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：改善耐castration抗性前列腺癌的化学疗法 抽象的 雄激素受体（AR）信号传导对于前列腺癌（PCA）发育和生长至关重要，即使 cast割的PCA（CRPC），疾病的致命阶段。多西他赛是CRPC的标准处理 患者由于有丝分裂灾难和AR信号传导的抑制作用而导致的患者。雄激素信号抑制剂 （ASI）还用于治疗CRPC后多甲赛的成功率有限。因此，迫切需要识别新的 目标并开发新的方法来治疗对现有疗法具有抗性的CRPC。 Brd4，a 保守的溴结构域和染色质读取器家族（BET）家族，促进基因 通过与核心正转录伸长因子（P-TEFB）相互作用的转录，由CDK9和 细胞周期蛋白T1。值得注意的是，AR信号功能能力的CRPC细胞优先对BRD4抑制剂JQ1敏感为 JQ1处理破坏了AR募集到靶基因基因座，从而导致直接抑制AR信号传导。 此外，JQ1增强了ASI在PCA中的疗效。 E3泛素连接酶的功能丧失突变 底物结合适配器斑点型POZ蛋白（SPOP）导致BRD4和JQ1抗性的稳定性。 因此，了解BRD4调控的调节机制并发展 即使在存在SPOP突变的情况下，也会引起BRD4降解的新方法。长期目标 这项研究是为了确定新颖和可毒的信号传导途径，为 耐药性CRPC患者。目的是定义polo样激酶1（PLK1）在调节中的作用 BRD4降解和AR信号传导，并利用这种独特的机制来开发一种新颖的方法 治疗。我们的初步数据表明，即使在 汤匙突变的存在。中心假设是BRD4结果的PLK1相关磷酸化 因此，在降解中，多西他赛相关的PLK1高程是一种克服抗Brd4的抗性的方法 抑制剂。该假设将通过追求三个特定目标来检验 - （1）剖析PLK1磷酸化的方式 BRD4调节AR信号传导； （2）了解BRD4磷酸化如何有助于PCA细胞增殖； （3）分析PLK1相关BRD4磷酸化的临床意义。这些互补的目标将 使用信号中间体的生化分析并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。研究的理由是 将是第一个探测PLK1对BRD4和AR信号的重要性的人，并检查是否有组合 多西他赛和BRD4抑制剂ABBV-744是一种治疗ASI耐药性CRPC的新方法。这个贡献是 显着，因为它将（i）定义PLK1调节BRD4降解和的分子机制 AR信号传导； （ii）验证多西他赛作为一种治疗剂，以增强BRD4抑制剂的功效。