AR Gene Rearrangements and AR Signaling in Prostate Cancer

项目总结/摘要 前列腺癌（PC）是最常见的男性癌症。手术或放射治疗是治愈性的 局部PC的治疗，而全身内分泌治疗是晚期或 转移性前列腺癌内分泌治疗的分子靶点是雄激素受体（AR），一种转录因子 由类固醇激素睾酮和双氢睾酮激活。因为PC细胞需要AR来 增殖和存活，抑制睾酮的产生（与促性腺激素释放激素类似物 和/或醋酸阿比特龙）和使用竞争性AR拮抗剂阻断睾酮作用（例如 恩杂鲁胺、阿帕鲁胺和达罗鲁米特）是内分泌治疗的基石。不幸的是， 内分泌治疗不能治愈，疾病将不可避免地发展为晚期去势抵抗性PC （CRPC）。CRPC是一种致命的疾病阶段，没有治愈性疗法。我们对肿瘤的分析 来自患者的标本表明，CRPC中最常见的改变之一是结构改变， AR基因重排。我们的初步数据表明，AR基因重排使AR与 内分泌调节和负反馈调节的转录因子 肿瘤抑制基因如PTEN丢失。这种解偶联使得AR活性对内分泌不敏感。 治疗和促进CRPC。该项目的长期目标是利用AR基因重排， 生物标志物，以指导更有效地使用当前和未来的CRPC治疗，并开发新的 可以克服AR基因重排效应的治疗剂。为了实现这些目标，我们将 开发具有AR基因重排和PTEN缺失的CRPC进展的新小鼠模型，以及 使用这些模型来确定AR基因重排促进PC进展的机制， 治疗抵抗这些模型将填补该领域长期存在的空白：缺乏反映 临床相关的AR改变。我们将测试这些模型的效用，以推进CRPC研究， 评估CRPC在整个生物体背景下对AR靶向治疗的应答。我们还将使用第三- 第二代基因组结构变异分析技术，以询问某些AR基因的结构 通过复杂的多步骤机制发生的重排。这项工作预计将澄清 CRPC中最常见和最复杂的AR基因重排模式的作用和起源。最后， 将使用一组 候选AR靶向治疗剂。我们还将使用计算方法来提名非AR目标 在携带AR基因重排的CRPC肿瘤中有效的治疗剂。总的来说，这项工作 有望增强对CRPC进展中AR基因重排的理解，并产生新的 可用于对抗这种致命疾病子集的模型、生物标志物和治疗方法。

PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is the most frequently diagnosed male cancer. Surgery or radiation therapy are curative treatments for localized PC while systemic endocrine therapies are standard-of-care for advanced or metastatic PC. The molecular target of endocrine therapy is the androgen receptor (AR), a transcription factor activated by the steroid hormones testosterone and dihydrotestosterone. Because PC cells require AR for proliferation and survival, inhibiting testosterone production (with gonadotropin releasing hormone analogs and/or abiraterone acetate) and using competitive AR antagonists to block testosterone actions (such as enzalutamide, apalutamide, and darolutamide) are the cornerstones of endocrine therapy. Unfortunately, endocrine therapy is not curative and the disease will inevitably progress to advanced castration-resistant PC (CRPC). CRPC is a lethal disease stage for which no curative therapies exist. Our analysis of tumor specimens from patients has shown that one of the most frequent alterations occurring in CRPC is structural rearrangement of the AR gene. Our preliminary data show that AR gene rearrangements uncouple the AR transcription factor from endocrine regulation and also from negative feedback regulation that occurs when tumor suppressor genes like PTEN are lost. This uncoupling renders AR activity insensitive to endocrine therapies and promotes CRPC. The long term goals of this project are to harness AR gene rearrangements as biomarkers to guide more effective use of current and future CRPC therapeutics, and to develop novel therapeutics that can overcome the effects of AR gene rearrangements. To achieve these goals, we will develop new mouse models of CRPC progression that harbor AR gene rearrangements and PTEN loss, and use these models to identify mechanisms by which AR gene rearrangements promote PC progression and therapeutic resistance. These models will fill a long-standing void in the field: a lack of mouse models reflecting clinically-relevant AR alterations. We will test the utility of these models for advancing CRPC research by evaluating CRPC responses to AR-targeted therapeutics in a whole-organism context. We will also use third- generation genome structural variation analysis techniques to interrogate the structure of certain AR gene rearrangements that occur via complex, multi-step mechanisms. This work is expected to provide clarity about the role and origin of the most frequent and complex patterns of AR gene rearrangements in CRPC. Finally, therapeutic vulnerabilities of CRPC models harboring AR gene rearrangements will be evaluated using a set of candidate AR-targeted therapeutics. We will also use computational methods to nominate non-AR-targeted therapeutics that will have efficacy in CRPC tumors harboring AR gene rearrangements. Collectively, this work is expected to enhance understanding of AR gene rearrangements in CRPC progression, and yield new models, biomarkers, and therapeutics that can be used to combat this lethal subset of the disease.