METB-08: INHIBITION OF HEXOKINASE 2 USING TUMOR GLYCOLYSIS INHIBITORS IDENTIFIED THROUGH A DRUG SCREEN INHIBITS GLIOBLASTOMA GROWTH IN VITRO AND IN VIVO

Current research in cancer has demonstrated that normal and cancer cells use glucose differently. Normal cells will use glycolysis and oxidative phosphorylation to generate ATP, whereas proliferating tumor cells have additional demands including biomass generation and harbor glycolysis rates up to 200 times higher than normal cells. To generate biomass, proliferating tumor cells preferentially use the Warburg effect or aerobic glycolysis and in the process consume less oxygen and produce large amounts of lactate. Our ongoing work has demonstrated that hexokinase 2 (HK2) but not HK1 or HK3 is a critical mediator of the Warburg effect in glioblastomas (GB). Currently, no direct inhibitor of HK2 exists. By using a systems biology approach and a rationale drug screen we identified several azole antifungal agents as inhibitors of tumor metabolism that reduce proliferation, lactate production, glucose uptake in GB cells but not in primary normal human astrocytes or normal neural stem cells. Dynamic metabolic flux analysis with 13C-labeling experiments followed by liquid chromatography-mass spectrometry (LC-MS) demonstrated that GB cell lines and GB glioma stem cell cultures treated with several azoles reduced some pro-anabolic glycolytic intermediates. Loss of HK2 in GB cells dampened the effect of several azoles suggesting that the mechanism of action is mediated in part through HK2. Furthermore, we tested several azole compounds known to cross the blood brain barrier in vivo. Clinically achievable doses of azoles as single agents increased survival in several orthotopic xenograft GB mouse models. Current studies are underway to determine the oncogenic molecular pathways inhibited by these drug compounds and whether azole treatment with the current standard of care (temozolomide and radiation) has a synergistic effect in vivo. In summary, the azole class of antifungals may represent a new way of targeting tumor metabolism in tumors dependent on aerobic glycolysis.