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Androgen Receptor- and Myc-Mediated Glutamine Metabolism in Prostate Cancer

前列腺癌中雄激素受体和 Myc 介导的谷氨酰胺代谢

基本信息

批准号：
8809478
负责人：
Daniel Edward Frigo
金额：
$ 20.25万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8809478
关键词：
Ablation Address Androgen Receptor Androgens Binding Biological Markers Cancer Cell Growth Cancer Etiology Carbon Castration Cell Cycle Cell Survival Cell physiology Cells Cellular Assay Cessation of life Citric Acid Cycle Clinical Clinical Data Data Detection Diagnosis Disease Energy-Generating Resources Equilibrium Event Glucose Glutamine Glycolysis Goals Health Hormones In Vitro Lead Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolic Metabolism Methods Molecular Nitrogen Nutrient Oncogenes Oncogenic Outcome Pathway interactions Pre-Clinical Model Process Prognostic Marker Receptor Signaling Research Resistance Role Sampling Second Primary Neoplasms Signal Transduction Staging Testing Therapeutic Therapeutic Intervention Tracer Xenograft procedure alpha ketoglutarate base cancer cell cancer therapy cell growth combat glutamine analog hormone therapy in vitro Assay in vivo in vivo Model men mouse model new therapeutic target novel novel therapeutics overexpression pre-clinical prostate cancer cell receptor standard care standard of care therapeutic target tumor progression tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): Androgen receptor (AR) signaling is an essential factor for the progression of prostate cancer. In prostate cancer, androgens bind to the receptor to activate a cascade of events that lead to aberrant cell growth. Consequently, hormone ablation therapies are the standard of care for progressive malignancies. Unfortunately, these treatments are only effective for a ~1-2 year period after which prostate cancer reoccurs in the castration-resistant form. There is currently no cure for this advanced stage of the disease. Although this stage of the disease is unaffected by existing hormone therapies, AR-regulated pathways are still active and continue to promote cancer progression. Thus, the processes downstream of the receptor, together with other oncogenic signals, remain viable targets for therapeutic intervention. Glycolysis is a well-studied, established way that cancer cells use glucose as an energy source. Conversely, the role of glutamine metabolism in prostate cancer progression is far less clear. Glutamine metabolism is utilized by the cell to balance of the level of carbon and nitrogen. A master regulator of glutamine metabolism is the canonical oncogene Myc. While Myc is best known for its ability to regulate the cell cycle, it has also been demonstrated in other cancers to regulate glutaminolysis, a metabolic process in which the cell uptakes glutamine and converts it into α-ketoglutarate and beyond to satisfy its metabolic needs. Preliminary data we have generated indicate that AR signaling promotes prostate cancer, in part, through increasing glutaminolysis. These data combined with existing clinical data suggest AR signaling, Myc, and glutamine metabolism may coordinate to drive prostate cancer progression. As such, understanding their relationship could lead to novel glutamine-directed therapeutics for the treatment of prostate cancer. Our long-term goal is to develop new metabolic-based therapeutic approaches for the detection and treatment of cancer. The primary goal of this application is to use a combination of preclinical models to understand the relationship(s) between AR signaling and glutamine metabolism to determine whether their intersection represents a viable therapeutic target. The central hypothesis is that AR signaling promotes prostate cancer cell growth through Myc-mediated glutamine metabolism. To test this hypothesis, two specific aims are proposed. In Aim 1, a combination of cellular assays will be used to define the roles of AR and Myc in glutamine metabolism in vitro. In Aim 2, intact and castrate mouse models of prostate cancer will be used to test whether specific aspects of AR and Myc signaling that regulate glutamine metabolism could represent novel therapeutic targets in vivo. From this research it is expected that targeting glutamine transporters will emerge as a novel way to combat prostate cancer. Further, data generated from this research could also provide the impetus to test whether glutamine analogs could be used as tracers for the detection of prostate cancer and if glutamine transporter expression levels may also have utility as prognostic markers.

描述（由申请人提供）：雄激素受体（AR）信号传导是前列腺癌进展的重要因素。在前列腺癌中，雄激素与受体结合，激活一系列导致细胞异常生长的事件。因此，激素消融治疗是进行性恶性肿瘤的标准治疗。不幸的是，这些治疗仅在约1-2年的时间内有效，之后前列腺癌以去势抵抗形式复发。目前还没有治愈这种晚期疾病的方法。虽然这个阶段的疾病不受现有激素治疗的影响，但AR调节的途径仍然活跃，并继续促进癌症进展。因此，受体下游的过程与其他致癌信号一起仍然是治疗干预的可行靶点。糖酵解是一种经过充分研究的、确定的癌细胞利用葡萄糖作为能量来源的方式。相反，谷氨酰胺代谢在前列腺癌进展中的作用远不清楚。细胞利用谷氨酰胺代谢来平衡碳和氮的水平。谷氨酰胺代谢的主要调节因子是典型的癌基因Myc。虽然Myc以其调节细胞周期的能力而闻名，但它也已在其他癌症中被证明可以调节谷氨酰胺分解，这是一种代谢过程，其中细胞摄取谷氨酰胺并将其转化为α-酮戊二酸及其他物质以满足其代谢需求。我们已经产生的初步数据表明，AR信号促进前列腺癌，部分是通过增加多巴胺的分解。这些数据结合现有的临床数据表明，AR信号传导、Myc和谷氨酰胺代谢可能协调驱动前列腺癌进展。因此，了解它们的关系可能会导致新的谷氨酰胺导向治疗前列腺癌的治疗。我们的长期目标是开发新的基于代谢的治疗方法，用于癌症的检测和治疗。本申请的主要目标是使用临床前模型的组合来理解AR信号传导和谷氨酰胺代谢之间的关系，以确定它们的交叉是否代表可行的治疗靶点。核心假设是AR信号通过Myc介导的谷氨酰胺代谢促进前列腺癌细胞生长。为了检验这一假设，提出了两个具体目标。在目的1中，将使用细胞测定的组合来确定AR和Myc在体外谷氨酰胺代谢中的作用。在目标2中，将使用前列腺癌的完整和去势小鼠模型来测试调节谷氨酰胺代谢的AR和Myc信号传导的特定方面是否可以代表体内新的治疗靶点。从这项研究中，预计靶向谷氨酰胺转运蛋白将成为对抗前列腺癌的新方法。此外，从这项研究中产生的数据也可以提供动力来测试谷氨酰胺类似物是否可以用作前列腺癌检测的示踪剂，以及谷氨酰胺转运蛋白表达水平是否也可以用作预后标志物。