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.

项目摘要/摘要前列腺癌（PC）是最常见的男性癌症，是男性癌症的第二大原因死亡。抑制雄激素受体（AR）的活性是复发或转移PC。 PC始终以耐致命的can割（CR）表型复发，该表型具有对AR-的抗性靶向疗法。临床和实验证据支持当前AR重新激活的范式这种抗药性的主要驱动力，支持CRPC的持续增长和发展。这些知识领导了开发抑制CRPC中AR重新激活的新疗法，但阻力仍然是持久的患者的问题。这项研究的长期目标是确定可以的机制尽管接受了AR靶向疗法，但仍支持持续的AR转录活动，并制定新的策略治疗CRPC患者。驱动该项目的中心发现是结构性的高频影响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患者内部和患者间的基础，这为建立机械理解的障碍带来了障碍它们的临床意义和治疗靶向。提案中提供的初步数据表明多种AR基因重排具有选择性下生长的CRPC细胞的生长优势靶向AR靶向疗法的压力，表明它们在中心，尽管理解不佳，但在反抗。初步数据还表明，这些AR基因重排的常见分子结果是缺乏AR配体结合结构域的截短的AR变体的合成。这些AR变体物种能够通过构成，配体独立的机制来支持持续的AR转录活性，和抗杀菌性。该项目的总体目标是了解一般性这种新的抗性机制发生在CRPC阶段肿瘤中，并确定新的治疗靶标。到实现这些目标，我们将开发新的基因组技术，以实现准确的识别和在CRPC患者的肿瘤中重建的AR基因结构的重建。我们也会使用基因组工程方法来了解各种AR基因重排在功能上是否是功能等效地推动对AR靶向疗法的抗药性，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将阐明实现本构的转录活性，重点是支持的共同调节器这些活动。这些共同调节器将作为抑制AR变体活性的目标评估 AR基因重排的下游。总体而言，这些研究的成功将阐明频繁但未开发的改变类别影响CRPC肿瘤中AR基因的变化类别，并确定新的分子靶标抑制CRPC中AR重新激活。