TAS::75 0849::TAS TOPIC 255 SELECTIVE AND POTENT INHIBITORS OF TUMOR SPECIFIC GL

TAS::75 0849::TAS 主题 255 肿瘤特异性 GL 的选择性和有效抑制剂

• 批准号: 8351294
• 负责人: PAUL PEARSON
• 金额: $ 18.31万
• 依托单位: RUGA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8351294
• 关键词: Address; Animals; Binding; Cancer Model; Cancer cell line; Chemicals; Clinical; Contracts; Data; Dependence; Dependency; Disease; Dose; Energy Metabolism; Entire transverse folds of palate; Glucose Transporter; Glycolysis; Goals; Growth; Hexose Transporter; Imaging Device; In Vitro; Kinetics; Label; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Metabolism; Modeling; Monitor; Neoplasm Metastasis; Oocytes; Ovarian; Phase; Positron-Emission Tomography; Process; Protein Isoforms; Radio; Renal Cell Carcinoma; SLC2A1 gene; Scanning; Screening procedure; Series; Small Business Innovation Research Grant; System; Testing; Time; Xenograft Model; Xenograft procedure; analog; base; cancer cell; cell type; cytotoxicity; glucose analog; glucose uptake; in vivo; inhibitor/antagonist; killings; member; novel; novel therapeutics; ovarian neoplasm; subcutaneous; tumor; tumor growth; tumor progression; uptake

Previously, we employed a novel, chemical synthetiC lethal screening approach in VHL-deficient renal cell carcinoma (RCC VHL-) to identify inhibitors of GLUT1, a glucose transporter critical for RCC energy metabolism and survival. Our lead molecules, defined as 3-Series, bind to GLUT1 and demonstrate in vitro and in vivo, dose-dependent cytotoxicity and inhibition of glucose uptake in RCC VHL-, but not in genetically matched wild-type cells. In addition, the inhibition of glucose uptake in tumors can be directly monitored in vivo by FDG-PET, a clinical imaging tool. We have also observed potent cytotoxicity and glucose uptake inhibition in multiple ovarian cancer cell lines that are VHL negative. In this proposal, we will test 3-Series for inhibition of glucose uptake, tumor growth and metastases in xenograft ovarian tumors in order to verify that sensitivity in ovarian tumors is also dependent upon glucose uptake inhibition. We will also analyze 3-Series GLUT1 binding kinetics. Our data support an emerging model of dependence on glycolysis in many cancer cell types. Our goal is to demonstrate that a novel therapeutic strategy based on targeted disruption of tumor metabolism is efficacious in at least two cancers, renal cell carcinoma and ovarian, that lack effective, curative therapies today.

此前，我们在 VHL 缺陷肾细胞中采用了一种新颖的化学合成致死筛选方法 癌症 (RCC VHL-) 鉴定 GLUT1 的抑制剂，GLUT1 是一种对 RCC 能量至关重要的葡萄糖转运蛋白 新陈代谢和生存。我们的先导分子（定义为 3 系列）与 GLUT1 结合并在体外得到证明 在 RCC VHL 中，体内具有剂量依赖性细胞毒性和葡萄糖摄取抑制作用，但在遗传方面则不然 匹配的野生型细胞。此外，可以直接监测肿瘤中葡萄糖摄取的抑制情况 vivo 通过 FDG-PET（一种临床成像工具）进行检测。我们还观察到有效的细胞毒性和葡萄糖摄取 对 VHL 阴性的多种卵巢癌细胞系有抑制作用。在此提案中，我们将测试 3 系列 抑制异种移植卵巢肿瘤中的葡萄糖摄取、肿瘤生长和转移，以验证 卵巢肿瘤的敏感性还取决于葡萄糖摄取抑制。我们还将分析 3 系列 GLUT1 结合动力学。我们的数据支持许多癌症依赖糖酵解的新兴模型 细胞类型。我们的目标是证明一种基于肿瘤靶向破坏的新型治疗策略 代谢对至少两种癌症有效，即肾细胞癌和卵巢癌，而这两种癌症缺乏有效的、 今天的治疗方法。