Improving chemotherapy of castration-resistant prostate cancer

标题：改善去势抵抗性前列腺癌的化疗 摘要 由于前列腺癌（PCa）的发展需要雄激素，雄激素消融（去势）是治疗前列腺癌的最佳方法。 晚期PCa患者的主要治疗。然而，复发性肿瘤在2年内出现，而 雄激素受体（AR）信号已经不适当地恢复，疾病进入一个阶段，称为 去势抵抗性前列腺癌（CRPC）。多西他赛是CRPC患者的标准治疗， 有限的成功。因此，迫切需要了解多西他赛的作用机制，以便开发新的途径。 以提高其功效。最近发现AR的核定位为微管 动力学依赖性，多西他赛在CRPC中的抗肿瘤作用主要是由于其抑制AR 核进口。然而，这些有趣的观察背后的详细分子机制仍然是 难以捉摸。本研究的长期目标是提供克服多西他赛耐药的新方法 的CRPC。Polo样激酶1（Plk 1）是许多细胞周期事件中的关键调节因子，在PCa中升高， 肿瘤分级。本文的目的是确定Plk 1在激活AR信号传导中的作用，并检查 是否其抑制可以增强多西他赛在CRPC中的疗效。Clip-170和p150胶合，两种调节剂 微管动力学，最近被确定为新的Plk 1底物。该提案的核心假设是 Plk 1对Clip-170和p150 Glued的相关活性增加了微管动力学，导致 AR信号传导的组成性激活和多西他赛抗性的发展。这一假设将得到检验 通过追求三个具体的目标-（1）测试Plk 1磷酸化的剪辑-170和p150 Glued如何有助于 CRPC细胞中的多西他赛耐药性;（2）分析Plk 1相关激酶活性是否有助于CRPC细胞中的多西他赛耐药性。 在小鼠中CRPC中的多西他赛抗性;和（3）询问Plk 1抑制和多西他赛的组合是否 是治疗CRPC的新途径。这些互补的目标将利用生物化学 信号传导中间体的分析和采用诱导型PCa小鼠模型的遗传策略， 培养系统和PCa异种移植方法。这项研究的基本原理是，它将是第一个 探索Plk 1对AR信号传导的重要性，并研究Plk 1如何诱导多西他赛耐药。 CRPC。这一贡献是重要的，因为它将（i）定义Plk 1 激活AR;（ii）遗传评估Plk 1如何与PTEN信号传导的丧失合作;和（iii）验证Plk 1 作为增强多西他赛疗效的关键治疗靶点。这项研究是创新的， 这种疾病来自一种新的Plk 1信号通路，挑战了Plk 1功能仅限于 调节有丝分裂事件。这些研究有望通过以下方式为改善患者治疗提供新的范例： 识别AR信号传导的关键调节因子，其对于产生和维持CRPC至关重要 表型。

Title: Improving chemotherapy of castration-resistant prostate cancer Abstract Because prostate cancer (PCa) requires androgen for development, androgen ablation (castration) is the primary treatment for patients with late stage PCa. However, recurrent tumors arise within 2 years, whereas androgen receptor (AR) signaling has been inappropriately restored, and the disease enters a stage called castration-resistant prostate cancer (CRPC). Docetaxel is the standard treatment for CRPC patients with limited success. Therefore, it is urgent to understand mechanisms of docetaxel so novel avenues can be developed to increase its efficacy. It was recently found that the nuclear localization of AR is microtubule dynamics dependent and that the anti-tumor effect of docetaxel in CRPC is largely due to its inhibition of AR nuclear import. However, the detailed molecular mechanisms behind these intriguing observations are still elusive. The long-term goals of this study are to provide novel approaches to overcome docetaxel resistance of CRPC. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is elevated in PCa and linked to tumor grades. The objective here is to define the role of Plk1 in activating AR signaling and to examine whether its inhibition can enhance the efficacy of docetaxel in CRPC. Clip-170 and p150Glued, two regulators of microtubule dynamics, were recently identified as novel Plk1 substrates. The central hypothesis of the proposal is that Plk1-associated activity towards Clip-170 and p150Glued increases microtubule dynamics, resulting in constitutive activation of AR signaling and development of docetaxel resistance. This hypothesis will be tested by pursuing three specific aims – (1) to test how Plk1 phosphorylation of Clip-170 and p150Glued contributes to docetaxel resistance in CRPC cells; (2) to analyze whether Plk1-associated kinase activity contributes to docetaxel resistance in CRPC in mice; and (3) to ask whether a combination of Plk1 inhibition and docetaxel is a novel avenue for treatment of CRPC. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models, culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the AR signaling and to examine how Plk1 induces docetaxel resistance in CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 activates AR; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1 as a critical therapeutic target to enhance the efficacy of docetaxel. 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 signaling that is critical for generating and maintaining the CRPC phenotype.