Targeting Polo-Like Kinase 1 in Prostate Cancer to Enhance Therapeutic Efficacy

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Title: Targeting Polo-like kinase 1 in prostate cancer to enhance therapeutic efficacy Abstract Prostate cancer (PCa) is the second most common cause of cancer death in men in the US. Over the past several decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed into a poor prognosis stage of castration-resistant prostate cancer (CRPC), which eventually led to mortality. And the current therapeutic agents for CRPC patients only extend survival by around 2.5 - 5 months. Therefore, novel and effective therapeutic strategies for CRPC patients are urgently needed. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with CRPC. The objective is to identify the role of Plk1/p62/Nrf2 signaling pathway in CRPC, and to exploit the potentially therapeutic strategies that could be benefit the CRPC patients. The central hypothesis is that Nrf2 is activated by a noncanonical mechanism involving p62 phosphorylation by Plk1 in CRPC. Our hypothesis will be tested by pursuing Three Specific Aims: (1) to determine the novel role of Plk1 as regulator of cellular response to oxidative stress. (2) examine the role of Plk1/p62/Nrf2 axis in tumor growth in mouse models. And (3) whether inhibition of Plk1/p62/Nrf2 signaling pathway enhance the efficacy of CRPC therapy. The expected results will reveal a novel molecular mechanism to show how Plk1 contributes to PCa progress, and will open up new avenues for application of Plk1 inhibitors as a therapeutic option. The team, with expertise in Plk1 in mouse models, Plk1 in cancer cell biology, PCa pathology, GU oncology and biostatistics, will be able to finish the proposed research in a timely manner.