AR gene rearrangements and AR signaling in prostate cancer

项目摘要/摘要 前列腺癌是最常见的男性癌症，也是男性癌症的第二大病因。 死亡。抑制雄激素受体(AR)的活性是复发或复发的主要治疗方式 转移性PC。PC总是复发，具有致命的去势抵抗(CR)表型，这种表型对AR- 有针对性的治疗。临床和实验证据支持当前的范式，即AR重新激活是一种 这一阻力的关键驱动因素，支持了CRPC的持续增长和进步。这一知识导致了 抑制CRPC中AR重新激活的新疗法的开发，但耐药性仍然存在 对病人来说是个问题。这项研究的长期目标是确定能够 支持持续的AR转录活性，尽管AR靶向治疗，并开发新的战略 治疗CRPC患者。推动该项目的核心发现是高频率的结构 影响AR基因结构的重排，特别是在CRPC期获得的肿瘤中 病人。主要的挑战是这些AR基因重排的多样性和异质性，在 病人内部和病人之间的基础，这构成了发展对 它们的临床意义和治疗靶向。提案中提供的初步数据显示， 不同的AR基因重排为选择性培养的CRPC细胞提供生长优势 AR靶向治疗的压力，表明它们在 抵抗。初步数据还显示，这些AR基因重排的一个共同的分子结果 是缺乏AR配体结合域的截短AR变异体的合成。这些AR变异物种能够 通过结构性、配基无关的机制支持持久的AR转录活性， 抗雄激素药耐药。本项目的总体目标是了解以下方面的一般性 这种新的耐药机制发生在CRPC期肿瘤中，并确定了新的治疗靶点。至 为了实现这些目标，我们将开发新的基因组学技术，使准确的识别和 CRPC患者肿瘤中重排AR基因结构的重建。我们还将 使用基因组工程方法了解不同的AR基因重排是否在功能上 等同于对AR靶向治疗的抗药性，并理解AR的必要性和充分性 促进这种表型的变体。最后，AR变异体结合染色质的分子机制 并实现结构性转录活动将被阐明，重点是支持 这些活动。这些联合调节剂将被评估为抑制AR变异体活性的目标 AR基因重排下游。总体而言，这些研究的成功将阐明 在CRPC期肿瘤中影响AR基因的常见但未被探索的改变类别和识别新的 抑制CRPC中AR再激活的分子靶点。

PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is the most frequently diagnosed male cancer and second leading cause of male cancer death. Inhibiting activity of the androgen receptor (AR) is the primary treatment modality for relapsed or metastatic PC. Invariably, PC recurs with a lethal castration-resistant (CR) phenotype that is resistant to AR- targeted therapies. Clinical and experimental evidence supports the current paradigm that AR reactivation is a key driver of this resistance, supporting continued growth and progression of CRPC. This knowledge has led to the development of new therapies that inhibit AR reactivation in CRPC, but resistance remains a persistent problem for patients. The long-term objectives of this research are to determine the mechanisms that can support persistent AR transcriptional activity despite AR-targeted therapy, and to develop new strategies for treating patients with CRPC. The central discovery driving this project is a high frequency of structural rearrangements affecting the architecture of the AR gene, specifically in tumors obtained from CRPC-stage patients. The major challenge is the diversity and heterogeneity of these AR gene rearrangements, on both an intra-patient and an inter-patient basis, which poses a barrier to developing a mechanistic understanding of their clinical significance and therapeutic targeting. Preliminary data presented in the proposal show that diverse AR gene rearrangements impart a growth advantage for CRPC cells grown under the selective pressure of AR-targeted therapies, indicating that they play a central, albeit poorly-understood, role in resistance. Preliminary data also show that a common molecular outcome of these AR gene rearrangements is synthesis of truncated AR variants lacking the AR ligand binding domain. These AR variant species are able to support persistent AR transcriptional activity through mechanisms that are constitutive, ligand independent, and antiandrogen resistant. The overarching goals of this project are to understand the generality with which this new resistance mechanism occurs in CRPC-stage tumors and identify new therapeutic targets. To achieve these goals, we will develop new genomics technologies that will enable accurate identification and reconstruction of the rearranged AR gene architectures occurring in the tumors of CRPC patients. We will also use genome engineering approaches to understand whether diverse AR gene rearrangements are functionally equivalent in driving resistance to AR-targeted therapy, and understanding the necessity and sufficiency of AR variants for promoting this phenotype. Finally, the molecular mechanisms by which AR variants bind chromatin and achieve constitutive transcriptional activity will be elucidated, with emphasis on co-regulators that support these activities. These co-regulators will be evaluated as targets for inhibiting activity of AR variants downstream of AR gene rearrangements. Overall, success with these studies will elucidate the role of a frequent yet unexplored class of alteration impacting the AR gene in CRPC-stage tumors and identify new molecular targets for inhibiting AR reactivation in CRPC.