Inhibiting CREB1/FoxA1 target gene-driven castration-resistant prostate cancer

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DESCRIPTION (provided by applicant): The applicant for this training fellowship has initiated an interdisciplinary training program under the guidance of a diverse mentoring team in hopes of developing the essential skillset required for a successful career in translational cancer research in the academic setting. This application outlines the mentored training plan and research project to be implemented over the remainder of the applicant's graduate research career. Included are the continued educational components, Sponsor and Co-Sponsor roles and training records, applicant's career aspirations, and professional development strategy that have been critically evaluated and tailored to address the applicant's unique personal and professional goals. Successful implementation of these component training elements and the completion of the proposed research will provide the applicant with a background in high-throughput molecular biology, in vivo and in vitro models of prostate carcinogenesis, bioinformatics, clinical translational research, ethical conduct of human subjects' research, grantsmanship, and symposium presentation. These will serve him in the future as he establishes a positive professional reputation and as he assembles and leads an independent research team. The applicant has proposed to utilize newly generated high-throughput sequencing data to comprehensively characterize gene expression profiles of advanced prostate cancer cells determined by the combinatorial activity of two transcription factors, CREB1 and FoxA1. This effort will identify potential therapeutic targets for future prostate cancer treatment strategies as well as biomarkers of disease progression. Additionally, owing to the kinase-inducible transcriptional activity of CREB1, this coregulatory pathway may be sensitive to inhibitors of upstream CREB1-activating factors, and thus represents a viable drug target. This proposition will be tested using experimental and clinically available inhibitors of te PKA and PI3K/Akt kinase signaling pathways. Prostate cancer represents a tremendous burden as the second leading cause of cancer related deaths in American men, and while androgen ablation therapy is effective in treating initial, androgen-dependent prostate cancer (ADPC), there is no effective treatment for those cases that relapse into the lethal, castration-resistant prostate cancer (CRPC) phase. The central hypothesis of this proposal is that CREB1 and FoxA1 coregulate critical gene networks central to CRPC and that targeting CREB1 transcriptional activation can inhibit CRPC growth driven by CREB1/FoxA1. In Specific Aim 1, the applicant will globally identify CREB1/FoxA1-coregulated genes central to clinically relevant disease pathways. In Specific Aim 2, the applicant will assess the impact of CREB1-targeting compounds and coregulated gene silencing on CRPC growth in vitro and in vivo. Together, the prescribed training plan and the novel research strategy will lay the foundation for the applicant's bright and prolific career in translational cancer research.