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

项目 2：靶向 N-Myc 和 EZH2 驱动的去势抵抗性前列腺癌

• 批准号: 9357039
• 负责人: David S. Rickman
• 金额: $ 35.06万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9357039
• 关键词: Address; Adenocarcinoma; Androgen Receptor; Androgens; Automobile Driving; Biological Markers; Biological Models; Biopsy; Cell Line; Cell Survival; Cessation of life; ChIP-seq; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Computer Simulation; Data; Development; Down-Regulation; EZH2 gene; Enhancers; Enrollment; Epigenetic Process; Exposure to; Foundations; Gene Expression; Gene Targeting; Genetic Transcription; Genomics; Goals; Histones; Homologous Gene; In Vitro; Institutes; Lead; Libraries; Ligands; Malignant neoplasm of prostate; Mediating; Medicine; Methyltransferase; Modeling; Molecular; Mutate; Mutation; N-Myc Protein; Nature; Neurosecretory Systems; Organoids; Pathologic; Pathway interactions; Patient Selection; Patients; Peptides; Phase I Clinical Trials; Phenotype; Phthalimides; Prostate Adenocarcinoma; Prostate-Specific Antigen; Receptor Signaling; Resistance; Role; SET Domain; STK6 gene; Serum; Signal Transduction; Solid; Structure; Subgroup; Testing; Therapeutic; Toxic effect; Transgenic Mice; Work; abiraterone; androgen deprivation therapy; aurora-A kinase; base; biomarker-driven; castration resistant prostate cancer; clinical biomarkers; drug efficacy; epigenomics; in vivo; in vivo Model; inhibitor/antagonist; insight; multidisciplinary; mutant; neoplastic cell; neuroendocrine phenotype; new therapeutic target; novel; novel therapeutic intervention; overexpression; personalized cancer care; phase 2 study; pre-clinical; predicting response; predictive marker; protein complex; protein degradation; receptor expression; resistance mechanism; response; response biomarker; small molecule; targeted treatment; transcriptome sequencing; transdifferentiation; tumor; tumor growth

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.

摘要：项目2 cast割抗性前列腺癌（CRPC）向雄激素信号独立性的转化已有 暴露于雄激素受体后，在转移性CRPC子集中成为一种抗性机制 （AR）靶向的疗法，例如阿比罗酮或恩扎拉胺。临床上，患者通常存在 在低或适度上升的血清前列腺特异性抗原（PSA）和转移性的情况下进展 活检可以显示与神经内分泌前列腺癌（NEPC）一致的病理或分子特征。 NEPC与低或不存在的AR表达，抑制AR信号传导，早期基因组保留有关 来自其腺癌前体的突变，并获得不同的基因组和表观基因组改变 （Beltran等人，《自然医学》，印刷中）。针对患者的新型治疗方法的开发 NEPC代表临床未满足的需求。在过去的六年中，我们的小组专注于表征 NEPC的分子景观，已经确定并验证了新的治疗靶标，包括N- MYC/Aurora A途径和特定的表观遗传修饰剂，例如（Zeste同源2的增强子）Ezh2。我们的 总体假设是N-MYC与Aurora-A和EZH2合作以驱动神经内分泌 表型和表征这种驾驶角色的表型将导致该肿瘤的更有效的靶向策略 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 驾驶NEPC的信号传导，还将基于评估Aurora-N-Myc的变构抑制剂的先前工作 复合物（例如MLN8237）和EZH2抑制剂，以开发更有效的组合策略以靶向 NEPC（AIM 1）。此外，我们旨在开发针对N-Myc/Aurora-A配合物的新型变构化合物 通过我们与WCM的三机构治疗学院发现研究所的合作（AIM 2）。最后我们 将开发临床生物标志物，以预测CRPC中N-MYC和EZH2的反应。我们将评估 来自NEPC患者的Aurora激酶A 2期研究的患者的治疗前转移活检 抑制剂MLN8237（Aurora-N-MYC复合物的变构抑制剂）和EZH2的1期试验 抑制剂GSK146和由RNA-Seq，Aurora-N-Myc-Ezh2确定的AR和N-MYC信号传导 复合形成，EZH2靶基因表达具有临床反应（AIM 3）。我们的目标是发展 针对由N-MYC和 不太依赖AR。在该项目的结尾，我们将对机制有更好的了解 基础N-MYC/EZH2驱动的NEPC，我们将确定对N-MYC和EZH2的反应的生物标志物 抑制。这项研究将成为开发新生物标志物驱动的稳固的临床前基础 治疗晚期前列腺癌患者的治疗策略。