Discovery of Genetic and Immunobiological Differences in African American and Caucasian American Prostate Cancers
Abstract
Prostate cancer remains the second leading cause of cancer-related death among U.S. men, disproportionately affecting African American (AA) men, who are often underrepresented in research studies. AA men with prostate cancer have higher incidences and mortality rates and exhibit much more aggressive and lethal disease compared to Caucasian American (CA) men; however, the biological mechanisms driving aggressive prostate cancer in this demographic have yet to be fully defined. Given the remarkable advancements and successes in immunotherapy over the past decade, the goal of this project is to understand the role of the immune system and how it may influence risk and outcomes in AA and CA prostate cancers. Understanding these fundamental differences will be essential in designing appropriate therapeutic targets, giving special considerations to race. Cancer has long been considered an inflammatory disease, which implies the immune system as an important factor in cancer development. The normal function of the immune system is to ward of disease by triggering an inflammatory response; however, since too much inflammation can damage normal tissues, the immune system attempts to maintain this fine balance by suppressing these responses. This occurs by turning on regulatory signals, known as checkpoints. Tumors have the ability to use these mechanisms to their advantage to escape anti-tumor immune destruction. Thus, the ability to re-harness the potency of the immune system using checkpoint inhibitors has become an active area of research interest. These strategies focusing on rewiring and reactivating a person’s immune system to attack the tumor combine both personalized and precision medicine, which are concepts that medicines should be tailored uniquely for the patient and the patient’s tumor. Since AA men are very often underrepresented in research studies, we will have the unique opportunity to utilize the large numbers of AA cases at the Center for Prostate Disease Research (~30%) to overcome this limitation in research. To address the first aim of this proposal, we will use gene expression studies comparing AA and CA tumors to identify various cell types and immune-related genes that are targetable for therapy. We will classify any differences in these immune cell types and markers to determine whether they contribute to aggressive AA disease. This will be followed by DNA sequencing of receptors on T cells within tumors and blood to determine the robustness of the immune response. For the second aim, we will validate our findings in Prostate Cancer Biorepository Network specimens, using these same techniques to confirm our results. In the third aim, we will determine whether certain immune cell types or immune-related genes are associated with clinical or pathologic endpoints (metastasis, PSA levels, Gleason Score, biochemical recurrence, tumor differentiation). Assessing the immune landscape in prostate cancer patient tissues prior to treatment and determining associations with clinical and pathological outcomes may assist in defining patient profiles that could be prognostic for disease progression or risk, especially as it pertains to race. AA men typically report greater negative side effects from treatment compared to CA men. Taking this into consideration for drug development will ultimately enhance the quality of life of AA men with prostate cancer. The overall goal of this proposal will be to define the immune landscape, as well as any differences that may exist between AA and CA tumors, the results of which will help inform future therapeutic options. T cell sequencing studies will also have future clinical utility for the improvement of personalized cancer vaccines. Findings from this project will have potential for near-term diagnostic and prognostic development, and even the possibility of generating companion diagnostics within the next 5 years. Grant support from the HDFA will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910302
Entities
People
- Cara Schafer
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine
- United States Army