Abstract IA15: Using gene expression analyses to identify MPNST therapeutics

Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. In NF1 patients, these devastating sarcomas often develop in existing benign neurofibroma. We hypothesized that some over-expressed genes in solid tumors would be driver genes and/or mark critical pathways and therapeutic targets. In one approach to identify MPNST driver genes we targeted 130 genes up-regulated in neurofibroma and MPNSTs versus normal cells in a lentiviral short hairpin (sh) RNA screen. A counter-screen in RAS mutant cells excluded common RAS-pathway driven genes. We identified 7 genes specific for survival of MPSNT cells, including the transcription factor MEIS1. In a second approach, we targeted known oncogenes that were expressed at higher levels in MPNST than in normal cells, including Aurora Kinase A. MPNST responded to the Aurora A kinase inhibitor alisertib, and the combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibited significantly increased antitumor efficacy compared to either monotherapy. Supported by NIH-NS-084855 (N.R. and Largaespada, D.), NS-28840 (N.R.), and NS-086219 (N.R. and Cripe, T.P.). Citation Format: Nancy Ratner. Using gene expression analyses to identify MPNST therapeutics [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA15.