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.

项目摘要(摘要) 雄激素受体(AR)靶向治疗如阿比特龙、苯扎鲁胺、阿帕鲁胺和达鲁他胺是有效的 晚期去势抵抗前列腺癌(CRPC)的治疗。然而，对这些疗法的抵抗力 代表了晚期CRPC临床治疗的一个重大障碍。尽管最初的临床受益，但大多数患者 在一年内复发，并出现获得性耐药性。对AR靶向治疗产生获得性耐药的一个新机制是 肿瘤细胞适应非典型AR活性以求生存的能力。初步研究表明，A基因表达增加 主调节转录因子(Tf)簇(ELF3、JDP2、Pbx1、Rara)与非典范AR相关 观察到具有获得性苯扎鲁胺抗性的活性。有趣的是，已知AR合作伙伴FOXA1的表达水平 和HOXB13，在耐药模型中暴露于苯扎鲁胺后未受影响或略有下降。Ar 染色质图谱显示AR在启动子和增强子区域与新的主要调节因子结合的独特模式 在DHT存在的情况下都不存在。初步数据还表明，这些主TF的减少抑制了非 临床前模型中典型的AR活性和逆转对苯扎鲁胺的获得性耐药性。这样做的总体目标是 应用是确定已识别的主调节因子对与以下相关的非规范AR活动的作用 在CRPC中获得对苯扎鲁胺的耐药性，并开发最佳治疗方案，使细胞恢复到 在临床上是可控的，并对苯扎鲁胺重新敏感。我们的中心假设是非正则AR周期 与抗药性相关的是由新的主要调控转录因子的招募驱动的。瞄准他们的 脆弱性可使耐药细胞对苯扎鲁胺重新敏感。其基本原理是通过多模式分子 特征，我们可以探索可以将这些癌细胞推回到典型的AR敏感状态的治疗方案 变成了苯扎鲁胺。我们将测试我们的中心假设，并通过追求 以下具体目标：(I)患者来源的异种移植模型中非典型AR活动的多模式表征 晚期疾病。(Ii)评估已确定的主调控因子在非规范AR活性中的功能作用。(Iii) 在多种PDX模型中评估候选联合疗法的抗肿瘤活性并收集药理学和 毒物学信息。影响：该项目的结果将极大地扩展我们对致死生物的知识 前列腺癌(PCA)，并提供最佳治疗策略，改善患有致命性前列腺癌的男性的预后，减少 癌症带来的不平等负担。我们的直接目标是利用来自分子研究的信息来识别这个子集 使用基于多基因组的标记物的非典型性AR活动驱动耐药性的患者。此外，我们的研究 将提供改变的AR环路驱动程序的机制和漏洞以及对药物发现的影响 并为这一亚群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研究 在设置I期和II期临床试验的情况下将发现纳入临床。