Overcoming drug resistance of castration-resistant prostate cancer

 描述(申请人提供)：克服耐去势前列腺癌的耐药性。在过去的十年里，对去势耐受前列腺癌(CRPC)的理解取得了巨大的进步，CRPC是一种在大多数情况下保持雄激素受体(AR)依赖的疾病状态。这种理解导致了靶向抑制AR信号将是治疗CRPC的有效方法的概念。作为支持，CRPC治疗的前景现在正在从以多西紫杉醇为基础的治疗转变为雄激素信号抑制药(ASI)的治疗，如阿比特龙，雄激素从头合成途径的抑制剂，以及苯扎鲁胺，一种直接的AR抑制剂。然而，基于ASI的治疗只能将患者的总体生存时间提高几个月。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的治疗效果。除了AR信号外，PTEN抑癌基因失活导致的PI3K通路的激活在CRPC中也起着公认的作用。这项研究的长期目标是确定新的和可用药的信号通路，为CRPC患者提供更有效的治疗选择。目的是明确Polo-like kinase1(Plk1)在激活AR信号和PI3通路中的作用，并将这一独特的途径开发为CRPC患者的新治疗靶点。中心假说是Plk1对AR和PTEN的相关活性分别导致AR信号和PI3K通路的结构性激活，从而导致CRPC的进展和ASI耐药的发展。这一假说将通过追求三个具体目标来验证-(1)确定Plk1激活AR信号的分子机制(S)；(2)检测Plk1相关活性是否影响体内PCa的进展；(3)测试Plk1对AR的磷酸化是否调节ASI的敏感性。这些互补的目标将通过对信号中间产物的生化分析以及采用功能获得和功能丧失策略以及可诱导的PCA小鼠模型、培养系统和人类PCA异种移植方法来实现。这项研究的基本原理是，首次探讨Plk1在AR和PI3K信号通路中的重要性，并研究Plk1如何在CRPC中诱导ASI抵抗。这一贡献具有重大意义，因为它将(I)确定Plk1激活AR的分子机制；(Ii)研究Plk1如何激活PI3K途径；(Iii)从遗传学角度评估Plk1如何与PTEN信号的丢失协同作用；以及(Iv)验证Plk1作为一个关键的治疗靶点，以增强 ASI的疗效。这项研究具有创新性，因为它从一种新的Plk1信号通路接近疾病，挑战了Plk1仅起调节有丝分裂事件功能的传统观点。这些研究有望通过确定AR/PI3K通路的关键调节因子，为改进患者的治疗提供新的范例，这些调节因子对CRPC表型的产生和维持至关重要。

 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.