINATION.
assistance · Last action 2026-04-21
$2,336,400
Department of Health and Human Services
EARLY INTERVENTION WITH ANTI-PROLIFERATIVE THERAPY CLOSE TO ART INITIATION TO LIMIT LONG-TERM SIV PERSISTENCE - PROJECT SUMMARY HIV PERSISTS DESPITE DECADES OF ANTIRETROVIRAL THERAPY (ART) BECAUSE OF A POPULATION OF LATENTLY INFECTED CD4+ T CELLS KNOWN AS THE HIV RESERVOIR. THE HIV RESERVOIR IS SUSTAINED BY PROLIFERATION OF INFECTED CD4+ T CELLS, WHICH DO NOT EXPRESS ENOUGH VIRAL PROTEIN TO BE ELIMINATED BY HIV-SPECIFIC IMMUNE RESPONSES. WHILE PROLIFERATION OF CELLS IS A PROMISING TARGET FOR CURING HIV AND ELIMINATING THE NEED FOR LIFELONG ART, A COMPREHENSIVE PRECLINICAL STRUCTURE TO DEVELOP A LYMPHOCYTE ANTI-PROLIFERATION THERAPEUTIC STRATEGY DOES NOT EXIST. THE OPTIMAL TIMING OF ANTI-PROLIFERATIVE (AP) THERAPY IS ALSO UNKNOWN. RECENT EVIDENCE SUGGESTS THAT CD4+ T CELL PROLIFERATION PLAYS A VITAL ROLE IN GENERATING MULTIPLE PROLIFERATIVE CLONES OF LATENTLY INFECTED CELLS EXTREMELY EARLY DURING UNTREATED HIV INFECTION. WE DEVELOPED A MATHEMATICAL MODEL WHICH SUGGESTS THAT MASSIVE CD4+ T CELL PROLIFERATION COINCIDENT WITH RECOVERY FROM CD4+ LYMPHOPENIA, OCCURS DURING WEEKS 1-4 OF PRIMARY HIV INFECTION AND IS VITAL FOR GENERATING MUCH OF THE HIV RESERVOIR. WE HYPOTHESIZE THAT EFFECTIVE AP THERAPY GIVEN DURING THIS CRITICAL THREE-WEEK WINDOW WILL LIMIT THE VOLUME AND ALTER THE CLONAL STRUCTURE OF THE HIV RESERVOIR. IN AIM 1 OF THIS APPLICATION, DR. ADAM SPIVAK WILL TEST SMALL MOLECULAR AGENTS TARGETING CD4+ T CELL PROLIFERATION GIVEN ALONE AND IN COMBINATION. A COMPREHENSIVE LIBRARY OF IMMUNOMODULATORY AND CHEMOTHERAPEUTIC AGENTS WITH HIGH THERAPEUTIC POTENTIAL WILL BE TESTED FOR THEIR AP EFFECTS EX VIVO ON UNINFECTED CD4+ T CELL CULTURES, EX VIVO ON LATENTLY HIV-1 INFECTED CELLS DERIVED FROM HUMAN DONORS, AND IN VIVO IN UNINFECTED RHESUS MACAQUES BY MEASURING IMPACT ON CD4+ T CELL TURNOVER USING DEUTERIUM WATER LABELING. FINALLY, DR. JOSHUA SCHIFFER WILL UTILIZE MATHEMATICAL MODELS WHICH CAPTURE DRUG PHARMACOKINETICS AND PHARMACODYNAMICS, AS WELL AS THE UNDERLYING DYNAMICS OF CD4+ T CELL SUBSETS WITHIN THE HIV RESERVOIR, TO OPTIMIZE SELECTION OF SINGLE DRUG OR COMBINATION ANTI-PROLIFERATIVE (AP) REGIMENS FOR DOSING OF SIV INFECTED ANIMALS IN AIM 2. DRUG REGIMENS WILL FIRST BE RANKED IN A TABULAR FORM ACCORDING TO PREDICTED POTENCY. THE MOST POTENT REGIMEN WITH KNOWN SAFETY IN HUMANS AND LACK OF CELL TOXICITY IN DR. SPIVAK’S EX VIVO MODEL WILL ULTIMATELY BE SELECTED FOR AIM 2. IN AIM 2, DR. JOSEPH MUDD WILL EVALUATE THE EFFECTS OF OPTIMIZED AP AGENTS ON EARLY RESERVOIR FORMATION DYNAMICS IN 24 SIV-INFECTED RHESUS MACAQUES: 6 WILL RECEIVE ART ALONE BETWEEN WEEKS 1-37 POST INFECTION; 6 WILL RECEIVE ART ALONE BETWEEN WEEKS 4-40 POST INFECTION; 6 WILL RECEIVE ART BETWEEN WEEKS 1-37 AND OPTIMIZED AP THERAPY BETWEEN WEEKS 1-4 POST INFECTION; 6 WILL RECEIVE ART BETWEEN WEEKS 4-40 AND OPTIMIZED AP THERAPY BETWEEN WEEKS 1-4 POST INFECTION. OPTIMIZED AP REGIMENS WILL BE SELECTED BASED ON DR. SPIVAK’S EXPERIMENTAL DATA FROM AIM 1 COUPLED WITH DR. SCHIFFER’S MATHEMATICAL MODELS. DURING ART, WE WILL MEASURE THE IN VIVO AP THERAPEUTIC EFFECT ON 1) SIV RESERVOIR VOLUME WITH TOTAL AND INTACT SIV DNA, 2) RESERVOIR CD4+ T CELL SUBSET COMPOSITION, 3) IN VIVO CD4+ T CELL TURNOVER WITH D2O LABELING, AND 4) SIV RESERVOIR CLONAL STRUCTURE USING INTEGRATION SITE SEQUENCING, BASED ON FREQUENT LONGITUDINAL SAMPLING OF BLOOD AND GUT TISSUES. AFTER 36 WEEKS OF ART, WE WILL STOP ART AND MONITOR VIRAL REBOUND FOR UP TO 4 MONTHS. WE HYPOTHESIZE THAT AP THERAPY BETWEEN WEEKS 1 AND 4 POST INFECTION WILL REDUCE TOTAL AND INTACT SIV DNA AND DECREASE RESERVOIR CLONALITY FOLLOWING 6 MONTHS OF ART AND INCREASE TIME TO SIV REBOUND AFTER ART INTERRUPTION.
assistance · Last action 2026-04-21
$2,299,509

Federal contract dollars to this establishment. Primary NAICS: 541715 - RESEARCH AND DEVELOPMENT IN THE PHYSICAL, ENGINEERING, AND LIFE SCIENCES (EXCEPT NANOTECHNOLOGY AND BIOTECHNOLOGY). Last action: 2026-06-11. Source: USAspending.gov, net obligations. Recipient address is the SAM registration / HQ address, not necessarily the worksite.

Inspection history

Date	Trigger	Violations	Serious	Penalty
2025-07-31	Complaint	1	—	$0
2023-08-30	Complaint	0	—	$0
2023-07-18	Referral	0	—	$0
2023-02-07	Complaint	3	2	$14,400

Source: OSHA IMIS. Citation amounts reflect initially assessed penalties; final amounts after appeal may differ.

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