Improving chemotherapy of castration-resistant prostate cancer.

改善去势抵抗性前列腺癌的化疗。

• 批准号: 10316730
• 负责人: XIAOQI LIU
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316730
• 关键词: Ablation; Affect; Androgen Receptor; Androgens; Binding; Biochemical; Bromodomain; Castration; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Chemoresistance; Chromatin; Clinical Research; Data; Development; Disease; Docking; Epigenetic Process; Event; Family; Fostering; Genetic Transcription; Genetically Engineered Mouse; Goals; Growth and Development function; Health; Investigation; Lead; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Methodology; Mission; Mitosis; Mitotic; Molecular; Mutation; Operative Surgical Procedures; Outcome; PLK1 gene; Paclitaxel; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Proteins; Public Health; Reader; Receptor Signaling; Regulation; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Site; Specimen; System; Testing; Therapeutic; Therapeutic Agents; Transcriptional Elongation Factors; United States National Institutes of Health; Work; Xenograft procedure; abiraterone; castration resistant prostate cancer; chemotherapy; clinically significant; cyclin T1; design; docetaxel; effective therapy; genetic approach; genomic locus; improved; in vivo; inhibitor/antagonist; innovation; loss of function mutation; member; mouse model; multicatalytic endopeptidase complex; novel; novel strategies; patient derived xenograft model; prostate cancer cell; prostate cancer progression; protein degradation; recruit; standard care; success; therapy resistant; ubiquitin-protein ligase

Title: Improving chemotherapy of castration-resistant prostate cancer Abstract Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development and growth, even in castration-resistant PCa (CRPC), the lethal stage of the disease. Docetaxel is the standard treatment for CRPC patients due to a combination of mitotic catastrophe and inhibition of AR signaling. Androgen signaling inhibitors (ASI) are also used to treat CRPC post-docetaxel with limited success. Therefore, it is urgent to identify new targets and develop novel approaches to treat CRPC that are resistant to the existing therapies. Brd4, a conserved member of the bromodomain and extraterminal (BET) family of chromatin readers, promotes gene transcription via interacting with core positive transcription elongation factor (P-TEFb), consisting of Cdk9 and cyclin T1. Significantly, AR signaling-competent CRPC cells are preferentially sensitive to Brd4 inhibitor JQ1 as JQ1 treatment disrupts AR recruitment to target gene loci, thus resulting in inhibition of AR signaling directly. Furthermore, JQ1 enhances the efficacy of ASI in PCa. Loss-of-function mutations in E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) cause stabilization of Brd4 and JQ1 resistance. Thus, it will be of clinical significance to understand the regulation mechanism of Brd4 regulation and to develop a new approach to cause Brd4 degradation even in the presence of SPOP mutations. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with therapy-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating Brd4 degradation and AR signaling, and to exploit this unique mechanism to develop a novel approach for treatment. Our preliminary data show that Plk1 phosphorylation of Brd4 leads to its protein degradation even in the presence of SPOP mutations. The central hypothesis is that Plk1-associated phosphorylation of Brd4 results in its degradation, thus docetaxel-associated Plk1 elevation is one approach to overcome resistance to Brd4 inhibitors. This hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1 phosphorylation of Brd4 regulates AR signaling; (2) to understand how Brd4 phosphorylation contributes to PCa cell proliferation; and (3) to analyze clinical significance of Plk1-associated Brd4 phosphorylation. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with 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 Brd4 and AR signaling and to examine whether a combination of docetaxel and Brd4 inhibitor ABBV-744 is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 regulates Brd4 degradation and AR signaling; and (ii) validate docetaxel as a therapeutic agent to enhance the efficacy of Brd4 inhibitors.

标题：改善去势抵抗性前列腺癌的化疗 摘要 雄激素受体（AR）信号传导对于前列腺癌（PCa）的发展和生长是必不可少的，即使在前列腺癌中也是如此。 去势抵抗性前列腺癌（CRPC），疾病的致死阶段。多西他赛是CRPC的标准治疗 患者由于有丝分裂灾难和AR信号传导抑制的组合。雄激素信号抑制剂 (ASI)也用于治疗多西他赛治疗后的CRPC，但成功率有限。因此，迫切需要识别新的 靶向并开发新的方法来治疗对现有疗法耐药的CRPC。Brd 4，a 染色质阅读器的布罗莫结构域和末端外（BET）家族的保守成员，促进基因 通过与核心正转录延伸因子（P-TEFb）相互作用进行转录，所述核心正转录延伸因子由Cdk 9和 细胞周期蛋白T1。值得注意的是，AR信号传导能力CRPC细胞优先对Brd 4抑制剂JQ 1敏感， JQ 1处理破坏了AR向靶基因座的募集，从而直接导致AR信号传导的抑制。 此外，JQ 1增强了ASI在PCa中的功效。E3泛素连接酶的功能缺失突变 底物结合衔接子斑点型POZ蛋白（SPOP）引起Brd 4和JQ 1抗性稳定。 因此，了解Brd 4的调控机制，开发Brd 4的抗肿瘤药物， 一种新的方法，即使在SPOP突变的存在下也能引起Brd 4降解。的长期目标 这项研究旨在确定新的和可药物化的信号通路，为以下疾病提供更有效的治疗选择： 耐药CRPC患者。目的是确定polo样激酶1（Plk 1）在调节 Brd 4降解和AR信号传导，并利用这种独特的机制开发一种新的方法， 治疗我们的初步数据表明，Brd 4的Plk 1磷酸化导致其蛋白质降解，即使在 SPOP突变的存在。中心假设是Plk 1相关的Brd 4磷酸化导致 因此，在其降解过程中，紫杉醇相关Plk 1升高是克服对Brd 4抗性的一种方法 抑制剂的这一假设将通过追求三个具体目标进行测试-（1）剖析Plk 1磷酸化如何 Brd 4的磷酸化调节AR信号传导;（2）了解Brd 4磷酸化如何促进PCa细胞增殖; （3）分析Plk 1相关Brd 4磷酸化的临床意义。这些相辅相成的目标将 使用信号中间体的生化分析和采用遗传策略来完成， PCa小鼠模型、培养系统和PCa异种移植方法。这项研究的基本原理是， 将是第一个探索Plk 1对Brd 4和AR信号传导的重要性，并研究是否可以结合 多西他赛和Brd 4抑制剂ABBV-744的联合应用是治疗AS I耐药CRPC的一种新方法。这种贡献 重要的是，它将（i）定义Plk 1调节Brd 4降解的分子机制， AR信号传导;和（ii）验证多西他赛作为治疗剂以增强Brd 4抑制剂的功效。