Targeting Dopamine Receptor 2 (Drd2) Signaling In Combination With Temozolomide Chemotherapy As A Novel Therapeutic Concept In Glioblastomas.

2069 Background: Glioblastomas are highly resistant to therapy and carry a poor prognosis. Novel therapeutic strategies are urgently needed to improve patient outcome. This study was designed to identify drugs that would sensitize glioblastoma cells to temozolomide (TMZ) chemotherapy. Methods: A genome-wide RNAi synthetic lethality screen was performed in glioblastoma cells to identify functional gene sets that would potentiate the effect of TMZ. The Connectivity Map database was then interrogated to identify potential drug candidates that would induce corresponding changes in gene expression. The highest ranked prospective compounds were validated in combination with TMZ in low-throughput cytotoxicity assays. Based on these findings, the most promising compound, the established anti-psychotic agent Thioridazine, was evaluated further in combination with TMZ in vivo in a clinically relevant orthotopic xenograft model. Results: Thioridazine significantly improved TMZ sensitivity in established glioblastoma...