Meningiomas are common tumors of the central nervous system and are the second most prevalent tumors in Neurofibromatosis type 2 patients. Despite their high frequency, currently there are no chemotherapeutic options for these tumors and treatment is limited to surgery and various forms of radiation therapy either as adjuvant or primary therapy. Some tumors are unresectable due to location and have histhopathologic aggressive features (designated as WHO grade II and III) with higher recurrence rates. When treatment is recommended, these tumors almost uniformly receive some form of radiation therapy. The aim of this study was to find new therapeutic options to couple with radiation, given its common use with non-surgical meningiomas. We are interested in targeting oncogenic pathways in the context of loss of the NF2 gene, which represents the most common genetic alteration in meningiomas, present is 50-70% of sporadic tumors and all of NF2 cases. We used cell-based assays searching for small molecule inhibitors that showed prevalent efficacy against NF2-deficient cells. Cell proliferation and clonogenic assays were employed to investigate the potential synergy effect of drugs and radiation combinations. Three pairs of NF2 isogenic meningioma cells (AC1, SF6717 and KT21MG1) were used to screen libraries of FDA approved compounds. The primary screen was performed using KT21MG1 cells. The top 5% compounds (86 compounds) showing preferential inhibition of NF2-deficient cells were selected for further validation. The secondary screen was used to validate useful targets with AC1 and SF6717 cells. Twelve compounds (∼15%) showed prevalent inhibitory activity on these cells. Small molecules targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor receptor (VEGFR) showed preferential synergistic inhibition of NF2 cells with radiation, compared to either radiation or drug treatment alone. Currently, preclinical testing is in progress to investigate the efficacy of these inhibitors in combination with radiation in a meningioma mouse model.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2759. doi:1538-7445.AM2012-2759