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：
8997483
负责人：
Daniel Edward Frigo
金额：
$ 16.98万
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/8997483
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 knock-down men mouse model new therapeutic target novel novel therapeutic intervention overexpression pre-clinical prostate cancer cell receptor standard care standard of care targeted treatment 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 ¿-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，雄激素与受体结合，激活一系列事件，导致异常的细胞生长、激素消融。不幸的是，这些疗法仅在约 1-2 年内有效，此后前列腺癌会以去势抵抗形式复发。目前尚无治愈这种晚期癌症的方法。尽管该疾病的这一阶段不受现有激素疗法的影响，但 AR 调节的途径仍然活跃，并继续促进癌症进展，因此，受体的下游过程以及其他致癌信号仍然是可行的靶点。糖酵解是癌细胞利用葡萄糖作为能量来源的一种经过充分研究的既定方式，但细胞利用谷氨酰胺代谢来平衡水平的作用尚不清楚。碳和谷氨酰胺代谢的主要调节因子是典型的癌基因 Myc，虽然 Myc 因其调节细胞周期的能力而闻名，但它也在其他癌症中被证明可以调节谷氨酰胺分解，即细胞摄取谷氨酰胺和氮的代谢过程。将其转换为 ¿我们生成的初步数据表明，AR 信号传导在一定程度上通过增加谷氨酰胺分解来促进前列腺癌。这些数据与现有的临床数据相结合，表明 AR 信号传导、Myc 和谷氨酰胺代谢可能协调驱动。因此，了解它们的关系可能会导致治疗前列腺癌的新型谷氨酰胺导向疗法。我们的长期目标是开发新的基于代谢的治疗方法来检测和治疗前列腺癌。该应用的主要目标是使用临床前模型的组合来了解 AR 信号传导和谷氨酰胺代谢之间的关系，以确定它们的交叉点是否代表可行的治疗靶点。中心假设是 AR 信号传导通过促进前列腺癌细胞生长。 Myc 介导的谷氨酰胺代谢。在目标 1 中，提出了两个具体目标，在目标 2 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。前列腺癌的小鼠模型将用于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标，根据这项研究，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，这项研究产生的数据还可以为测试谷氨酰胺类似物是否可以用作检测前列腺癌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提供动力。