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.

项目摘要（摘要）雄激素受体（AR）靶向疗法，例如阿比罗酮，恩扎拉胺，apalutamide和darolutamide是有效的患有晚期耐Castrate前列腺癌（CRPC）患者的治疗方法。但是，对这些疗法的抵抗力代表了高级CRPC临床管理的重大障碍。尽管最初的临床益处，大多数患者一年内获得的抵抗力复发。获得的对AR靶向治疗的新兴机制是肿瘤细胞适应非典型AR活性以生存的能力。初步表明A表达增加主调节转录因子（TF）群集（ELF3，JDP2，PBX1，RARA）与非典型AR相关联用获得的enzalutamide耐药性观察到的活性。有趣的是，已知AR伴侣的表达水平，FoxA1 在耐药模型中暴露于恩扎拉胺后，hoxb13不受影响，要么略有下降。 ar 染色质分析显示了AR与新型主调控TF在启动子和增强子区域的独特结合模式在DHT存在下不存在。初步数据还表明，这些主TF抑制了非 - 在临床前模型中，经典AR活性和逆转对enzalutamide的抗性。总体目标应用是确定已鉴定的主调节TF在与与非规范性AR活性相关的非官方AR活性的作用在CRPC中获得了enzalutamide的耐药性，并开发出最佳的治疗选择，将细胞转移到表型中在临床上可管理并重新敏感到enzalutamide。我们的中心假设是非规范的AR Cistrome 与抗药性相关的是由新型的主调节转录因子的募集驱动。针对他们脆弱性可以将抗性细胞重新敏感到enzalutamide。理由是通过多模式分子表征，我们可以探索可以将这些癌细胞推回经典AR状态敏感的治疗选择到enzalutamide。我们将通过追求以下特定目的：（i）在患者衍生的异种移植模型中非传统AR活性的多模式表征晚期疾病。（ii）评估已鉴定的主调节TF在非典型AR活性上的功能作用。（iii）评估多种PDX模型中候选组合疗法的抗肿瘤活性，并收集药理学和毒理学信息。影响：该项目的结果将大大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，以改善致命PCA男性的预后，减少癌症的不平等负担。我们的近期目标是利用分子研究的信息来识别子集使用多摩尼克标记的非经典AR活性驱动耐药性的患者。此外，我们的研究将提供改变的AR Cistrome司机的机制和脆弱性以及对药物发现的影响并为此患者开发最佳的治疗选择。我们的长期目标是翻译我们的临床前在I和II期临床试验的情况下，发现诊所的结果。