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

 描述(申请人提供)：雄激素受体(AR)信号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，激活一系列事件，导致细胞异常生长。因此，激素消融疗法是治疗进展性恶性肿瘤的标准疗法。不幸的是，这些治疗方法只在1-2年内有效，之后前列腺癌以耐去势的形式再次发生。目前还没有治愈这种晚期疾病的方法。虽然疾病的这一阶段不受现有激素疗法的影响，但AR调节的通路仍然活跃，并继续促进癌症的进展。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。糖酵解是癌细胞利用葡萄糖作为能量来源的一种成熟的研究方法。相反，谷氨酰胺代谢在前列腺癌进展中的作用远不清楚。谷氨酰胺代谢被细胞用来平衡碳和氮的水平。谷氨酰胺代谢的主要调节者是典型的癌基因Myc。虽然Myc最为人所知的是它调节细胞周期的能力，但它也在其他癌症中被证明可以调节谷氨酰胺分解，在这个代谢过程中，细胞摄取谷氨酰胺并将其转化为酮戊二酸，以满足其代谢需求。我们产生的初步数据表明，AR信号促进前列腺癌，部分是通过增加谷氨酰胺分解。这些数据结合现有的临床数据表明，AR信号、Myc和谷氨酰胺代谢可能协同作用推动前列腺癌的进展。因此，了解它们之间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癌症。这项应用的主要目标是使用临床前模型的组合来了解AR信号和谷氨酰胺代谢之间的关系(S)，以确定它们的交集是否代表一个可行的治疗靶点。中心假说是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。为了验证这一假设，本文提出了两个具体目标。在目标1中，将使用细胞检测的组合来确定AR和Myc在体外谷氨酰胺代谢中的作用。在目标2中，完整和去势的前列腺癌小鼠模型将被用来测试调节谷氨酰胺代谢的AR和Myc信号的特定方面是否可以代表体内的新治疗靶点。根据这项研究，靶向谷氨酰胺转运体有望成为对抗前列腺癌的一种新方法。此外，这项研究产生的数据还可以提供动力，以测试谷氨酰胺类似物是否可以用作前列腺癌的示踪剂，以及谷氨酰胺转运体的表达水平是否也可以用作预后标记。

 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.