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

在此之前，我们采用了一种新的化学合成致死筛选方法，在VHL缺陷的肾细胞中， GLUT 1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GLUT 1结合，并在体外证明 在体内，剂量依赖性细胞毒性和抑制RCC VHL-葡萄糖摄取，但在遗传上没有。 匹配的野生型细胞。此外，肿瘤中葡萄糖摄取的抑制可以直接监测， FDG-PET是一种临床成像工具。我们还观察到了有效的细胞毒性和葡萄糖摄取 在VHL阴性的多种卵巢癌细胞系中的抑制。在本提案中，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， 卵巢肿瘤的敏感性也依赖于葡萄糖摄取抑制。我们还将分析3系列 GLUT 1结合动力学。我们的数据支持一个新兴的模型，依赖糖酵解在许多癌症 细胞类型。我们的目标是证明一种基于靶向破坏肿瘤的新治疗策略， 代谢在至少两种癌症中是有效的，肾细胞癌和卵巢癌，它们缺乏有效的， 今天的治疗方法

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.