Abstract 2898: Inhibition of heat shock protein 90 through HSP990 causes cell cycle arrest, growth inhibition, and apoptosis in glioblastoma tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Heat shock protein (HSP) 90 is a molecular chaperone that modulates stability of several client proteins, many of which are key regulators of signaling pathways in glioblastoma multiforme (GBM). The potential for simultaneously targeting multiple effectors makes HSP90 an appealing therapeutic target. Here, we evaluated the biological activity of HSP990, a novel HSP90 inhibitor (Novartis Pharma AG) in a panel of adult glioma primary xenograft lines (n=15). HSP990 treatment resulted in a dose-dependent growth inhibition with IC50 values in the low nM range in each of the primary lines. HSP990 caused G2/M cell cycle arrest and apoptosis-induction within 72 hours of treatment. In addition, treatment with HSP990 resulted in up-regulation of HSP70, and decrease in activity of client proteins AKT, CDC2, CDC25C and activation of caspase 8 and 3, in tested cell lines. A range of sensitivity based on EGFR status was observed. EGFR-amplified cells showed depletion of client proteins and growth inhibition at lower dose of HSP990 (10nM) than wildtype EGFR cells (30nM). Furthermore, neurosphere formation assays revealed that HSP990 was effective against the growth of glioblastoma stem cells (GSCs) in 6 tested glioblastoma xenograft lines (IC50 less than 10nM).These results suggest that that both cell cycle effects and induction of apoptosis are mechanisms governing HSP990 activity against glioblastoma. Further studies are warranted to characterize the mechanisms by which HSP990 exerts its anti-glioma effects which in turn may provide valuable insights in developing HSP990 as a novel personalized GBM treatment based on specific molecular signatures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2898. doi:10.1158/1538-7445.AM2011-2898