Project 2: Targeting N-Myc and EZH2-driven Castrate Resistant Prostate Cancer

摘要：项目2 抗去势前列腺癌(CRPC)向雄激素信号非依赖性转化的研究 雄激素受体暴露后作为转移性CRPC亚群的耐药机制 (Ar)--阿比特龙或苯扎鲁胺等靶向疗法。临床上，患者通常表现为 血清前列腺特异性抗原(PSA)低或轻度升高与转移的进展 活检可以显示出与神经内分泌前列腺癌(NEPC)一致的病理或分子特征。 NEPC与AR低表达或缺失、AR信号受抑制、早期基因组保留有关 腺癌前体的突变，以及不同基因组和表观基因组改变的获得 (Beltran等人，《自然医学》，出版中)。慢性阻塞性肺疾病患者新治疗方法的发展 NEPC代表着临床上未得到满足的需求。在过去的六年里，我们的团队一直专注于描述 并已确定和验证了新的治疗靶点，包括N- MYC/Aurora A途径和特定的表观遗传修饰物，如(Enhancer Of Zust Homolog 2)EZH2。我们的 最重要的假设是N-Myc与Aurora-A和EZH2共同驱动神经内分泌 表型和这种驱动作用的特征将导致对该肿瘤更有效的靶向策略 实体。为了解决这一假设，我们建议表征EZH2和N-Myc之间的相互作用 在驱动NEPC中的信号传递，还将建立在评估Aurora-N-Myc变构抑制剂的先前工作的基础上 复合体(如MLN8237)和EZH2抑制剂开发更有效的联合策略来靶向 NEPC(目标1)。此外，我们的目标是开发针对N-Myc/Aurora-A络合物的新型变构化合物 通过我们与WCM的三机构治疗发现研究所的合作(AIM 2)。最后我们 将开发临床生物标记物来预测在CRPC中靶向N-Myc和EZH2的反应。我们将评估 参加极光激酶A第二阶段研究的NEPC患者的治疗前转移活检 抑制剂MLN8237(Aurora-N-Myc复合体的变构抑制剂)和EZH2的一期试验 RNA-seq、Aurora-N-myc-EZH2确定的GSK146及其相关的AR和N-Myc信号转导 复合体的形成和EZH2靶基因的表达与临床反应(目标3)。我们的目标是发展 针对N-Myc和N-Myc驱动的晚期CRPC生物标志物选择亚群的更有效靶向策略 减少对AR的依赖。在这个项目结束时，我们将对这些机制有更好的了解 潜在的N-Myc/EZH2驱动的NEPC，我们将识别出响应N-Myc和EZH2的生物标记物 抑制力。这项研究将为开发新的生物标记物驱动的临床前奠定坚实的基础 晚期前列腺癌患者的治疗策略。

SUMMARY: PROJECT 2 Transformation of castration resistant prostate cancer (CRPC) towards androgen signaling independence has emerged as a resistance mechanism in a subset of metastatic CRPC following exposure to androgen receptor (AR)-targeted therapies such as abiraterone or enzalutamide. Clinically, patients typically present with progression in the setting of a low or modestly rising serum prostate specific antigen (PSA) and metastatic biopsies can show pathologic or molecular features consistent with neuroendocrine prostate cancer (NEPC). NEPC is associated with low or absent AR expression, suppressed AR signaling, retention of early genomic mutations from its adenocarcinoma precursor, and acquisition of distinct genomic and epigenomic alterations (Beltran et al., Nature Medicine, in press). The development of novel therapeutic approaches for patients with NEPC represents a clinical unmet need. Over the last six years, our group has focused on characterizing the molecular landscape of NEPC and have identified and validated new therapeutic targets, including the N- Myc/Aurora A pathway and specific epigenetic modifiers such as (Enhancer of Zeste Homolog 2) EZH2. Our overarching hypothesis is that N-Myc cooperates with both Aurora-A and EZH2 to drive the neuroendocrine phenotype and that characterizing this driving role will lead to more effective targeting strategies for this tumor entity. To address this hypothesis we propose to characterize the interaction between the EZH2 and N-Myc signaling in driving NEPC and will also build on prior work evaluating allosteric inhibitors of the Aurora-N-Myc complex (e.g., MLN8237) and the EZH2 inhibitors to develop more effective combination strategies to target NEPC (Aim 1). In addition, we aim to develop novel allosteric compounds targeting N-Myc/Aurora-A complex through our collaboration with the Tri-Institutional Therapeutics Discovery Institute at WCM (Aim 2). Finally we will develop clinical biomarkers to predict response in targeting N-Myc and EZH2 in CRPC. We will evaluate pre-treatment metastatic biopsies from patients with NEPC enrolled in a Phase 2 study of the aurora kinase A inhibitor MLN8237 (an allosteric inhibitor of the Aurora-N-Myc complex) and a Phase 1 trial of the EZH2 inhibitor GSK146 and correlate AR and N-Myc signaling determined by RNA-seq, Aurora-N-myc-EZH2 complex formation, and EZH2 target gene expression with clinical response (Aim 3). Our goal is to develop more effective targeting strategies for a biomarker-selected subgroup of late stage CRPC driven by N-Myc and less dependent on the AR. At the end of this project we will have a better understanding of the mechanisms underlying N-Myc/EZH2 driven NEPC and we will have identified biomarkers of response to N-Myc and EZH2 inhibition. This study will serve as a solid preclinical foundation for the development of new biomarker-driven therapeutic strategies for treating patients with advanced prostate cancer.