AR gene rearrangements and AR signaling in prostate cancer

前列腺癌中的 AR 基因重排和 AR 信号传导

基本信息

批准号：
10363701
负责人：
Scott M. Dehm
金额：
$ 35.66万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10363701
关键词：
AR gene Affect Affinity Androgen Antagonists Androgen Receptor Androgen Suppression Androgens Architecture Automobile Driving Binding Biological Markers CRISPR/Cas technology Cancer Patient Castration Cell Line Cessation of life Chromatin Clinical DNA DNA sequencing Data Detection Development Diagnosis Disease Engineering Failure Frequencies Gene Rearrangement Generations Genes Genetic Transcription Genome engineering Genomics Goals Growth Heterogeneity Individual Knowledge Lead Ligand Binding Domain Ligands Link Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Messenger RNA Metastatic Prostate Cancer Modality Modeling Molecular Molecular Target Monitor Outcome Patients Phase Phenotype Play Portraits Protein Isoforms Proteins Receptor Signaling Recording of previous events Recurrence Relapse Research Resistance Role Technology Testing Therapeutic Translating Tumor stage Variant Work abiraterone androgen sensitive base cancer genomics castration resistant prostate cancer clinical implementation clinically significant effective therapy enzalutamide genetic regulatory protein genomic tools hormone therapy improved male mortality new therapeutic target novel novel therapeutics patient derived xenograft model pressure prostate cancer cell receptor expression reconstruction recruit resistance mechanism response screening single molecule real time sequencing success targeted treatment therapeutic target transcription factor treatment response tumor

项目摘要

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.

项目概要/摘要前列腺癌（PC）是最常诊断的男性癌症，也是男性癌症的第二大原因死亡。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 总是以致命的去势抵抗 (CR) 表型复发，该表型对 AR 具有抵抗力靶向治疗。临床和实验证据支持当前的范式，即 AR 重新激活是一种这种耐药性的关键驱动因素，支持 CRPC 的持续增长和进展。这些知识导致抑制 CRPC 中 AR 再激活的新疗法的开发，但耐药性仍然持续存在患者的问题。这项研究的长期目标是确定可以的机制尽管有 AR 靶向治疗，但仍支持持续的 AR 转录活性，并开发新的策略治疗 CRPC 患者。推动该项目的核心发现是高频结构影响 AR 基因结构的重排，特别是在 CRPC 阶段获得的肿瘤中患者。主要的挑战是这些 AR 基因重排的多样性和异质性，无论是在患者内部和患者间的基础，这对发展机械理解构成了障碍它们的临床意义和治疗目标。提案中提供的初步数据表明不同的 AR 基因重排赋予在选择性条件下生长的 CRPC 细胞生长优势 AR 靶向疗法的压力，表明它们在以下方面发挥着核心作用，尽管人们对此知之甚少反抗。初步数据还表明，这些 AR 基因重排的共同分子结果是缺少 AR 配体结合域的截短 AR 变体的合成。这些 AR 变异物种能够通过组成型、配体独立的机制支持持久的 AR 转录活性，和抗雄激素抵抗。该项目的总体目标是了解这种新的耐药机制发生在 CRPC 阶段的肿瘤中，并确定了新的治疗靶点。到为了实现这些目标，我们将开发新的基因组学技术，以实现准确的识别和重建 CRPC 患者肿瘤中发生的重排 AR 基因结构。我们还将使用基因组工程方法来了解不同的 AR 基因重排是否具有功能性相当于推动 AR 靶向治疗的耐药性，并了解 AR 的必要性和充分性促进这种表型的变体。最后，AR 变体结合染色质的分子机制并实现组成型转录活性将被阐明，重点是支持的共同调节因子这些活动。这些协同调节因子将被评估为抑制 AR 变体活性的靶标 AR基因重排的下游。总的来说，这些研究的成功将阐明影响 CRPC 阶段肿瘤中 AR 基因的常见但尚未探索的改变类别，并确定新的改变抑制 CRPC 中 AR 再激活的分子靶点。