Pilot Project 1

点击翻译按钮获取中文摘要

African Americans (AAs) exhibit higher incidence of and mortality from prostate cancer (PCa) than whites. Although much of the disparate cancer burden can be explained by differences in social determinants of health, a significant portion of this disparity remains after controlling for these factors. The studies proposed here address the urgent need to elucidate the molecular mechanisms underlying the more aggressive PCa biology in AA men, to manipulate these mechanisms for therapeutic application and to determine the importance of these mechanisms for response to current therapeutic strategies. At Duke Cancer Institute (DCI), we have identified novel alternatively spliced genes in AA versus white PCa and have shown that AA variants track with more aggressive cancer invasion characteristics of PCa in AA men. We have also identified novel single nucleotide polymorphisms located in splicing regulatory regions of such genes that associate with PCa risk, aggressiveness and survival. Subsets of these genes are androgen receptor (AR) targets, relevant given the role that AR signaling plays in PCa progression, use of anti-androgen therapy and association of AR signaling with PCa health disparities. In parallel, at North Carolina Central University (NCCU), we have interrogated AMP-activated protein kinase (AMPK) signaling, which operates in a regulatory loop with AR, thus having therapeutic implications for race-related PCa. Using the Bio-manufacturing Research Institute and Technology Enterprise at NCCU, we identified 8 novel small molecule AMPK activators. The proposed work is a joint translational science pilot project to further develop the existing NCCU-DCI partnership, support focused collaboration in cancer research, enhance cancer research at NCCU and cancer health disparities research at DCI and support the development of 2 junior faculty and a minority postdoc. Our objectives are to 1) interrogate and modulate race-related AR target splice variants and 2) elucidate genetic factors important for response to anti-androgen therapy among and between racial groups. Specifically, we aim to 1) define the biological significance of modulating the levels of race-related AR target RNA splice variants on PCa cell biology, using novel RNA therapeutics and small molecules, 2) define the biological significance of cis- acting splicing elements of alternatively spliced AR target genes in AA PCa to alternative RNA splicing events and AA race-related PCa cell biology, by expressing variants containing the AA or white genotype and assessing alterations on splicing and PCa cell biology and 3) define the biological factors related to alternative RNA splicing events and AMPK signaling that are critical for response to the anti-androgen, Abiraterone Acetate, among and between racial groups, performing association analyses of correlatives with clinical parameters in a clinical trial. The rationale for and impact of the work proposed here is that it will reveal molecular mechanisms that can pave the way toward development of novel precision biomarkers for PCa risk, aggressiveness, therapeutic response and/or survival prediction among minorities as well as precision therapeutics for PCa disparities.