Improving chemotherapy of castration-resistant prostate cancer

改善去势抵抗性前列腺癌的化疗

• 批准号: 9973149
• 负责人: XIAOQI LIU
• 金额: $ 34.83万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973149
• 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; Fostering; 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; Nuclear Receptors; Outcome; PLK1 gene; PTEN gene; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Public Health; RNA Splicing; Receptor Activation; Receptor Signaling; Recurrent tumor; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Time; Transactivation; Tumor-Derived; Variant; Work; Xenograft Model; Xenograft procedure; antitumor effect; beta Tubulin; cancer cell; castration resistant prostate cancer; chemotherapy; design; docetaxel; event cycle; genetic approach; improved; innovation; mouse model; mutant; novel; novel strategies; overexpression; predictive marker; prevent; prostate cancer cell; prostate cancer progression; receptor function; response; standard care; success; therapeutic target; tumor

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：改进去势抵抗前列腺癌的化疗 摘要 由于前列腺癌(PCa)的发育需要雄激素，雄激素去势(去势)是 晚期前列腺癌患者的初步治疗。然而，复发的肿瘤在2年内出现，而 雄激素受体(AR)信号被不适当地恢复，疾病进入一个称为 耐去势前列腺癌(CRPC)。多西紫杉醇是治疗慢性前列腺癌患者的标准治疗方法 有限的成功。因此，迫切需要了解多西紫杉醇的作用机制，以便寻找新的途径。 为了提高其疗效而开发的。新近发现，AR的核定位为微管。 多西紫杉醇在CRPC中的抗肿瘤作用在很大程度上是由于其抑制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。这项研究的长期目标是提供克服多西紫杉醇耐药性的新方法。 CRPC公司的。Polo-like kinase1(Plk1)是许多细胞周期事件的关键调节因子，在前列腺癌中升高并与之相关 到肿瘤级别。这里的目的是定义Plk1在激活AR信号中的作用并检查 抑制其是否能增强多西紫杉醇治疗慢性前列腺癌的疗效。Clip-170和p150Glued，两个调控因子 微管动力学是最近发现的一种新的Plk1底物。该提案的核心假设是 Plk1对Clip-170和p150Glued的相关活性增加了微管动力学，导致 AR信号的结构性激活和多西紫杉醇耐药的发展。这一假设将得到检验。 通过追求三个特定的目标-(1)测试CLIP-170和p150Glued的Plk1磷酸化如何有助于 多西紫杉醇对CRPC细胞的耐药性；(2)分析Plk1相关激酶活性是否参与了 多西紫杉醇在小鼠CRPC中的耐药性；以及(3)询问Plk1抑制和多西紫杉醇联合应用 是治疗慢性前列腺癌的新途径。这些互补的目标将通过使用生物化学来实现 用可诱导的PCA小鼠模型分析信号中间产物和采用遗传策略， 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 探讨Plk1在AR信号转导中的作用及其诱导多西紫杉醇耐药的机制 CRPC。这一贡献意义重大，因为它将(I)定义Plk1的分子机制 激活AR；(Ii)从基因上评估Plk1如何与PTEN信号丢失协同作用；以及(Iii)验证Plk1 作为提高多西紫杉醇疗效的关键治疗靶点。这项研究在接近的时候是创新的 这种疾病来自一种新的Plk1信号通路，挑战了传统观点，即Plk1仅在 调节有丝分裂事件。这些研究有望通过以下方式为改进患者治疗提供新的范例 确定AR信令的关键调节器，该调节器对CRPC的生成和维护至关重要 表型。