Analysis of Molecular Networks Uncovers Potential Targets in Vestibular Schwannoma

Objective: Understanding molecular pathway mechanisms of the formation of vestibular schwannoma may lead to potential therapeutic targets. Study Design: We performed gene expression profiling of 49 schwannomas (36 sporadic and 13 NF2-associated cases) and 7 normal control vestibular nerves. Results: We identified over 4,000 differentially expressed genes between control and schwannoma with network analysis uncovering proliferation and antiapoptotic pathways previously not implicated in vestibular schwannomas. Using several distinct clustering technologies, we could not reproducibly identify subtypes of schwannomas suggesting that our schwannoma cohort was molecularly distinct from normal tissue yet highly similar among themselves. At the molecular level the PI3K/AKT/mTOR signaling network was overexpressed in our schwannoma cohort and evaluated for therapeutic targeting. Testing compounds BEZ235 and PKI-587 both novel dual inhibitors of PI3K and mTOR attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that ablation of the PI3K/AKT/mTOR pathway with next generation inhibitors lead to decreased cell viability and increased cell death. Conclusion: The discovery of novel molecular targets in vestibular schwannoma by transcriptional profiling as compared with appropriate controls may lead to effective therapeutic strategies and shed insight into the molecular ontogeny of this tumor.