AR Gene Rearrangements and AR Signaling in Prostate Cancer

前列腺癌中的 AR 基因重排和 AR 信号转导

基本信息

批准号：
10656833
负责人：
Scott M. Dehm
金额：
$ 40.31万
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 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656833
关键词：
AR gene Acceleration Acetates Address Affinity Androgen Receptor Androgen Suppression Androgens Architecture Binding Biological Biological Markers Cancer Patient Cells Cessation of life Complex Computing Methodologies DNA sequencing Data Diagnosis Disease Endocrine Exons Failure Feedback Frequencies Future Gene Rearrangement Generations Genetic Transcription Genetically Engineered Mouse Genome Genome Mappings Genotype Goals Gonadotropin-Releasing Hormone Analog Growth Heterogeneity Homeostasis In Vitro Knock-out Knowledge Length Ligand Binding Domain Malignant Neoplasms Malignant neoplasm of prostate Medicine Metastatic Prostate Cancer Modeling Molecular Molecular Target Mus Nobel Prize Operative Surgical Procedures Optics Outcome Output PI3K/AKT PTEN gene Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Physiology Production Proliferating Prostate Prostate Cancer therapy Protein Analysis Quality of life Radiation therapy Receptor Signaling Recurrence Recurrent tumor Regulation Repression Resistance Role Specimen Stanolone Structure Techniques Testing Testosterone Therapeutic Tissues Tumor Suppressor Genes Variant Whole Organism Work abiraterone antagonist anticancer research castration resistant prostate cancer clinically relevant combat curative treatments enzalutamide hormone therapy improved in vivo male mortality mouse model neoplastic cell new therapeutic target novel therapeutics patient derived xenograft model pressure programs prostate cancer cell prostate cancer model prostate cancer progression protein function receptor expression resistance mechanism response screening standard of care steroid hormone targeted treatment therapeutic development therapy resistant transcription factor transcriptome sequencing tumor

项目摘要

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.

项目摘要/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全身内分泌疗法的局部PC治疗是高级或转移PC。内分泌疗法的分子靶标是雄激素受体（AR），它是转录因子被类固醇激素睾丸激素和二氢睾丸激素激活。因为PC单元需要AR的增殖和存活，抑制睾丸激素的产生（促性腺激素释放激素类似物和/或乙酸酯），并使用竞争性的AR拮抗剂阻止睾丸激素作用（例如 enzalutamide，apalutamide和darolutamide）是内分泌疗法的基石。很遗憾，内分泌疗法不能治愈，这种疾病将不可避免地发展为抗cast割PC （CRPC）。 CRPC是一个致命的疾病阶段，不存在治疗疗法。我们对肿瘤的分析来自患者的标本表明，CRPC中发生的最常见改变之一是结构性 AR基因的重排。我们的初步数据表明，AR基因重排使AR脱离内分泌调节的转录因子以及从负面反馈调节中发生的转录因子像PTEN这样的肿瘤抑制基因丢失。这种解偶联使AR活动对内分泌不敏感治疗和促进CRPC。该项目的长期目标是利用基因重排为生物标志物可以更有效地使用当前和未来的CRPC疗法，并开发新颖可以克服AR基因重排的影响的治疗剂。为了实现这些目标，我们将开发新的CRPC进展的鼠标模型，该模型具有AR基因重排和PTEN损失，并且使用这些模型来识别AR基因重排的机制促进PC的进展和治疗性抗性。这些模型将填补现场长期存在的空隙：缺乏反映的鼠标模型临床上的AR改变。我们将测试这些模型的实用性，以推进CRPC研究评估CRPC在全生物背景下对AR靶向治疗剂的反应。我们还将使用第三产生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进行重排。预计这项工作将提供有关 CRPC中AR基因重排的最常见和复杂模式的作用和起源。最后，将使用一组携带AR基因重排的CRPC模型的治疗漏洞使用一组候选AR靶向治疗。我们还将使用计算方法提名非目标将在具有AR基因重排的CRPC肿瘤中具有功效的治疗剂。总的来说，这项工作预计将增强对CRPC进展中AR基因重排的理解，并产生新的模型，生物标志物和治疗剂可用于对抗这种致命的疾病子集。