Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC

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， 需要基于分子机制的联合治疗策略。我们发现了一种雄激素受体 (AR)-和c-Myb共调节的DNA损伤反应（DDR）基因签名，其与以下高度相关： 去势抵抗、转移和mCRPC患者总生存期降低。在这个DDR基因签名中 同源重组（HR）DNA修复基因和HR调节基因（HRM）是高度代表性的。 DDR基因标签中相对大百分比的HR/HRM基因强调了以下重要性： 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， Enzalutamide（ENZ），第二代抗雄激素药物，可阻断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)聚（ADP-核糖）聚合酶1（PARP 1）抑制剂抑制前列腺癌生长。在此之前， 奥拉与BRCA 1/2或其他HR基因相关的多种恶性肿瘤的综合致死性有关 缺陷及其靶点PARP 1在碱基切除修复（BER）中起着至关重要的作用，据报道， 作为一个辅助因子。在这个项目中，我们提出测试的假设，靶向AR（ENZ）和 “导入”策略中的PARP（奥拉）将通过酶介导的 HR/HRM基因活性下调和OLA介导的PARP酶活性抑制 BER和PARP在AR转录活性中的辅因子作用。导入试验设计将允许我们 通过将基线与序列相联系， 调节个体癌症中的靶基因。我们将在三个具体目标中检验这一假设。 目标1.表征接受以下治疗的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，并鉴定对以下反应的预测性生物标志物： 使用临床前模型共同靶向AR（ENZ）和PARP功能（奥拉）的联合疗法。 目标3：进行一项临床试验，在使用ENZ治疗CRPC患者后添加PARP 抑制剂奥拉，以实现更大的治疗反应，并与酶调节的HR/HRM相关 基因标记来进行治疗反应。

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.