Improving chemotherapy of castration-resistant prostate cancer.

标题：改进去势抵抗前列腺癌的化疗 摘要 雄激素受体(AR)信号对前列腺癌(PCA)的发生和生长是必不可少的，即使在 抗阉割的前列腺癌(CRPC)，疾病的致命阶段。多西紫杉醇是治疗慢性前列腺癌的标准疗法 患者由于有丝分裂灾难和AR信号抑制的共同作用。雄激素信号转导抑制剂 (ASI)也用于治疗CRPC多西紫杉醇后的疗效有限。因此，当务之急是找到新的 靶向并开发新的方法来治疗对现有疗法具有抵抗力的CRPC。BRD4，a 是染色质阅读器溴结构域和端外蛋白(BET)家族的保守成员，促进基因 与核心正性转录延伸因子(P-TEFb)相互作用的转录，包括CDK9和 细胞周期蛋白T1。值得注意的是，具有AR信号活性的CRPC细胞对Brd4抑制剂JQ1 AS优先敏感 JQ1处理干扰AR向靶基因位点的募集，从而直接抑制AR信号转导。 此外，JQ1增强了ASI在PCa中的疗效。E3泛素连接酶功能缺失突变 底物结合的斑点型POZ蛋白(SPOP)导致Brd4和JQ1抗性的稳定。 因此，深入了解Brd4调控的调控机制，对进一步研究Brd4的调控机制具有重要的临床意义。 一种即使在SPOP突变的情况下也能导致Brd4降解的新方法。的长期目标 这项研究旨在找出新的和可用药的信号通路，以提供更有效的治疗方案 治疗耐药的CRPC患者。目的是确定Polo-like kinase1(Plk1)在调节 BRD4降解和AR信号，并利用这一独特的机制来开发一种新的方法 治疗。我们的初步数据显示，Brd4的Plk1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Plk1相关的Brd4的磷酸化导致 因此，在其降解过程中，多西紫杉醇相关的Plk1上调是克服对Brd4耐药性的一种方法 抑制剂。这一假设将通过追求三个具体目标来检验-(1)剖析Plk1磷酸化如何 目的：(2)了解Brd4磷酸化对PCa细胞增殖的影响； (3)分析Plk1相关的Brd4磷酸化的临床意义。这些互补的目标将 通过对信号中间产物的生化分析和使用遗传策略来完成 PCA小鼠模型、培养系统和PCA异种移植方法学。这项研究的基本原理是它 将首先探讨Plk1对Brd4和AR信号的重要性，并检查一种组合 多西紫杉醇和Brd4抑制剂ABBV-744的结合是治疗ASI耐药CRPC的新方法。这一贡献是 重要的是它将(I)定义Plk1调节Brd4降解的分子机制和 (Ii)验证多西紫杉醇作为一种治疗药物以增强Brd4抑制剂的疗效。

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.