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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：
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.