Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC

项目总结(项目3) 转移性去势抵抗前列腺癌(MCRPC)仍然是一种无法治愈的疾病，对于这种疾病，新的 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共同调节的DNA损伤反应(DDR)基因签名与 MCRPC患者的去势抵抗、转移和总存活率降低。在这个DDR基因签名中 同源重组(HR)DNA修复基因和HR调节器(HRM)基因高度表达。 在DDR基因特征中相对较大比例的HR/HRM基因强调了 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 苯扎鲁胺(ENZ)，一种阻止雄激素与雄激素结合的第二代抗雄激素 受体(AR)抑制大多数HR/HRM基因的表达，并与奥拉帕利有协同作用 聚(ADP-核糖)聚合酶1(PARP1)抑制剂(Ola)抑制前列腺癌生长。此前， 在具有BRCA1/2或其他HR基因的多种恶性肿瘤中，OLA与合成致死性有关 缺陷及其靶点PARP1在碱基切除修复(BER)中起着关键作用，据报道 作为AR的辅助因素。在这个项目中，我们建议检验以下假设：以AR(Enz)和 引入策略中的PARP(Ola)将通过enz介导在mCRPC中产生合成致死性 HR/HRM基因活性下调及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。先导性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 个别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。 目的1.研究男性mCRPC患者骨髓活检组织中HR/HRM基因特征。 苯扎鲁胺和/或阿比特龙，雄激素信号转导的新型抑制剂。 目的2.进一步表征生物标志物的协同作用潜力，并找出生物标志物 使用临床前模型共同靶向AR(ENZ)和PARP功能(OLA)的联合治疗。 目的3.进行一项临床试验，治疗慢性前列腺癌患者使用ENZ，然后添加PARP 阻滞剂Ola达到更好的治疗效果并与ENZ调节的HR/HRM相关 基因签名对治疗反应的影响。

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.