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治疗耐药的分子机制，并开发克服耐药的有效策略。最近，我们对去势抵抗性前列腺癌中持续雄激素受体（AR）信号传导的理解取得了重大进展，导致了两种下一代雄激素导向疗法阿比特龙和恩杂鲁胺（MDV 3100）的开发和FDA批准，这预示着前列腺癌治疗的新时代。然而，雄激素导向治疗后的疾病进展仍然是前列腺癌临床管理中最关键的挑战。缺乏配体的组成型活性、选择性剪接的AR变体（AR-V）的表达上调 结合结构域已被认为在疾病进展中起重要作用。然而，雄激素导向疗法增加AR-V表达的精确机制和AR-V调节靶基因表达介导治疗抗性的精确机制仍然知之甚少。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，因此是拟议研究的主要研究重点。 基于我们和其他人的发现，我们提出AR-V的上调是前列腺癌对目前临床上接受的所有雄激素导向疗法的不可避免的反应，并且从雄激素依赖性全长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二聚化导致释放的AR活性，从而推动疾病进展。鉴于阿比特龙和enzalutamide的效力以及阿比特龙进展时雄激素合成持续抑制的证据，这种耐药机制可能对阿比特龙和enzalutamide尤其重要。提出了三个具体的目标来检验假设。目的1：阐明雄激素导向治疗诱导AR-V的机制。目的2：阐明AR-Vs调控靶基因表达的机制。目的3：将循环肿瘤细胞中的AR-V表达与阿比特龙/恩杂鲁胺反应相关联。 这项拟议的研究与公共卫生有关，因为它解决了目前所有雄激素导向疗法所固有的耐药机制，包括新药阿比特龙和恩杂鲁胺。此外，我们希望将AR-V作为一种预后标志物，以指导选择可能从阿比特龙和enzalutamide治疗中获益的患者。总体而言，本研究的结果预计将对合理的药物设计和联合用药产生直接影响，以克服当前治疗的缺点，并减少患者的痛苦和改善患者的生活质量。

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.