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

概要：项目2 去势抵抗性前列腺癌（CRPC）向雄激素信号传导独立性的转化， 在暴露于雄激素受体后的转移性CRPC亚组中出现耐药机制 （AR）靶向治疗，如阿比特龙或恩杂鲁胺。临床上，患者通常表现为 在低或适度升高的血清前列腺特异性抗原（PSA）和转移性前列腺癌背景下的进展 活组织检查可显示与神经内分泌前列腺癌（NEPC）一致的病理或分子特征。 NEPC与AR表达低或缺失、AR信号传导抑制、早期基因组DNA保留、以及与AR表达相关。 从其腺癌前体突变，并获得不同的基因组和表观基因组改变 （Beltran等人，Nature Medicine，in press）.新的治疗方法的发展， NEPC代表临床未满足的需求。在过去的六年里，我们的团队专注于描述 NEPC的分子景观，并确定和验证了新的治疗靶点，包括N- Myc/Aurora A途径和特异性表观遗传修饰剂，如（Zeste同源物2的增强子）EZH 2。我们 最重要的假设是N-Myc与Aurora-A和EZH 2两者合作来驱动神经内分泌 表型和表征这种驱动作用将导致更有效的针对这种肿瘤的靶向策略 实体为了解决这一假设，我们提出表征EZH 2和N-Myc之间的相互作用， 信号在驱动NEPC中的作用，并将建立在先前评估Aurora-N-Myc变构抑制剂的工作基础上 复合物（例如，MLN 8237）和EZH 2抑制剂，以开发更有效的联合策略，靶向 国家环境保护方案（目标1）。此外，我们还致力于开发针对N-Myc/Aurora-A复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（目标2）。最后我们 将开发临床生物标志物来预测CRPC中靶向N-Myc和EZH 2的反应。我们将评估 来自入组极光激酶A II期研究的NEPC患者的治疗前转移性活检 抑制剂MLN 8237（Aurora-N-Myc复合物的变构抑制剂）和EZH 2的1期试验 通过RNA-seq，Aurora-N-myc-EZH 2测定抑制剂GSK 146和相关AR和N-Myc信号传导 复合物形成和EZH 2靶基因表达与临床应答（Aim 3）。我们的目标是开发 针对由N-Myc驱动的晚期CRPC的生物标志物选择亚组的更有效靶向策略， 更少地依赖AR。在这个项目结束时，我们将有一个更好的了解机制， 潜在的N-Myc/EZH 2驱动的NEPC，我们将鉴定对N-Myc和EZH 2应答的生物标志物 抑制作用这项研究将作为一个坚实的临床前基础，为发展新的生物标志物驱动的 治疗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.