The aberrant androgen receptor underlies abiraterone/enzalutamide resistance

 描述（由申请人提供）：最近FDA批准了阿比特龙和Enzalutamide（两种靶向雄激素受体（AR）信号传导轴的新药），这扩大了去势抵抗性前列腺癌（CRPC）患者的治疗选择并改善了结局。这些药物极大地改变了CRPC的治疗前景，尽管很大一部分患者没有从中获得任何临床益处。因此，出现了解决对这些药剂的耐药性机制的严重未满足的需求。本申请的总体目的是剖析对阿比特龙和恩杂鲁胺治疗耐药的分子驱动因素。本申请的主要假设是“由组成型活性AR剪接变体介导的异常AR信号传导是阿比特龙和恩杂鲁胺原发性和获得性耐药的基础。“拟议的研究将在翻译环境中进行，包括前瞻性收集接受阿比特龙或enzalutamide标准治疗的转移性CRPC患者的临床注释标本。提出了三个具体目的：（目的1）确定基于血液的关键AR剪接变体AR-V7的检测是否表明对阿比特龙或恩杂鲁胺的原发性或获得性耐药;（目的2）以全面的方式定义异常AR的转录景观，目的是确定AR-V在药物应答和抗性中的相对重要性和临床意义，在其他假定的竞争性抗性机制的背景下;以及（目的3）确定AR二聚体在介导异常AR信号传导中的作用。如果成功，该项目将确定AR-V7非侵入性检测的潜在临床效用，将确定许多竞争性耐药机制的相对重要性和临床意义，并将确立AR-V作为对AR靶向药物耐药的驱动因素。总的来说，拟议的研究有可能改变转移性CRPC的临床管理，并将有助于推动下一波靶向异常AR信号传导轴的方法的发展。

 DESCRIPTION (provided by applicant): The recent FDA approvals of abiraterone and enzalutamide, two new agents targeting the androgen receptor (AR) signaling axis, have expanded the treatment options and improved outcomes for patients with castration-resistant prostate cancer (CRPC). These drugs have dramatically changed the therapeutic landscape of CRPC even though a significant proportion of patients do not derive any clinical benefit from them. Thus, there has emerged a critically unmet need to address the mechanisms of resistance to these agents. The overall objective of this application is to dissect molecular drivers of therapeutic resistance to abiraterone and enzalutamide. The main hypothesis of this application is that "aberrant AR signaling, mediated by the constitutively active AR splice variants, underlies primary and acquired resistance to abiraterone and enzalutamide." The proposed studies will be conducted in a translational setting, involving prospective collection of clinically annotated specimens from patients with metastatic CRPC undergoing standard-of-care treatment with abiraterone or enzalutamide. Three Specific Aims are proposed: (Aim 1) to determine whether blood-based detection of a key AR splice variant, AR-V7, indicates primary or acquired resistance to abiraterone or enzalutamide; (Aim 2) to define the transcriptional landscape of the aberrant AR in a comprehensive fashion, with the goal of determining the relative importance and clinical significance of AR-Vs in drug response and resistance, in the context of other putative competing resistance mechanisms; and (Aim 3) to determine the role of AR dimers in mediating aberrant AR signaling. If successful, this project will determine the potential clinical utility of a non-invasive assay for AR-V7, will define the relative importance ad clinical significance of a number of competing resistance mechanisms, and will establish AR-Vs as drivers of resistance to AR-targeting agents. Overall, the proposed studies have the potential to transform the clinical management of metastatic CRPC and will help to drive the development of the next wave of approaches targeting the aberrant AR signaling axis.