Title: Development of Next Generation Galeterone Analogs for Prostate Cancer Therapy Project Summary/Abstract: The long-term goal of this project is to identity and development small molecules for the effective treatment, including inhibition of tumor growth and metastasis of African American (AA) prostate cancer (PC). PC exhibits the most striking racial disparity, as AA men are at 1.7 times higher risk of being diagnosed and 2.4 times higher risk of dying of PC compared to European Americans (EA) men (1, 2). In our active NCI R01 grant award (R01CA224696), the objective is to determine the therapeutic potential of lead next generation galeterone analog (NGGA), VNPP433-3β that simultaneously target AR/AR-V7, Mnk/eIF4E and mTORC1 signaling for the treatment of all forms of PC, including metastatic disease. To expand my current R01 research to address PC disparities and to take advantage of the ability of our clinical agent, galeterone (gal) and our novel class of NGGAs to target multiple oncogenic signaling pathways (3), we will collaborate with Dr. Bi-Dar Wang who has substantial research experience and expertise in prostate cancer disparities research. Dr. Wang and colleagues have identified novel genome-wide race-specific RNA splicing events as critical drivers of aggressive prostate cancer and therapeutic resistance in African American (AA) men. Specifically, they identified novel genome-wide, race-specific RNA splicing events as critical drivers of PC aggressiveness and therapeutic resistance in AA men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of cloned AA-enriched variants, PIK3CD-S or FGFR3-S, in EA PC cell lines enhances AKT/mTOR signaling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models (4-6). Based on the findings that gal/NGGAs strongly modulate signaling pathways (e.g. AR/AR-V7/V567es, Mnk-eIF4E and mTORC1 signaling in a variety of PC cell lines) that are proven to be differential unregulated and are associated with PC disparities between AA and EA men and the findings that gal/NGGAs possess superb multiple desirable anti-PC activities as single agents and can synergize (with increased anti-PC activity) when combined with FDA approved PC drugs (3), we hypothesize that gal/NGGAs will be effective against various AA PC cell lines and tumors that are resistant to current PC therapies. We will test our hypothesis through 3 specific aims: Aim 1. Screen for effective therapeutic agents from our in-house compounds, including gal and the lead NGGAs against a variety of PC cell lines derived from AA and EA patients. Aim 2. Determine the molecular mechanisms underlying the antiproliferative activities of two lead compounds, alone and in combination with FDA-approved PC drugs. Aim...