An inevitable mechanism of resistance to androgen-directed therapy

描述(由申请人提供)：本申请的长期目标是了解雄激素导向疗法耐药的分子机制，并开发有效的策略来克服耐药。最近，我们在了解雄激素受体(AR)信号在去势耐受前列腺癌中的持续作用方面取得了重大进展，导致了两种下一代雄激素导向疗法的开发和FDA的批准，即阿比特龙和苯扎鲁胺(MDV3100)，这预示着前列腺癌治疗的新纪元。然而，在前列腺癌的临床治疗中，雄激素导向治疗后的疾病进展仍然是最关键的挑战。缺乏配体的结构性活性选择性剪接AR变异体(AR-V)的上调表达 结合结构域被认为在疾病的发展中起着重要作用。然而，雄激素导向治疗增加AR-V表达的确切机制以及AR-V调控靶基因表达介导治疗耐药的确切机制仍不清楚。这两个问题对于了解雄激素导向治疗的耐药性和开发克服耐药性的有效方法至关重要，因此也是拟议研究的主要调查重点。根据我们和其他人的研究结果，我们认为AR-VS上调是前列腺癌对目前临床上接受的所有雄激素导向治疗的必然反应，从雄激素依赖的全长AR(AR-FL)同源二聚化转变为雄激素非依赖性AR-FL/AR-V和AR-V/AR-V二聚化导致AR活性释放，从而推动疾病的进展。考虑到阿比特龙和苯扎鲁胺的有效性，以及在阿比特龙进展时持续抑制雄激素合成的证据，这种耐药机制可能对阿比特龙和苯扎鲁胺特别关键。本文提出了三个具体的目标来检验这些假设。目的1：探讨雄激素诱导AR-V的机制。目的2：阐明AR-VS调控靶基因表达的机制。目的：探讨循环肿瘤细胞AR-V表达与阿比特龙/苯扎鲁胺反应的关系。这项拟议的研究与公共健康相关，因为它解决了目前所有雄激素导向疗法固有的耐药机制，包括新药阿比特龙和苯扎鲁胺。此外，我们希望建立AR-VS作为预后标记物，以指导选择可能受益于阿比特龙和苯扎鲁胺治疗的患者。总体而言，这项研究的结果有望对合理的药物设计和组合产生直接影响，以克服现有治疗方法的缺点，减少患者的痛苦，提高患者的生活质量。

DESCRIPTION (provided by applicant): The long-term objectives of this application are to understand the molecular mechanisms of resistance to androgen-directed therapies and to develop effective strategies to overcome the resistance. Recent significant advances in our understanding of continued androgen receptor (AR) signaling in castration-resistant prostate cancer have led to the development and FDA approval of two next-generation androgen-directed therapies, abiraterone and enzalutamide (MDV3100), which heralded a new era of prostate cancer therapy. However, disease progression after androgen-directed therapies remains the most critical challenge in the clinical management of prostate cancer. Upregulated expression of constitutively-active, alternatively-spliced AR variants (AR-Vs) that lack the ligand binding-domain has been implicated to play an important role in disease progression. However, the precise mechanism by which androgen-directed therapies increase AR-V expression and the precise mechanism by which AR-Vs regulate target-gene expression in mediating therapeutic resistance remain poorly understood. These are two issues vital to understanding resistance to androgen-directed therapies and developing effective means to overcome the resistance, and therefore are the main focus of investigation of the proposed study. Based on the findings from ours and others, we propose that upregulation of AR-Vs is an inevitable response of prostate cancers to all androgen-directed therapies currently accepted in the clinic and that a shift from androgen-dependent full-length AR (AR-FL) homodimerization to androgen-independent AR-FL/AR-V and AR-V/AR-V dimerization leads to unleashed AR activity, driving disease progression. Given the potency of abiraterone and enzalutamide and the evidence for ongoing suppression of androgen synthesis at the time of progression on abiraterone, this resistance mechanism may be especially critical for abiraterone and enzalutamide. Three specific aims are proposed to test the hypotheses. Aim 1: Delineate the mechanism of AR-V induction following androgen-directed therapies. Aim 2: Elucidate the mechanism by which AR-Vs regulate target-gene expression. Aim 3: Correlate AR-V expression in circulating tumor cells with abiraterone/enzalutamide response. The proposed research is relevant to public health because it addresses a resistance mechanism that is inherent to all current androgen-directed therapies, including the new drugs abiraterone and enzalutamide. Moreover, we hope to establish AR-Vs as a prognostic marker to guide the selection of patients who will likely benefit from abiraterone and enzalutamide therapies. Overall, the outcome of this study is expected to have a direct impact on rational drug design and combination to overcome the shortcoming of current therapies and on reducing suffering and improving quality of life of the patients.