U54CA274375

The Stromal Microenvironment as a Co-Organizer of Bladder Carcinogenesis and Progression - Overall Project Summary

Bladder cancer (BC) is the second most common urologic malignancy, affecting 573,278 people worldwide in 2020. Pathologically, BC is diagnosed as non-muscle-invasive (NMI) and muscle-invasive (MI) disease. Early bladder lesions are defined here as NMIBC. There are major clinical gaps in NMIBC, including the lack of mechanistic insights defining NMIBC progression and the lack of a platform for risk stratification of NMIBC that recur but never progress (referred to as "non-progressors") from those that progress into MIBC (referred to as "progressors") and consequently demonstrate poor prognosis.

The goal of our center is to tackle this clinical issue by deciphering the underlying mechanisms restraining or promoting the progression of early lesions (Project 1 & 2) and leveraging this novel biology as candidate biomarkers to risk-stratify aggressive NMIBC (Project 3). This proposal seeks to shift the current research paradigm in the field of NMIBC by proposing a conceptually innovative tug-of-war between a tumor-restraining mechanism (Project 1) and a tumor-promoting mechanism (Project 2) in determining the outcome of early bladder lesions/NMIBC in becoming "progressors" or "non-progressors" (Project 3).

Clinically, why "non-progressors" often recur but seldom progress, and what are the driving forces advancing "progressors" into MIBC with poor survival remain fundamental questions in the field. Our tug-of-war hypothesis with two opposing forces is conceptually different from most other studies, which primarily focus on one side of the coin. Furthermore, the integration of knowledge from Project 1 and 2 as a unified spatial proteomics and transcriptomics map by the Shared Resource Core will reveal spatial and temporal relationships between distinct fibroblast populations with opposing functions, their physical interactions with tumor and immune cell clusters, as well as their relationship to the biomarkers from Project 3.

Benchmark of success: The knowledge gained here will shift clinical practice paradigm by informing future NMIBC management through 1) the development of novel urinary profiling strategies that could risk stratify aggressive NMIBC (Project 1-3) and 2) the identification of targets for future precision intervention, either by enhancing/sustaining the tumor-restraining mechanisms (Project 1) and/or inhibiting the tumor-promoting mechanisms (Project 2). The overall success of our program is further ensured by an extraordinary multi-investigator team that integrates three "organ-specific" bladder cancer investigators within Cedars-Sinai Medical Center. All have active R01s and individual NCI-funding track record in performing basic science research, translational bladder cancer research, or leading multi-center clinical trials on the discovery and validation of biomarkers. Finally, they propose to collect valuable retrospective and prospective NMIBC cohorts, which are essential to address the clinical questions posed within this proposal and will become available to the research community as a shared resource to advance the field.

Methodist Hospital

TO PROVIDE AN ORGANIZATIONAL FOCUS AND STIMULUS FOR THE HIGHEST QUALITY CANCER RESEARCH THAT EFFECTIVELY PROMOTES INTERDISCIPLINARY CANCER RESEARCH AIMED TOWARD THE ULTIMATE GOAL OF REDUCING CANCER INCIDENCE, MORTALITY AND MORBIDITY. THE CANCER CENTER SUPPORT GRANT (CCSG) PROVIDES THE RESOURCES AND INFRASTRUCTURE TO FACILITATE THE COORDINATION OF INTERDISCIPLINARY PROGRAMS ACROSS A BROAD SPECTRUM OF RESEARCH FROM BASIC LABORATORY RESEARCH TO CLINICAL INVESTIGATION TO POPULATION SCIENCE. THE CCSG SUPPORTS SALARIES FOR SCIENTIFIC LEADERSHIP OF THE CENTER, SHARED RESOURCES FOR FUNDED CENTER INVESTIGATORS, CERTAIN ADMINISTRATIVE COSTS, PLANNING AND EVALUATION, AND DEVELOPMENTAL FUNDS FOR NEW RECRUITMENTS AND FEASIBILITY STUDIES.

93.397 - Cancer Centers Support Grants

National Cancer Institute (NCI) [HHS - NIH]

Houston, Texas 770302703 United States

Single Zip Code

Translational and Basic Science Research in Early Lesions (TBEL) (U54 Clinical Trial Not Allowed) (RFA-CA-21-054)

Amendment Since initial award the total obligations have increased 294% from $1,745,043 to $6,871,892.