Identifying new targeted
therapies that kill
tumor cells while sparing normal tissue is a major challenge of
cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of
renal cell carcinomas (RCCs). RCCs, like many other
cancers, are dependent on aerobic glycolysis for
ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of
glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by
STF-31, which selectively kills RCCs by specifically targeting
glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding
glucose uptake in vivo without toxicity to normal tissue. Activity of
STF-31 in these experimental renal
tumors can be monitored by [(18)F]fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human
tumors. Our results show that the Warburg effect confers distinct characteristics on
tumor cells that can be selectively targeted for
therapy.