Overcoming drug resistance of castration-resistant prostate cancer

 描述（由申请人提供）：克服去势抵抗性前列腺癌的耐药性。在过去的十年中，对去势抵抗性前列腺癌（CRPC）的理解取得了巨大进展，CRPC是一种在大多数情况下保持雄激素受体（AR）依赖性的疾病状态。这种理解导致了这样的概念，即靶向抑制AR信号传导将是治疗CRPC的有效方法。作为支持，CRPC治疗的前景正在从基于紫杉醇的治疗转变为雄激素信号传导抑制剂（ASI）治疗，如阿比特龙（一种从头雄激素合成途径的抑制剂）和恩杂鲁胺（一种直接AR抑制剂）。然而，基于ASI的治疗仅使患者的总体生存期提高了几个月。因此，迫切需要了解ASI耐药的潜在机制，并开发新的途径来提高基于ASI的治疗的疗效。除了AR信号传导之外，由于功能丧失的PTEN肿瘤抑制因子引起的PI 3 K途径的激活在CRPC中具有明确的作用。这项研究的长期目标是确定新的和可药物化的信号通路，为CRPC患者提供更有效的治疗选择。目的是确定Polo样激酶1（Plk 1）在激活AR信号传导和PI 3通路中的作用，并利用这种独特的通路作为CRPC患者的新治疗靶点。中心假设是Plk 1对AR和PTEN的相关活性分别导致AR信号传导和PI 3 K通路的组成性激活，从而导致CRPC进展和ASI抗性的发展。该假设将通过追求三个特定目的来检验-（1）鉴定Plk 1活性激活AR信号传导的分子机制;（2）检查Plk 1相关活性是否影响体内PCa进展;和（3）测试AR的Plk 1磷酸化是否调节ASI敏感性。这些互补的目标将通过使用信号传导中间体的生化分析以及采用具有诱导型PCa小鼠模型、培养系统和人PCa异种移植方法的功能获得和功能丧失策略来实现。这项研究的基本原理是，它将是第一个探索Plk 1对AR和PI 3 K信号通路的重要性，并研究Plk 1如何诱导CRPC中的ASI抗性。这一贡献是重要的，因为它将（i）定义Plk 1激活AR的分子机制;（ii）检查Plk 1如何激活PI 3 K通路;（iii）遗传评估Plk 1如何与PTEN信号传导的丧失合作;和（iv）验证Plk 1作为关键的治疗靶点以增强免疫调节作用。 ASI的功效。这项研究是创新的，因为它从一种新的Plk 1信号通路来研究这种疾病，挑战了Plk 1仅用于调节有丝分裂事件的传统观点。这些研究准备通过鉴定对产生和维持CRPC表型至关重要的AR/PI 3 K途径的关键调节因子，为改善患者治疗提供新的范例。

 DESCRIPTION (provided by applicant): Overcoming drug resistance of castration-resistant prostate cancer. Over the last decade, tremendous progress has been made in the understanding of castration-resistant prostate cancer (CRPC), a disease state that retains androgen receptor (AR)-dependent in most cases. That understanding led to the notion that targeted inhibition of AR signaling would be an effective approach for treatment of CRPC. In support, the landscape for CRPC treatment is now changing from docetaxel-based therapy to treatment with Androgen Signaling Inhibitors (ASI), such as abiraterone, an inhibitor of de novo androgen synthesis pathway, and enzalutamide, a direct AR inhibitor. However, ASI- based treatment only improves the overall patient survival by several months. Therefore, understanding the underlying mechanisms of ASI resistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgently needed. Besides AR signaling, activation of the PI3K pathway due to lose-of-function PTEN tumor suppressor has a well-established role in CRPC. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with CRPC. The objective is to define the role of Polo-like kinase 1 (Plk1) in activating AR signaling and the PI3 pathway and to exploit this unique pathway as a novel therapeutic target for CRPC patients. The central hypothesis is that Plk1-associated activity towards AR and PTEN causes constitutive activation of AR signaling and the PI3K pathway, respectively, thus CRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing three Specific Aims - (1) to identify the molecular mechanism(s) by which Plk1 activity activates AR signaling; (2) to examine whether Plk1-associated activity affects PCa progression in vivo; and (3) to test whether Plk1 phosphorylation of AR regulates ASI sensitivity. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing gain-of-function and loss-of-function strategies with inducible PCa mouse models, culture systems and human PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the AR and the PI3K signaling pathways and to examine how Plk1 induces ASI resistance in CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 activates AR; (ii) examine how Plk1 activates the PI3K pathway; (iii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iv) validate Plk1 as a critical therapeutic target to enhance the efficacy of ASI. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the AR/PI3K pathways that are critical for generating and maintaining the CRPC phenotype.