Improving chemotherapy of castration-resistant prostate cancer.

改善去势抵抗性前列腺癌的化疗。

基本信息

批准号：
10663219
负责人：
XIAOQI LIU
金额：
$ 25.29万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/10663219
关键词：
Ablation Acetylation Affect Androgen Receptor Androgens Binding Biochemical Bromodomain Cancer Patient Castration Cell Cycle Cell Cycle Progression Cell Proliferation Cells Chemoresistance Chromatin Clinical Research Creativeness Data Development Disease Docking Epigenetic Process Event Family Fostering Genetic Transcription Genetically Engineered Mouse Goals Growth and Development function Health Investigation 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 enzalutamide genetic approach genomic locus improved in vivo inhibitor 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 refractory cancer standard care success therapy resistant ubiquitin-protein ligase

项目摘要

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抽象的雄激素受体 (AR) 信号传导对于前列腺癌 (PCa) 的发生和生长至关重要，即使在去势抵抗性 PCa (CRPC)，该疾病的致死阶段。多西他赛是 CRPC 的标准治疗方法患者由于有丝分裂灾难和 AR 信号传导抑制相结合。雄激素信号抑制剂 (ASI) 也用于治疗多西紫杉醇后的 CRPC，但效果有限。因此，迫切需要寻找新的靶向并开发治疗对现有疗法耐药的 CRPC 的新方法。 Brd4，一个染色质读取器溴结构域和末端外 (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，该因子由 Cdk9 和细胞周期蛋白T1。值得注意的是，具有 AR 信号传导能力的 CRPC 细胞优先对 Brd4 抑制剂 JQ1 敏感，因为 JQ1 治疗会破坏 AR 向靶基因位点的募集，从而直接抑制 AR 信号传导。此外，JQ1 增强了 ASI 在 PCa 中的疗效。 E3 泛素连接酶功能丧失突变底物结合接头斑点型 POZ 蛋白 (SPOP) 导致 Brd4 和 JQ1 抗性稳定。因此，了解Brd4的调控机制并开发出具有临床意义的药物。即使存在 SPOP 突变也能导致 Brd4 降解的新方法。的长期目标这项研究旨在确定新颖且可药物化的信号通路，为以下疾病提供更有效的治疗选择：患有治疗抵抗性 CRPC 的患者。目的是确定 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开发一种新方法治疗。我们的初步数据表明，Brd4 的 Plk1 磷酸化会导致其蛋白质降解，即使在 SPOP 突变的存在。中心假设是 Plk1 相关的 Brd4 磷酸化结果因此，多西紫杉醇相关的 Plk1 升高是克服 Brd4 耐药性的一种方法抑制剂。该假设将通过追求三个具体目标来检验 - (1) 剖析 Plk1 磷酸化的方式 Brd4 调节 AR 信号传导； (2)了解Brd4磷酸化如何促进PCa细胞增殖； (3)分析Plk1相关Brd4磷酸化的临床意义。这些互补的目标将通过对信号中间体进行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。这项研究的理由是将是第一个探讨 Plk1 对 Brd4 和 AR 信号传导的重要性并检查组合是否多西紫杉醇和 Brd4 抑制剂 ABBV-744 的组合是治疗 ASI 耐药 CRPC 的新方法。这个贡献是意义重大，因为它将 (i) 定义 Plk1 调节 Brd4 降解的分子机制，以及 AR信令； (ii) 验证多西紫杉醇作为治疗剂以增强 Brd4 抑制剂的功效。