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.

项目摘要（项目3） 转移性castration抗性前列腺癌（MCRPC）仍然是一种无法治愈的疾病 需要基于分子机制的组合治疗策略。我们确定了雄激素受体 （AR） - 和C-MYB调节的DNA损伤反应（DDR）基因特征，与高度相关 MCRPC患者的castration抗性，转移和降低的总体生存率。在此DDR基因签名中 同源重组（HR）DNA修复基因和HR调节剂（HRM）基因高度代表。 DDR基因签名中的HR/HRM基因相对较大的比例强调了 这组以前列腺癌进展的基因。我们的初步临床前研究表明 enzalutamide（enz），一种第二代抗雄激素，阻断雄激素与雄激素结合 接收器（AR）抑制了大多数HR/HRM基因的表达，并与Olaparib协同作用 （OLA），一种聚（ADP-核糖）聚合酶1（PARP1）抑制剂，以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中的合成致死性有关 缺陷及其目标PARP1在基本惊喜维修（BER）中起着至关重要的作用，据报道 充当AR共同因素。在这个项目中，我们建议检验靶向AR（ENZ）和的假设 PARP（OLA）在“引导”策略中将通过ENZ介导的MCRPC产生合成的致死性 HR/HRM基因活性的下调和OLA介导的PARP酶促活性的抑制 在BER和PARP的AR转录活性的辅助作用中。带领试验设计将使我们能够 有效地确定生物学发现的临床相关性，通过将基线联系到顺序 调节单个癌症中靶基因。我们将以三个具体目标来检验这一假设。 AIM 1。特征在于用MCRPC治疗的男性骨髓活检中的HR/HRM基因特征 enzalutamide和/或abiraterone，雄激素信号的新型抑制剂。 目标2。进一步表征并确定对反应的预测生物标志物的协同潜力 使用临床前模型共同目标AR（ENZ）和PARP功能（OLA）的组合疗法。 AIM 3。进行临床试验，以治疗ENZ的CRPC患者，然后添加PARP 抑制剂OLA实现更大的热响应并相关的ENZ调节的HR/HRM 对治疗反应的基因签名。