U54CA274370

Project Summary: Prostate Inflammatory Lesions as a Proving Ground for Development of Aggressive Prostate Cancer

Epidemiological and pathological studies have implicated lifestyle, microbial, and environmental factors in prostate cancer etiology/risk. A potential link between these factors and prostate carcinogenesis is the presence of chronic inflammation associated with atrophy (PIA) in prostates of aging men. Yet, there is a paradox surrounding the role of the immune response in prostate cancer: "the inflammation paradox". On one hand, inflammation may be a driver of carcinogenesis. On the other hand, the immune system is known to seek and destroy cancer cells. The majority of prostate cancer lesions are "immune deserts", and immune checkpoint inhibitors (ICIs) are ineffective in most cases.

Why is there an evidently strong immune reaction in non-neoplastic regions in PIA, but a lack of a robust immune response in most prostate cancers? We hypothesize that chronic inflammation in PIA represents evidence of an innate immune response that drives carcinogenesis. However, in this inflammatory "proving ground", only cells that can epigenetically switch off this response can emerge to become aggressive neoplastic precursors. We hypothesize that the paucity of immune infiltrates and lack of PD-L1 is evidence that prostate cancer cells develop a number of different mechanisms that evade anti-tumor adaptive immunity. We postulate that additional cell non-autonomous immune suppressive mechanisms enable disease progression.

We propose three synergistic research projects (two basic, one translational) to mechanistically test key questions stemming from our "proving ground" hypothesis.

Project 1 (Basic Science): We hypothesize that the STING induction in PIA drives acute and chronic inflammation, leading to cell injury/cell death and proliferation. Second, in a subset of PIA cells, epigenetic silencing of STING dampens the immune response, allowing them to emerge as overt pre-neoplastic cells. We will test this in animal models and in translational studies employing annotated and molecularly characterized prostatectomies.

The combination of PTEN loss and MYC copy number gain is an independent predictor of poor outcome in prostate cancer. We hypothesize that the combination of MYC and PTEN stimulates a cell non-autonomous immune evasion mechanism induced by the recruitment of immunosuppressive myeloid cells and fibroblast activation protein (FAP)-positive fibroblasts. Project 2 (Basic Science) will test these hypotheses in animal models and in human tissues.

Recently introduced imaging technologies have raised the hypothesis that PET/CT imaging results may be able to predict molecular and tumoral micro-environmental characteristics of aggressive prostate cancer. PET imaging for PSMA using PYL PET/CT has been FDA approved for imaging high-risk men prior to prostatectomy. In Project 3 (Translational), we employ PET/CT scanning for PSMA and combine this with MPMRI to address these hypotheses. Also in Project 3, we will apply newly developed/developing PET imaging agents to non-invasively and longitudinally study the extent of M2 macrophages and cancer-associated fibroblasts in our mouse prostate progression cancer models.

The Johns Hopkins University

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]

Baltimore, Maryland 212870013 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 314% from $1,468,402 to $6,082,974.