Project description:Notch-targeted gamma-secretase inhibitors (GSIs) exhibited limited efficacy in glioblastoma patients. We identified that farnesyltransferase inhibitors (FTIs) increased sensitivity to GSIs in glioblastoma stem cells. To interrogate the mechanisms mediating the interaction between these two classes of compounds, we studied the impact on gene expression profiles by the combination of tipifarnib (FTI) and RO4929097 (GSI). We found that this combination treatment significantly suppressed genes implicated cell cycle progression. Real-time PCR validated the activities of tipifarnib to modulate expression of cell cycle regulators. We also showed that RO4929097 sensitized glioblastoma stem cells to compounds targeting some of these cell cycle regulators, such as AURKB and CDK4/6. These results suggest that regulation of cell cycle progression partially mediates the ability of FTIs to sensitize glioblastoma stem cells to GSIs.
Project description:We have previously determined the insulin-like growth factor 1 receptor (IGF1R) to be amplified and overexpressed in paediatric glioblastoma. In order to probe the efficacy and mechanisms of action of various inhibitors of the receptor, we have carried out expression profiling of paediatric glioblastoma cells treated with 5x IC50 of the compounds PPP and NVP-AEW541 over a 24 hour time-course.
