Therapeutic targeting of master regulators in non-canonical AR driven advanced lethal prostate cancers

非经典 AR 驱动的晚期致命性前列腺癌中主调节因子的治疗靶向

• 批准号: 10737204
• 负责人: Remi Adelaiye-Ogala
• 金额: $ 58.92万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737204
• 关键词: Abate; Address; Androgen Receptor; Animals; Architecture; Automobile Driving; Back; Binding; Biological Assay; Biology; Cancer Burden; Cells; ChIP-seq; Chromatin; Clinic; Clinical; Clinical Management; Combined Modality Therapy; DNA; Data; Disease; ELF3 gene; Enhancers; Exposure to; Gene Expression; Genetic Transcription; Goals; Knowledge; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Neighborhoods; Organoids; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Physicians; Play; Population; Pre-Clinical Model; Proteins; Proteomics; RARA gene; Reporting; Resistance; Resistance development; Resolution; Role; Scientist; Signal Transduction; Systemic Therapy; Testing; Therapeutic; Toxicology; Translating; abiraterone; addiction; advanced disease; advanced prostate cancer; antagonist; cancer cell; castration resistant prostate cancer; drug discovery; effective therapy; enzalutamide; high risk; improved; improved outcome; interest; men; multimodality; multiple omics; neoplastic cell; novel; optimal treatments; patient derived xenograft model; patient subsets; pharmacologic; pre-clinical; preclinical trial; promoter; protein expression; receptor expression; recruit; relapse patients; targeted treatment; therapeutic target; therapy resistant; transcription factor; transcriptome sequencing; transcriptomics; treatment strategy; tumor; tumor heterogeneity

PROJECT SUMMARY (ABSTRACT) Androgen receptor (AR) targeted therapies such as abiraterone, enzalutamide, apalutamide, and darolutamide are effective treatments for patients with advanced castrate-resistant prostate cancer (CRPC). However, resistance to these therapies represents a significant hurdle in the clinical management of advanced CRPC. Despite initial clinical benefit, most patients relapse with acquired resistance within a year. An emerging mechanism of acquired resistance to AR-targeted therapy is the ability of tumor cells to adapt a non-canonical AR activity for survival. Preliminary suggests that increased expression of a master regulatory transcription factor (TF) cluster (ELF3, JDP2, PBX1, RARA) is associated with the non-canonical AR activity observed with acquired enzalutamide resistance. Interestingly, expression levels of known AR partners, FOXA1 and HOXB13, were either unaffected or slightly decreased following exposure to enzalutamide in resistant models. AR chromatin profiling showed a unique binding pattern of AR to novel master regulatory TFs at promoter and enhancer regions that were absent in the presence of DHT. Preliminary data also suggests a decrease in these master TFs suppresses non- canonical AR activity and reverses acquired resistance to enzalutamide in preclinical models. The overall objective of this application is to determine the role of identified master regulatory TFs on non-canonical AR activity associated with acquired enzalutamide resistance in CRPC and develop optimal therapeutic options that shift cells back to a phenotype that is clinically manageable and re-sensitized to enzalutamide. Our central hypothesis is that non-canonical AR cistrome associated with resistance is driven by the recruitment of novel master regulatory transcription factors. Targeting their vulnerability can re-sensitize resistant cells to enzalutamide. The rationale is that through multimodal molecular characterization, we can explore therapeutic options that can push back these cancer cells to a canonical AR state sensitive to enzalutamide. We will test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: (i) Multimodal characterization of non-canonical AR activity in patient-derived xenograft models of advanced disease. (ii) Assess the functional role of identified master regulatory TF on non-canonical AR activity. (iii) Assess the antitumor activity of candidate combination therapies in multiple PDX models and gather pharmacological and Toxicology information. Impact: Results from this project will significantly expand our knowledge of the biology of lethal prostate cancer (PCa) and provide optimal treatment strategies that improve outcomes for men with lethal PCa, reducing the unequal burden of cancer. Our immediate goal is to leverage information from molecular studies to recognize the subset of patients where resistance is driven by non-canonical AR activity using multi-omic-based markers. Furthermore, our study will provide the mechanisms and vulnerabilities of the altered AR cistrome drivers and the implications for drug discovery and developing optimal therapeutic options for this subset of patients. Our long-term goal is to translate our preclinical findings into the clinic in the setting of phase I & II clinical trials.

项目概要（摘要） 雄激素受体（AR）靶向治疗（如阿比特龙、恩杂鲁胺、阿帕鲁胺和达罗鲁米特）有效 晚期去势抵抗性前列腺癌（CRPC）患者的治疗。然而，对这些疗法的耐药性 代表了晚期CRPC临床管理中的一个重大障碍。尽管最初的临床获益，大多数患者 在一年内复发并获得耐药性。对AR靶向治疗的获得性耐药的一种新机制是 肿瘤细胞适应非典型AR活性以存活的能力。初步研究表明， 主调节转录因子（TF）簇（ELF 3、JDP 2、PBX 1、RARA）与非典型AR相关 在获得性恩杂鲁胺耐药的情况下观察到活性。有趣的是，已知的AR伴侣FOXA 1 和HOXB 13，在耐药模型中暴露于enzalutamide后未受影响或轻微降低。AR 染色质分析显示AR与启动子和增强子区域的新型主调节TF的独特结合模式 在DHT存在的情况下不存在。初步数据还表明，这些主TF的减少抑制了非 典型AR活性，并逆转临床前模型中对Enzalutamide的获得性耐药性。本报告的总体目标 应用是确定鉴定的主调节TF对与以下相关的非典型AR活性的作用： 在CRPC中获得Enzalutamide耐药性，并开发最佳治疗选择，使细胞恢复到 在临床上可管理，并对Enzalutamide重新致敏。我们的中心假设是，非典型AR顺反子 与耐药性相关的疾病是由新的主调节转录因子的募集驱动的。针对他们 脆弱性可以使耐药细胞对恩杂鲁胺重新敏感。基本原理是，通过多模态分子 表征，我们可以探索治疗选择，可以将这些癌细胞推回到典型的AR状态敏感 恩杂鲁胺。我们将测试我们的中心假设，并通过追求 （i）患者来源的异种移植物模型中非典型AR活性的多模式表征 晚期疾病。(ii)评估鉴定的主调节TF对非典型AR活性的功能作用。（三） 在多种PDX模型中评估候选联合治疗的抗肿瘤活性，并收集药理学和 毒理学信息。影响：该项目的结果将显着扩大我们对致命生物学的了解。 前列腺癌（PCa），并提供最佳的治疗策略，改善致命PCa男性的结局，减少 不平等的癌症负担。我们的近期目标是利用分子研究的信息来识别子集 使用基于多组学的标记物，由非典型AR活性驱动耐药的患者。此外，我们的研究 将提供改变的AR顺反子驱动程序的机制和脆弱性以及对药物发现的影响 并为这部分患者开发最佳治疗方案。我们的长期目标是将我们的临床前 在I期和II期临床试验的背景下，将研究结果应用于临床。