Development of a Novel Therapeutic Strategy for Prostate Cancer in African American Men
Abstract
African American men are more likely to be diagnosed with prostate cancer, tend to be diagnosed at younger age and with more advanced disease, and are more than twice more likely to die of prostate cancer than white men. While the precise reasons for these disparities are unknown, socioeconomic factors affecting access to and utilization of health care as well as genetic and environmental factors are implicated. Successful completion of this project will provide insights into the biology underlying these prostate cancer disparities, will improve our ability to specifically target highly aggressive prostate cancer, and will identify novel diagnostic and therapeutic approaches across prostate cancer subgroups. A growing body of literature has shed light on genomic and transcriptomic differences underlying these observed disparities. Significantly less is known about the role of epigenetics. Prior studies have demonstrated that the androgen receptor (AR) cistrome, the set of AR binding sites, is extensively reprogrammed in prostate tumorigenesis and disease progression. How or whether the prostate cancer AR cistrome differs in men of African ancestry (AA) and whether this contributes to observed racial disparities are not known. To address this knowledge gap, in Preliminary Studies, we generated and analyzed the AR cistrome on human prostate tissue specimens, including primary tumor and normal samples from men of AA and tumors from men of European ancestry (EA). Building on the epigenetic discoveries, we also performed RNA-seq and metabolomic profiling on independent sets of normal prostate specimens from AA men and EA men. Our data suggest an exciting working model whereby increased androgen signaling drives higher levels of lipogenesis in AA prostate tumors. In our proposed study, we first aim to validate these preliminary observations in a significantly larger cohort of prostate cancer specimen. We will establish the largest dataset of epigenome from AA prostate cancer by defining the AR cistrome and gene expression changes in AA prostate cancer tissue compared to benign tissue (from matched patient) and compared to EA prostate cancer tissue. In Aim 2 of our study, we will establish the lipidomic landscape of prostate cancer from a diverse spectrum of prostate cancer patients (including patients who have localized disease and patients with metastatic disease (both hormone sensitive and castration resistant)) using non-invasive procedure and body fluid. This large-scale lipid/fatty acid profiling will enable us to identify unique lipid signatures that are predictive of aggressive prostate cancer and treatment response. We have provided very strong evidence using a multi-omic approach that highlight the importance of lipid/fatty acid driven metabolism in prostate cancer tumorigenesis. We are excited to direct the field to a new direction and to evaluate the clinical utility of biomarkers of lipid/fatty acid metabolism pathway in disease prognosis. Last, we propose to evaluate the impact of disrupting lipid/fatty acid metabolism using small molecule inhibitor on tumor growth. We have developed a novel, first-in-class small molecule inhibitor that we propose to test in vivo using newly established prostate cancer models generated from AA prostate cancer. Successful execution of this last aim will pave the way for introducing a novel metabolic inhibitor to the clinic. Overall, we have outline three independent, non-overlapping, however, complementary aims that is designed to increase our understanding of the epigenetic landscape of AA prostate cancer and exploit newly identified vulnerabilities in AA prostate cancer to develop a novel treatment option that can increase efficacy of current standard of care agents. The feasibility of our project is strengthened by our team’s technical abilities and unique geographical location and access to target patient population. Houston is the most diverse large U.S.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210859
Entities
People
- Salma Kaochar
Organizations
- Baylor College of Medicine
- United States Army