Therapeutic Efficacy of Riluzole in Prostate Cancer

描述（由申请人提供）：有氧糖酵解和氨解是癌细胞的主要标志。在糖酵解和谷氨酸解过程中，葡萄糖分别转化为乳酸盐，谷氨酰胺转化为谷氨酸盐。除了其作为重要的生物合成前体的作用之外，谷氨酸代谢与脂肪生成和雄激素生物合成途径密切相关。AR及其信号通路的抑制仍然是雄激素刺激（AS）和去势抵抗性前列腺癌（CRPCa）的关键治疗靶点。在功能上和代谢上与谷氨酸和糖酵解途径相关的PCa细胞的标志之一是由于关键酶脂肪酸合成酶（FAS）的过表达而增加的从头脂肪酸合成。 为了评估谷氨酸的临床相关性，我们测量了正常男性（n=60）和原发性PCa（n=197）或转移性CRPCa（n=109）患者的血清谷氨酸水平。我们最近报道了与Gleason评分d 7相比，Gleason评分e 8的血清谷氨酸水平显著更高，这与PCa的临床侵袭性相关。我们还发现谷氨酸受体GRM 1在原发性和转移性PCa组织中过表达。GRM 1受体在雄激素非依赖性或CRPCa细胞系（例如，PC-3、DU-145、VCaP）的表达也高于AS-LNCaP或原代PCa细胞系E006 AA。 阿曲唑是一种耐受性良好的FDA批准的口服药物，用于治疗肌萎缩侧索硬化症（ALS），并在几项积极的临床试验中用于抑郁症，癫痫和其他良性神经系统疾病，已被证明是GRM 1的有效药理学抑制剂。阿曲唑降低AS和CRPCa细胞系的增殖、迁移和侵袭，并诱导细胞凋亡。我们最近的数据表明，阿曲唑降低PCa细胞中FAS的表达。基于阿曲唑的抗肿瘤活性，我们假设阿曲唑可作为PCa的新型治疗剂。 为了检验我们的假设，我们将研究：（目的1）阿曲唑对（i）皮下去势抵抗（CR）进展模型中肿瘤生长和（ii）原位异种移植模型自发转移能力的影响。(Aim 2）确定阿曲唑对原发性和转移性肿瘤中FAS表达和凋亡标志物的影响。在这个目标中，我们将能够通过检查阿曲唑治疗与肿瘤异种移植物中FAS表达和脂肪酸含量之间的关联来验证我们的体外数据。此外，我们将研究潜在的机制，其中阿曲唑下调FAS在PCa细胞的表达。 这些临床前探索性研究应该验证我们的体外数据，并验证阿曲唑和抗GRM 1靶向治疗的疗效，从而开发在PCa患者中使用GRM 1阻断剂的临床试验。

DESCRIPTION (provided by applicant): Aerobic glycolysis and glutaminolysis are the major hallmarks of cancer cells. During glycolysis and glutaminolysis, glucose is converted to lactate and glutamine to glutamate, respectively. Other than its role as a significant biosynthetic precursor, glutamate metabolism is intimately linked to lipogenesis and androgen biosynthetic pathways. Inhibition of the AR and its signaling pathways remain a key therapeutic target for both androgen-stimulated (AS) and castrate-resistant prostate cancer (CRPCa). One of the hallmarks of PCa cells which are functionally and metabolically linked to glutamate and glycolytic pathways is an increased de novo fatty acid synthesis due to overexpression of the key enzyme, fatty acid synthase (FAS). To assess the clinical relevance of glutamate, we measured serum glutamate levels in normal men (n=60) and patients with primary PCa (n=197) or metastatic-CRPCa (n=109). We recently reported significantly higher serum glutamate levels in Gleason score e 8 compared to Gleason score d 7 which is associated with clinical aggressiveness of PCa. We also found that glutamate receptor GRM1 is overexpressed in primary and metastatic PCa tissues. GRM1 receptor expression in androgen-independent or CRPCa cell lines (e.g., PC-3, DU-145, VCaP) was also higher than in the AS-LNCaP or primary PCa cell line, E006AA. Riluzole, a well-tolerated FDA-approved oral medicine for the treatment amyotropic lateral sclerosis (ALS) and in several active clinical trials for depression, epilepsy, and other benign neurological diseases, has been shown to be a potent pharmacological inhibitor of GRM1. Riluzole decreased proliferation, migration, and invasion and induced apoptosis in both AS and CRPCa cell lines. Our most recent data demonstrated that Riluzole decreases FAS expression in PCa cells. Based on antitumor activities of Riluzole, we hypothesize that Riluzole serves as a novel therapeutic agent for PCa. To test our hypothesis, we will investigate: (Aim 1) The effect of Riluzole on (i) tumor growth in a subcutaneous castrate-resistant (CR) progression model and (ii) spontaneous metastatic ability of an orthotopic xenograft model. (Aim 2) Determine the effect of Riluzole on FAS expression and apoptotic markers in primary and metastatic tumors. In this Aim, we will be able to verify our in vitro data by examining the association between Riluzole treatment and FAS expression and fatty acid content in tumor xenografts. In addition, we will investigate the underlying mechanisms by which Riluzole downregulates FAS expression in PCa cells. These preclinical exploratory studies should verify our in vitro data and validate therapeutic efficacy of Riluzole and anti-GRM1 targeted therapy leading to the development of clinical trials using GRM1-blocking agents in PCa patients.