P01CA269019

Pathways of Injury and Repair in Barrett's Carcinogenesis - Program Summary

The central hypothesis of this program project is that "altered squamous epithelial integrity (PRJ 1) and inflammatory injury (PRJ 2) activate signaling pathways including EPHB2 (PRJ 3) that affect precursor cells at the squamocolumnar junction (SCJ) transition, esophageal submucosal gland (ESMG), and basal squamous niches, resulting in the alteration of regulatory factors that include NOTCH, MYC, P63, and SOX9, leading to acinar ductal metaplasia (ADM), multi-layered epithelium (MLE), Barrett's esophagus (BE), and ultimately esophageal adenocarcinoma (EAC)."

The specific aims of our program are:
1) To elucidate signaling pathways by which mutated VSIG10L alters epithelial integrity leading to MLE and BE-like metaplasia on novel mouse models.
2) To define the spatial and temporal pattern of CXCL8 (IL-8) in ESMG following esophageal injury and phenotype the inflammatory infiltrate that leads to the development of ADM in ESMG associated with BE/EAC.
3) To identify mediators of EPHB2 signaling that lead to c-MYC activation and metaplastic cellular differentiation after injury in the development of BE and its progression to EAC.
4) To define how altered epithelial integrity, inflammatory cells, and alteration of signaling molecules that control differentiation (EPHB2) lead to metaplasia by altering transcription factors.
5) Integrate projects by providing investigators effective support through core resources with state-of-the-art biorepository, bioinformatics, and administrative services.

These objectives build and synergize on the considerable clinical, basic science, and translational expertise available at our institutions, 1) to focus laboratory research on understanding the genetic susceptibility and molecular changes that influence the development of BE and EAC; and 2) to then translate laboratory discoveries into clinical applications for effective detection, molecular risk stratification, and prevention of progression from BE to EAC.

Case Western Reserve University

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Cleveland, Ohio 44106 United States

Single Zip Code

National Cancer Institute Program Project Applications (P01 Clinical Trial Optional) (PAR-20-077)

Amendment Since initial award the total obligations have increased 191% from $2,268,872 to $6,603,958.