Abstract 3375: Targeting glucose metabolism by 2-deoxyglucose in gastrointestinal stromal tumors

Abstract

Abstract Introduction Most patients with gastrointestinal stromal tumors (GIST) respond to imatinib (IM) but eventually progress with then limited therapeutic options. Fluorodeoxyglucose (FDG) is used for visualizing tumors by positron emission tomography (PET) and has been particularly helpful for predicting tumor response in highly FDG-avid GIST. 2-deoxy-glucose (2DG) inhibits glucose metabolism in cancer cells, which depend exclusively on aerobe glycolysis for ATP production (Warburg Effect). 2DG is currently investigated in several clinical trials. Here we evaluated the therapeutic potential of 2DG in GIST in vitro and in vivo. Methods Two IM-sensitive (IM-S; GIST-T1, GIST882) and 3 IM-resistant (IM-R; GIST430, GIST48, GIST48B) cell lines were studied. Cell viability was evaluated by Sulforhodamin B (SRB) assay after 6 days of 2DG treatment and combinations with IM and ABT-263, a BH3-mimetic. Immunoblotting was done for KIT- and KIT-downstream signaling and markers of apoptosis. For in vivo experiments nude mice bearing GIST-T1 xenografts were treated for 21 days with 500mg/kg/d 2DG or vehicle control. Results Cell viability assays in KIT-expressing cell lines displayed IC50 values for 2DG between 0.5mM (GIST882) and 2.5mM (GIST48), while KIT-negative GIST48B was less sensitive (6mM). Notably, treating GIST-T1 in low-glucose media (1g/L, LG) reduced IC50 (1.1mM to 0.33mM) in a glucose dependent manner. Immunoblot studies revealed a dose- and glucose dependent inhibition of KIT glycosylation by 2DG with complete inhibition at 1mM in LG, which coincided with inhibition of KIT-phosphorylation and KIT-downstream signaling. The combination of 2DG with IM had additive antiproliferative effects in IM-S cell lines. In IM-R GIST430 a synergistic induction of apoptosis could be observed when combining KIT-inhibiting concentrations of 2DG with ABT-263 1µM. Treatment of mice with 2DG alone did not affect tumor growth. At this dose 2DG dependent inhibition of KIT-glycosylation or -phosphorylation was not observed. Conclusions 2DG shows promising GIST-specific antiproliferative effects by inhibiting KIT-glycosylation and -phosphorylation in vitro. These effects were additive when combined with imatinib. Further studies will investigate alternate treatment schedules as well as drug combinations with the aim of translating 2DG into a clinical trial in GIST. Citation Format: Thomas Mühlenberg, Susanne Grunewald, Martin Schuler, Sebastian Bauer. Targeting glucose metabolism by 2-deoxyglucose in gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2014-3375