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.
