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.
African Americans are diagnosed with prostate cancer and die from prostate cancer more often than whites. The goal of this project is to understand the underlying genetic differences among African American and white prostate cancer and the importance of these differences to prostate cancer aggressiveness and response to treatment. This research will be done together by a laboratory at North Carolina Central University (NCCU), an Institution Serving Underserved health disparity Populations and underrepresented Students, and a laboratory at the Duke Cancer Institute (DCI), a National Cancer Institute-designated Cancer Center. Therefore, the focused research on differences in cancer among racial groups will enhance the capacity of such research being performed at both NCCU and the DCI. In addition, this research project will provide training in this field to two junior researchers and a minority fellow. The outcome of this project could have profound implications for the prevention, diagnosis and treatment of this disease for African Americans, reducing the number of African American men who are diagnosed with prostate cancer and who die from prostate cancer.
|Freedman, Jennifer A; Wang, Yanru; Li, Xuechan et al. (2018) Single-nucleotide polymorphisms of stemness genes predicted to regulate RNA splicing, microRNA and oncogenic signaling are associated with prostate cancer survival. Carcinogenesis 39:879-888|
|Wang, Yanru; Freedman, Jennifer A; Liu, Hongliang et al. (2017) Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. Int J Cancer 141:731-743|
|Oladapo, Helen O; Tarpley, Michael; Sauer, Scott J et al. (2017) Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells. Cancer Lett 411:136-149|
|Ehe, Ben K; Lamson, David R; Tarpley, Michael et al. (2017) Data on peptides identified by mass spectrometry analysis of in vitro DYRK1A-mediated phosphorylation sites on GLI1. Data Brief 15:577-583|
|Ehe, Ben K; Lamson, David R; Tarpley, Michael et al. (2017) Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1. Biochem Biophys Res Commun 491:767-772|