STF-31 represents the second class of small molecules that we have identified that selectively kill RCCs (6
). This class of drug has a distinct mechanism of killing than the previously described STF-62247. Whereas STF-62247 selectively induces autophagic cell death in a HIF-independent manner, the 3-series class acts by disrupting glucose uptake and utilization. The GLUT1-selective cytotoxicity induced by these drugs provides direct evidence that many cancer cell types are dependent on glycolysis, including most of RCCs (24
). RCCs are selectively sensitive to STF-31 because aberrant HIF stabilization (either HIF-1 or HIF-2) results in diminished mitochondrial activity, causing these cells to become highly dependent on glucose uptake for glycolysis and ATP production (). By inhibiting glucose uptake, STF-31 specifically targets the Achilles’ heel of RCCs. Normal kidney cells are not strictly dependent on glycolysis or GLUT1 for viability and use other glucose transporters, such as GLUT2, and are therefore insensitive to STF-31 toxicity. Our findings indicate that the differential metabolism of cancer cells can be exploited for the preferential targeting of these cells by small molecules.
Fig. 6 STF-31 is synthetically lethal to cells dependent on GLUT1 for aerobic glycolysis. VHL regulates both HIF-1 and HIF-2, which can increase GLUT1 expression. HIF-1 also inhibits the mitochondria, causing cells to switch to aerobic glycolysis. STF-31 compounds (more ...)
Our results have a number of implications for the development of new cancer therapeutics. First, this method of screening for compounds that are synthetically lethal to the loss of VHL should be adaptable to other tumor types with distinct genotypes, such as the loss of function of tumor suppressor genes or gain of function of oncogenes. Second, the selective cytotoxicity of STF-31 is not restricted to VHL-deficient tumors. We initially sought to identify small molecules directly synthetically lethal to VHL mutation. However, subsequent experiments illustrate that STF-31 is generally synthetically lethal to cancer cells that have high GLUT1 levels and require glycolysis. It is likely that a number of other cancer types have additional genetic or epigenetic alterations that make them highly dependent on aerobic glycolysis for energy production and therefore sensitive to STF-31.
Note also that targeting GLUT1 in human renal cell cancers should be feasible because Glut1
heterozygous knockout mice are viable and recapitulate the human GLUT1 deficiency syndrome, which is effectively treated by a ketogenic diet (25
). We did not observe any toxicity in normal tissue, including brain, in these studies. Finally, our data show that the effectiveness of the 3-series compounds can be monitored by in vivo imaging. This property offers the potential advantages of enabling dosage optimization and identification of which kidney cancers will respond best to treatment in phase I clinical trials. Diagnosing and predicting the response of RCC by FDG-PET imaging will be aided by simultaneous computed tomography (CT), which is useful in evaluating responses to receptor tyrosine kinase inhibition (27
). Furthermore, FDG-PET imaging of RCC will likely benefit patients with high-grade tumors or tumors that have metastasized beyond the kidney. Being able to track the response of a particular tumor is both cost-effective and lends itself to personalized medicine, which are two of the primary objectives of future cancer therapies.