Exploring Therapeutic Targets in Schwannoma Through Integrative Analysis

Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve and spinal schwannomas (SS) arise form nerves within the spinal canal. SS are the most common intradural extramedullary spinal tumors, representing 30% of such lesions and both VS and SS both cause significant morbidity. The current treatment strategies for VS and SS include surgery or radiation with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown. We first performed gene expression profiling of 49 VS schwannomas and seven normal control vestibular nerves to identify tumor-specific gene expression patterns. We identified over 2000 differentially expressed genes between control and schwannoma with network analysis uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, we could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2 associated schwannomas suggesting that VS comprises of a highly similar entity. We next performed a transcript analysis comparing VS to SS. Surprisingly; we identified few differential transcripts demonstrating that schwannoma in general is a homogenous entity. Current studies are focused on copy number, DNA methylation profiling and genome wide sequencing analysis. Preliminary data suggests that NF2 is the major driver of schwannoma as previously implicated. Interestingly, we identified several novel and recurrent point mutations of NF2 in exon 1 of both VS and SS, which may lead to loss of function. Our most recurrent activated pathway in schwannoma was overexpression of PI3K/AKT/mTOR signaling pathway, which is directly druggable and evaluated this pathway for therapeutic targeting. Testing compounds BEZ235 and PKI-587, both novel dual inhibitors of PI3K and mTOR, attenuated tumor growth in a pre-clinical cell line model of schwannoma (HEI-293). Our In vitro findings demonstrated that pharmacological inhibition of the PI3K/AKT/mTOR pathway with next generation compounds lead to decreased cell viability, and increased cell death in VS, SS but not normal schwann cells. Future work is testing these compounds in vivo using relevant cell lines and primary cultures of VS/SS. Our findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in VS and suggest inhibition of this pathway as a potential treatment strategy.