Therapeutic Efficacy of Riluzole in Prostate Cancer

利鲁唑治疗前列腺癌的疗效

基本信息

批准号：
8889227
负责人：
SHAHRIAR KOOCHEKPOUR
金额：
$ 22.16万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-08 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889227
关键词：
Affect Amyotrophic Lateral Sclerosis Anabolism Androgen Receptor Androgens Apoptosis Apoptotic Benign Biological Assay Cancer Cell Growth Cancer Patient Cell Death Cell Line Cells Cholesterol Homeostasis Cleaved cell Clinical Clinical Trials DU145 Data Development Diet Disease Enzymes Epilepsy Event FDA approved Fatty Acids Fatty acid glycerol esters Fatty-acid synthase GRM1 gene Gland Gleason Grade for Prostate Cancer Glucose Glutamate Metabolism Pathway Glutamate Receptor Glutamates Glutamine Glycolysis Growth Health Image Analysis In Vitro Investigation LNCaP Life Link Luc Gene Malignant neoplasm of prostate Measures Mediating Mental Depression Metabolic Metabolic Pathway Metastatic Prostate Cancer Methods Modeling Molecular Mus Neoplasm Metastasis Oral Medicine PC3 cell line Pathway interactions Patients Pharmaceutical Preparations Primary Lateral Sclerosis Primary Neoplasm Prostate-Specific Antigen Receptor Signaling Reporting Research Subjects Resistance Retrospective Studies Riluzole Role Series Serum Signal Pathway Staging TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Agents Therapeutic Intervention Tissue Harvesting Tissues Treatment Efficacy Tumor Tissue VCaP Xenograft Model Xenograft procedure addiction aerobic glycolysis antitumor effect base bioluminescence imaging cancer cell caspase-3 cell growth cholesterol absorption clinically relevant deprivation in vivo inhibitor/antagonist insight lipid biosynthesis men migration nervous system disorder novel novel therapeutics overexpression pre-clinical prostate cancer cell prostate cancer cell line prostate carcinogenesis receptor receptor expression subcutaneous targeted treatment therapeutic target tumor growth tumor xenograft tumorigenesis

项目摘要

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.

描述（由申请人提供）：有氧糖酵解和谷氨酰胺分解是癌细胞的主要标志。在糖酵解和谷氨酰胺溶解过程中，葡萄糖分别转化为乳酸和谷氨酰胺为谷氨酸。除了其作为重要的生物合成前体的作用外，谷氨酸代谢与脂肪生成和雄激素生物合成途径密切相关。抑制AR及其信号通路仍然是雄激素刺激（AS）和耐Castrate前列腺癌（CRPCA）的关键治疗靶标。由于关键酶过表达，脂肪酸合酶（FAS）的过表达，在功能和代谢上与谷氨酸和糖酵解途径相关的PCA细胞的标志之一是从头脂肪酸合成的增加。为了评估谷氨酸的临床相关性，我们测量了正常男性（n = 60）的血清谷氨酸水平和原发性PCA（n = 197）或转移性-CRPCA（n = 109）的患者。与格里森评分D 7相比，我们最近报道了格里森评分E 8的血清谷氨酸水平明显更高，这与PCA的临床攻击性有关。我们还发现，谷氨酸受体GRM1在原发性和转移性PCA组织中过表达。雄激素非依赖性或CRPCA细胞系中的GRM1受体表达（例如PC-3，DU-145，VCAP）也高于AS-LNCAP或原代PCA细胞系E006AA中的GRM1受体。 Riluzole是一种耐受性良好的FDA批准的口腔药物，用于治疗乳腺发性侧面硬化症（ALS），在几项活跃的抑郁症，癫痫和其他良性神经系统疾病的活跃临床试验中，已被证明是GRM1的有效药理抑制剂。 Riluzole降低了AS和CRPCA细胞系中的增殖，迁移和侵袭，并诱导的凋亡。我们最近的数据表明，riluzole降低了PCA细胞中的FAS表达。基于Riluzole的抗肿瘤活性，我们假设Riluzole是PCA的新型治疗剂。为了检验我们的假设，我们将研究：（目标1）riluzole对（i）皮下castrate耐药性（CR）进展模型和（ii）正常反应性异种移植模型的自发转移能力的影响。（AIM 2）确定Riluzole对原发性和转移性肿瘤中FAS表达和凋亡标记的影响。在此目标中，我们将能够通过检查riluzole处理与Fas表达与脂肪酸含量在肿瘤异种移植物中的关联来验证我们的体外数据。此外，我们将研究riluzole下调PCA细胞中FAS表达的潜在机制。这些临床前探索性研究应验证我们的体外数据，并验证Riluzole和抗GRM1靶向疗法的治疗功效，从而在PCA患者中使用GRM1阻断剂进行临床试验的发展。