Improving chemotherapy of castration-resistant prostate cancer

改善去势抵抗性前列腺癌的化疗

• 批准号: 9146063
• 负责人: XIAOQI LIU
• 金额: $ 35.46万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146063
• 关键词: Ablation; Affect; Agreement; Androgen Receptor; Androgens; Apoptosis; Binding; Biochemical; Cancer Patient; Castration; Cell Cycle; Cell Nucleus; Cells; Clinical; Clinical Research; Clip; Cytoplasm; Data; Development; Disease; Event; Figs - dietary; Fostering; Genetic; Genetically Engineered Mouse; Goals; Health; Human; In Vitro; Interphase; Investigation; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methodology; Microtubule Depolymerization; Microtubule Stabilization; Microtubules; Mission; Mitotic; Molecular; Mus; Nuclear; Nuclear Import; Outcome; PLK1 gene; PTEN gene; Patient-Focused Outcomes; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Public Health; RNA Splicing; Receptor Activation; Receptor Signaling; Recurrent tumor; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Staging; System; Testing; Therapeutic; Time; Transactivation; Tumor-Derived; Variant; Work; Xenograft Model; Xenograft procedure; abstracting; antitumor effect; base; beta Tubulin; cancer cell; castration resistant prostate cancer; chemotherapy; design; docetaxel; improved; innovation; mouse model; mutant; novel; novel strategies; overexpression; predictive marker; prevent; prostate cancer cell; receptor function; response; standard care; success; therapeutic target; tumor; tumor progression

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.

标题：改善耐castration抗性前列腺癌的化学疗法 抽象的 由于前列腺癌（PCA）需要雄激素进行发育，因此雄激素消融（castration）是 晚期PCA患者的一级治疗。但是，复发性肿瘤在2年内出现，而 雄激素受体（AR）信号传导已不当恢复，该疾病进入了一个称为的阶段 cast割的前列腺癌（CRPC）。多西他赛是CRPC患者的标准治疗方法 有限的成功。因此，迫切要了解多西他赛的机制，因此新型途径可以是 开发以提高其有效性。最近发现AR的核定位是微管 动力学依赖性以及多西他赛在CRPC中的抗肿瘤作用很大程度上是由于其对AR的抑制作用 核进口。但是，这些有趣的观察背后的详细分子机制仍然是 难以捉摸。这项研究的长期目标是提供新的方法来克服多西他赛电阻 CRPC。 polo样激酶1（PLK1）是许多细胞周期事件中的关键调节剂，在PCA中升高并链接 到肿瘤成绩。这里的目的是定义PLK1在激活AR信号传导中的作用 它的抑制作用是否可以提高CRPC中多西他赛的效率。夹170和p150glued，两个调节器 微管动力学最近被鉴定为新型PLK1底物。提案的中心假设 是PLK1相关的对夹170和P150Glued的活性增加了微管动力学，从而导致 AR信号传导和多西他赛电阻的发展的构成激活。该假设将进行检验 通过追求三个具体目标 - （1）测试夹170和P150Glud的PLK1磷酸化如何有助于 CRPC细胞中多西他赛的耐药性； （2）分析PLK1相关的激酶活性是否有助于 小鼠CRPC中多西他赛的耐药性； （3）询问PLK1抑制和多西他的组合是否 是治疗CRPC的新型途径。这些完整的目标将使用生化实现 通过诱导PCA小鼠模型对信号传导中间体和采用遗传策略的分析， 培养系统和PCA异种移植方法。研究的理由是，它将是第一个 探测PLK1对AR信号传导的重要性，并检查PLK1如何诱导多西他赛电阻 CRPC。这种贡献很重要，因为它将（i）定义PLK1的分子机制 激活AR； （ii）基因评估PLK1如何与PTEN信号丢失合作； （iii）验证PLK1 作为提高多西他赛效率的关键治疗靶标。这项研究是创新的 来自新型PLK1信号通路的疾病，挑战了PLK1仅起作用的传统观点 调节有丝分裂事件。这些研究被毒死，为改善患者疗法提供了新的范式 识别AR信号的关键调节器，这对于生成和维护CRPC至关重要 表型。