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

基本信息

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
项目类别：
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

项目摘要

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、阿帕鲁胺和达洛鲁胺有效晚期去势抵抗性前列腺癌（CRPC）患者的治疗。然而，对这些疗法的抵抗这是晚期 CRPC 临床管理的一个重大障碍。尽管最初的临床获益，大多数患者一年内因获得性耐药而复发。 AR靶向治疗获得性耐药的一个新兴机制是肿瘤细胞适应非典型 AR 活性以求生存的能力。初步表明a的表达增加主调控转录因子 (TF) 簇 (ELF3、JDP2、PBX1、RARA) 与非规范 AR 相关观察到获得性恩杂鲁胺耐药性的活性。有趣的是，已知 AR 伙伴 FOXA1 的表达水平和 HOXB13，在耐药模型中暴露于恩杂鲁胺后不受影响或略有下降。增强现实染色质分析显示 AR 与启动子和增强子区域的新型主调控 TF 具有独特的结合模式当 DHT 存在时，这些现象就消失了。初步数据还表明，这些主转录因子的减少会抑制非典型的 AR 活性并逆转临床前模型中对恩杂鲁胺的获得性耐药性。本次活动的总体目标应用程序的目的是确定已识别的主监管TF对与相关的非规范AR活动的作用在 CRPC 中获得恩杂鲁胺耐药性并开发最佳治疗方案，将细胞转变回表型临床上可以控制，并对恩杂鲁胺重新敏感。我们的中心假设是非规范 AR 顺反子与耐药性相关的因素是由新的主调控转录因子的招募驱动的。针对他们的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式分子通过表征，我们可以探索可以将这些癌细胞推回典型 AR 状态敏感的治疗方案恩杂鲁胺。我们将测试我们的中心假设并通过追求以下目标来实现此应用程序的目标以下具体目标：(i) 患者来源的异种移植模型中非典型 AR 活性的多模式表征的晚期疾病。 (ii) 评估已确定的主监管 TF 对非规范 AR 活动的功能作用。 (三) 评估候选联合疗法在多个 PDX 模型中的抗肿瘤活性，并收集药理学和毒理学信息。影响：该项目的结果将显着扩展我们对致命生物学的了解前列腺癌 (PCa) 并提供最佳治疗策略，改善患有致命 PCa 的男性的预后，减少癌症负担不平等。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 活动驱动耐药的患者。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漏洞以及对药物发现的影响并为这部分患者制定最佳治疗方案。我们的长期目标是将我们的临床前研究转化为在 I 期和 II 期临床试验中将研究结果带入临床。