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

标题：靶向Polo-like kinase1治疗前列腺癌以提高治疗效果 摘要 前列腺癌(PCA)是美国男性癌症死亡的第二大原因。在过去的时间里 几十年来，雄激素剥夺疗法一直是慢性前列腺癌患者的主要治疗选择。 晚期前列腺癌；然而，大多数患者发展到耐去势的预后不良阶段。 前列腺癌(CRPC)，最终导致死亡。以及目前治疗慢性前列腺癌的药物 患者只能延长大约2.5-5个月的生存时间。因此，新的和有效的治疗策略 CRPC患者是迫切需要的。这项研究的长期目标是识别可用药的信号 为慢性前列腺癌患者提供更有效的治疗选择的途径。目标是确定角色 目的：研究Plk1/p62/Nrf2信号通路在CRPC中的作用，并探讨其潜在的治疗策略。 造福于CRPC患者。中心假设是Nrf2是由一种非规范机制激活的 参与了Plk1在CRPC中对p62的磷酸化。我们的假设将通过追求三个具体目标来检验： (1)确定Plk1作为细胞氧化应激反应调节因子的新作用。(2)审视角色定位 Plk1/p62/Nrf2轴在小鼠肿瘤生长中的作用以及(3)是否抑制Plk1/p62/Nrf2信号 途径可提高CRPC治疗的疗效。预期的结果将揭示一种新的分子机制 展示Plk1如何促进PCa进展，并将为Plk1抑制剂的应用开辟新的途径 作为一种治疗选择。该团队在小鼠模型中研究Plk1，在癌细胞生物学中研究Plk1，在PCA方面拥有专业知识 病理学、骨肿瘤和生物统计学，将能够及时完成拟议的研究。

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.