Prostate cancer affects African American (AA) men disproportionately in the US, but even more so in the state of South Carolina, with 3 times higher mortality rates for AA men when compared to European American (EA) men. Neuroendocrine prostate cancer (NEPC) is a subtype of castrate resistant prostate cancer with aggressive clinical features and poor overall survival. NEPC is associated with androgen independence and a lack of therapeutic options. Although de novo NEPC is rare, recent studies support the idea that transformation of prostate adenocarcinoma cells through a process of neuroendocrine differentiation (NED) into NEPC as a mechanism of resistance to androgen receptor-directed therapies (ADT). The investigators have identified a lifestyle factor known as advanced glycation end-products (AGEs) that promote a more aggressive prostate cancer phenotype through the induction of a specific microRNA (miR-204) and MYC (a known driver of NEPC). The role of miR-204 in prostate cancer was considered controversial with some groups reporting a tumor suppressor and others an oncogenic role. More recent studies now show that miR-204 plays an oncogenic role in AR negative cells representing NEPC and as a tumor suppressor in AR positive cells representing prostate adenocarcinoma. We show that AGEs upregulate miR-204, MYC and drive NED in vitro and drive aggressive tumor growth in vivo. Relevant as both AGEs and miR-204 are elevated in AA men, when compared to EA men, with prostate cancer. We also show that inhibition of miR-204 can inhibit the neuroendocrine phenotype, including the downregulation of MYC. This innovative study is the first to link a lifestyle factor (AGE) and a plasma biomarker (miR-204) together as drivers of racial disparities in prostate cancer aggression, and as drivers that can be clinically targeted and may be informative for novel therapeutic interventions to delay or prevent the emergence of NEPC during ADT. Work supported by NIH/NCI Project #1U54CA210963

Citation Format: Ashley E. Knowell, Lourdes M Nogueira, Taiwo Biotidara, Brandon Sutton, Arabia Satterwhite, Michael Lilly, Shanora Brown, Dave Turner, Victoria Findlay. Lifestyle-associated metabolites drive neuroendocrine differentiation in prostate cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A075.