Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC

靶向雄激素受体和 PARP 来实现 CRPC 的综合致死性

• 批准号: 8999530
• 负责人: Timothy Charles Thompson
• 金额: $ 32.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-02 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999530
• 关键词: Androgen Antagonists; Androgen Receptor; Androgens; BRCA1 gene; Base Excision Repairs; Binding; Biological; Biological Markers; Biopsy Specimen; Bone marrow biopsy; Cancer Center; Cancer Patient; Castration; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; DNA Damage; DNA Repair Gene; Disease; Down-Regulation; Gene Expression; Gene Targeting; Generations; Genes; Growth; In Vitro; Individual; Institution; Lead; Link; MYB gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Neoplasm Metastasis; Patients; Play; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Proto-Oncogene Proteins c-myb; Receptor Signaling; Reporting; Resistance; Role; Signal Transduction; Testing; Therapeutic; abiraterone; base; castration resistant prostate cancer; clinically relevant; cofactor; cytotoxicity; genetic signature; homologous recombination; in vivo; inhibitor/antagonist; men; novel; pre-clinical; preclinical study; predictive marker; prostate cancer cell; prostate cancer model; response; treatment response; trial design; tumor; tumor progression

PROJECT SUMMARY (Project 3) Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease for which novel molecular mechanism-based combination therapy strategies are needed. We identified an androgen receptor (AR)- and c-Myb–co-regulated DNA damage response (DDR) gene signature that is highly correlated with castration-resistance, metastasis, and reduced overall survival in mCRPC patients. In this DDR gene signature homologous recombination (HR) DNA repair genes and HR modulator (HRM) genes are highly represented. The relatively large percentage of HR/HRM genes in the DDR gene signature underscores the importance of this group of genes to prostate cancer progression. Our preliminary preclinical studies demonstrated that enzalutamide (ENZ), a 2nd-generation anti-androgen that blocks androgen from binding to the androgen receptor (AR), suppressed the expression of a majority of the HR/HRM genes and synergized with olaparib (OLA), a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor in suppressing prostate cancer growth. Previously, OLA has been associated with synthetic lethality in multiple malignancies with BRCA1/2 or other HR gene deficiencies and its target, PARP1, plays a crucial role in base excision repair (BER) and was reported to function as an AR co-factor. In this project, we propose to test the hypothesis that targeting AR (ENZ) and PARP (OLA) in a “lead-in” strategy will generate synthetic lethality in mCRPC through ENZ-mediated downregulation of HR/HRM gene activity and OLA-mediated suppression of PARP’s enzymatic activity in BER and PARP’s cofactor role of AR transcriptional activity. The lead-in trial design will allow us to efficiently determine the clinical relevance of our biological findings by linking baseline to sequential modulation of target genes in individual cancers. We will test this hypothesis in three specific aims. Aim 1. Characterize the HR/HRM gene signature in bone marrow biopsies of men with mCRPC treated with enzalutamide and/or abiraterone, novel inhibitors of androgen signaling. Aim 2. Further characterize the synergistic potential of and identify predictive biomarkers of response to combination therapies that co-target AR (ENZ) and PARP function (OLA) using preclinical models. Aim 3. Conduct a clinical trial of treating CRPC patients with ENZ followed by the addition of the PARP inhibitor OLA to achieve greater therapeutic response and to correlate an ENZ-regulated HR/HRM gene signature to the therapeutic responses.

项目概要（项目 3） 转移性去势抵抗性前列腺癌（mCRPC）仍然是一种无法治愈的疾病，新的治疗方法 需要基于分子机制的联合治疗策略。我们鉴定出雄激素受体 (AR)-和 c-Myb-共同调节 DNA 损伤反应 (DDR) 基因特征，与 mCRPC 患者的去势抵抗、转移和总生存率降低。在这个 DDR 基因签名中 同源重组 (HR) DNA 修复基因和 HR 调节 (HRM) 基因的代表性很高。 DDR 基因特征中 HR/HRM 基因所占比例相对较高，这凸显了以下因素的重要性： 这组基因与前列腺癌的进展有关。我们的初步临床前研究表明 恩杂鲁胺 (ENZ)，一种第二代抗雄激素药物，可阻止雄激素与雄激素结合 受体 (AR)，抑制大多数 HR/HRM 基因的表达并与奥拉帕尼协同作用 (OLA)，一种聚（ADP-核糖）聚合酶 1 (PARP1) 抑制剂，可抑制前列腺癌的生长。之前， OLA 与 BRCA1/2 或其他 HR 基因的多种恶性肿瘤的综合致死率相关 缺陷及其靶标 PARP1 在碱基切除修复 (BER) 中发挥着至关重要的作用，据报道 作为 AR 辅助因子。在这个项目中，我们建议测试针对 AR (ENZ) 和 “导入”策略中的 PARP (OLA) 将通过 ENZ 介导在 mCRPC 中产生合成致死率 HR/HRM 基因活性下调和 OLA 介导的 PARP 酶活性抑制 BER 和 PARP 在 AR 转录活性中的辅助因子作用。引入试验设计将使我们能够 通过将基线与序列联系起来，有效地确定我们的生物学发现的临床相关性 个体癌症中靶基因的调节。我们将在三个具体目标上检验这一假设。 目标 1. 表征接受以下药物治疗的 mCRPC 男性患者骨髓活检中的 HR/HRM 基因特征 恩杂鲁胺和/或阿比特龙，雄激素信号传导的新型抑制剂。 目标 2. 进一步表征协同潜力并确定响应的预测生物标志物 使用临床前模型共同靶向 AR (ENZ) 和 PARP 功能 (OLA) 的联合疗法。 目标 3. 进行一项用 ENZ 治疗 CRPC 患者并随后添加 PARP 的临床试验 抑制剂 OLA 可实现更好的治疗反应并关联 ENZ 调节的 HR/HRM 治疗反应的基因特征。