title: Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chan
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Sutphin
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Sandra
authors.initials: S
authors.lastname: Turcotte
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Lai
authors.forename: Alice
authors.initials: A
authors.lastname: Banh
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Reynolds
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.forename: Jason
authors.initials: J
authors.lastname: Wu
authors.forename: David E
authors.initials: DE
authors.lastname: Solow-Cordero
authors.forename: Muriel
authors.initials: M
authors.lastname: Bonnet
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.forename: Donna M
authors.initials: DM
authors.lastname: Bouley
authors.forename: Edward E
authors.initials: EE
authors.lastname: Graves
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D000255:Adenosine Triphosphate; D005947:Glucose