Treatment of Castration-resistant Prostate Cancer (CRPC)

去势抵抗性前列腺癌 (CRPC) 的治疗

• 批准号: 9312773
• 负责人: XIAOQI LIU
• 金额: $ 35.46万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-07 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312773
• 关键词: Ablation; Affect; Androgen Receptor; Androgens; Biochemical; Cancer Patient; Castration; Cell Death; Cell Death Inhibition; Cells; Clinical Research; DNA Sequence Alteration; Data; Development; Disease; Event; Fostering; Genetic; Genetically Engineered Mouse; Goals; Growth; Growth and Development function; Health; Human; Investigation; Knock-out; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methodology; Mission; Mitotic; Modeling; Molecular; Nuclear; Outcome; PLK1 gene; PTEN gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Prevention; Prognostic Marker; Prostate; Public Health; Receptor Signaling; Research; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Work; Xenograft Model; Xenograft procedure; abiraterone; beta catenin; cancer cell; castration resistant prostate cancer; design; diagnostic biomarker; docetaxel; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; knock-down; mouse model; new therapeutic target; next generation sequencing; novel; novel strategies; prostate cancer cell; public health relevance; success; therapeutic target; transgenic adenocarcinoma of mouse prostate; tumor growth; tumor xenograft

 DESCRIPTION (provided by applicant) Androgen ablation (castration) is one major approach to treat prostate cancer (PCa), as androgen receptor (AR) signaling is essential for PCa development and growth. Enough evidence supports the notion that AR signaling continues to be active in castration-resistant prostate cancer (CRPC). Consequently, abiraterone and enzalutamide, two androgen signaling inhibitors (ASI) are becoming the major drugs to treat CRPC post- docetaxel. Unfortunately, ASI can only improve the overall patient survival for 2-5 months. Therefore, it is urgent to identify new targets and develop novel approaches to treat ASI-resistant CRPC. Accumulating data suggests that the β-catenin pathway is a good target for CRPC, because the -catenin pathway was identified as one of the top signaling pathways with significant genomic alterations in CRPC and activation of the β- catenin pathway contributes to elevation of AR signaling. However, how the β-catenin pathway can be targeted in CRPC is still elusive. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the β-catenin pathway, thus AR signaling, and to exploit this unique pathway as a novel therapeutic target for CRPC patients. Axin2, a key regulator of the β- catenin pathway, was identified as a novel Plk1 substrate. The central hypothesis is that a combination of inhibition of Plk1 with BI2536 and the β-catenin pathway with IWR1 is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing three Specific Aims - (1) to determine whether a combination of inhibition of Plk1 and β-catenin pathway is a novel approach to treat ASI-resistant CRPC using patient- derived xenografts; (2) to test whether inhibition of Plk1 activates the β-catenin pathway in genetically engineered mice; and (3) to dissect how Plk1 phosphorylation of Axin2 regulates the β-catenin pathway and AR signaling. 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 the β-catenin and AR signaling and to examine whether a combination of inhibition of Plk1 and the β-catenin pathway is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will () define the molecular mechanism by which Plk1 regulates the β-catenin and AR signaling; and (ii) validate Plk1 as a critical therapeutic target to enhance the efficacy of inhibitors that targt the β-catenin pathway. 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 β-catenin and AR signaling that is critical for generating and maintaining the CRPC phenotype.

 雄激素消融（去势）是治疗前列腺癌（PCa）的一种主要方法，因为雄激素受体（AR）信号传导对于PCa发育和生长至关重要。有足够的证据支持AR信号在去势抵抗性前列腺癌（CRPC）中继续活跃的观点。因此，阿比特龙和恩杂鲁胺这两种雄激素信号传导抑制剂（ASI）正在成为多西他赛之后治疗CRPC的主要药物。不幸的是，ASI只能提高2-5个月的患者总生存率。因此，迫切需要确定新的靶点并开发新的方法来治疗ASI-CRPC。累积的数据表明β-连环蛋白途径是CRPC的良好靶点，因为β-连环蛋白途径被鉴定为CRPC中具有显著基因组改变的顶级信号传导途径之一，并且β-连环蛋白途径的激活有助于AR信号传导的升高。然而，如何在CRPC中靶向β-连环蛋白通路仍然是难以捉摸的。这项研究的长期目标是确定新的和可药物化的信号通路，为AS I耐药的CRPC患者提供更有效的治疗选择。目的是确定polo样激酶1（Plk 1）在调节β-catenin通路中的作用，从而调节AR信号传导，并利用这种独特的通路作为CRPC患者的新治疗靶点。Axin 2是β-连环蛋白途径的关键调节因子，被鉴定为新型Plk 1底物。中心假设是，用BI 2536抑制Plk 1和用IWR 1抑制β-连环蛋白通路的组合是治疗AS I耐药CRPC的新方法。该假设将通过追求三个特定目的来测试-（1）确定Plk 1和β-连环蛋白通路的抑制的组合是否是使用患者来源的异种移植物治疗AS I抗性CRPC的新方法;（2）测试Plk 1的抑制是否激活基因工程小鼠中的β-连环蛋白通路;以及（3）分析Axin 2的Plk 1磷酸化如何调节β-catenin通路和AR信号。这些互补的目标将使用信号中间体的生化分析和采用遗传策略与PCa小鼠模型，培养系统和PCa异种移植方法来实现。这项研究的基本原理是，它将是第一个探索Plk 1对β-catenin和AR信号传导的重要性，并检查Plk 1和β-catenin通路的抑制是否是治疗AS I耐药CRPC的新方法。这一贡献是重要的，因为它将（）定义Plk 1调节β-catenin和AR信号传导的分子机制;和（ii）验证Plk 1作为关键的治疗靶点，以增强靶向β-catenin途径的抑制剂的功效。这项研究是创新的，因为它从一种新的Plk 1信号通路来研究这种疾病，挑战了Plk 1仅用于调节有丝分裂事件的传统观点。这些研究有望通过鉴定β-连环蛋白和AR信号传导的关键调节因子（对产生和维持CRPC表型至关重要），为改善患者治疗提供新的范例。