Abstract 67: Selective cytotoxic targeting of von Hippel-Lindau-deficient renal cell carcinoma cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Loss of the von Hippel-Lindau (VHL) tumor suppressor gene, an essential alteration in the development of renal cancer, can be targeted through a synthetic lethal manner. In our screen we identified a compound, STF-31536, which is selectively cytotoxic toward VHL-deficient renal cancer cells in a HIF-dependent manner. This compound did not induce apoptosis and inhibits glucose transport. These findings are significant since we have previously shown another compound STF-62247 was cytotoxic toward VHL-deficient cells and induced autophagy in a HIF-independent manner. We have also shown that STF-31536 induces cell death in vitro and in vivo, however the mechanism and target of this compound is currently unknown. In order to identify the target of STF-31536, we have coupled analogs of STF-31536 to an affinity resin. Activity of these analogs was confirmed by cytotoxicity assays. Selected affinity chromatography reagents coupled to resin were used for binding assays to determine direct drug-target interactions. The potential targets were purified and identified by gel electrophoresis after collecting fractions from the column. Renal cell carcinoma cells deficient in VHL are characterized by elevated expression of VEGF and glucose transporter 1 (Glut-1). Immunoblots for Glut-1 transporter in protein fractions eluted from the column show binding of STF-31536 to Glut-1. Therefore, we show loss of the von Hippel-Lindau (VHL) tumor suppressor gene can be targeted by this small molecule through a synthetic lethal manner by disrupting glucose transport. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 67.