fu, jun, koul, dimpy, wang, shuzhen, yao, jun, yuan, yin, sulman, erik p., lang, frederick f. and yung, alfred w.k. (2013) A Novel HSP90 inhibitor, NVP-HSP990 Targets the Cell Cycle Regulators to Produce Anti-glioma Effect in Olig2-expressing Glioma Stem Cells. Cancer Research, 73 (10). pp. 3062-3074.

Abstract

Glioblastoma multiforme’s genetic heterogeneity and signaling alterations decrease the effectiveness of single-agent therapies. Heat shock protein 90 (HSP90) is a key molecular chaperone that modulates a group of proteins, many of which are key deregulated signals in glioma cells. The ability to target multiple proteins by inhibiting HSP90 is therefore an appealing therapeutic objective for GBM. Previous work identifying glioma stem cells (GSCs) and demonstrating the initiation of gliomas by GSCs in animals offered hope for the development of anti-glioma therapeutics. Our study evaluated a HSP90 inhibitor, NVP-HSP990 (Novartis), in a panel of GSC lines. NVP-HSP990 treatment resulted in a dose-dependent inhibition of GSC growth, with IC50 values in the low nanomolar range. Our results distinguished between two subgroups of GSCs, revealing a subset of cells expressing Olig2 that were more sensitive to NVP-HSP990. Moreover, NVP-HSP990 markedly impaired GSC maintenance and triggered neuronal differentiation as demonstrated by the expression of neuronal markers TuJ1 and NeuN in responder GSC lines. NVP-HSP990 also disrupted the cell-cycle control mechanism by decreasing CDK2 and CDK4 and induced apoptosis-related molecules. Parallel to the in vitro activity of the compound, our in vivo study of an intracranial model of GSCs showed prolonged median survival times in treated cohorts. Therefore, our findings suggest that GBM with high Olig2 expression might be more susceptible to NVP-HSP990 treatment and HSP90 signaling in GBM warrants further investigations.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/7755