Gene-expression profiling elucidates molecular signaling networks that can be therapeutically targeted in vestibular schwannoma

Abstract

ObjectVestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown.MethodsIn this study the authors performed gene-expression profiling of 49 schwannomas and 7 normal control vestibular nerves to identify tumor-specific gene-expression patterns. They also interrogated whether schwannomas comprise several molecular subtypes using several transcription-based clustering strategies. The authors also performed in vitro experiments testing therapeutic inhibitors of over-activated pathways in a schwannoma cell line, namely the PI3K/AKT/mTOR pathway.ResultsThe authors identified over 4000 differentially expressed genes between controls and schwannomas with network analysis, uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, they could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2–associated schwannomas, suggesting that they are highly similar entities. The authors identified overexpression of PI3K/AKT/mTOR signaling networks in their geneexpression study and evaluated this pathway for therapeutic targeting. Testing the 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 pharmacological inhibition of the PI3K/AKT/mTOR pathway with next-generation compounds led to decreased cell viability and increased cell death.ConclusionsThese 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.

Genetic landscape of sporadic vestibular schwannoma

“…One of these pathways, insulin receptor signaling, has been implicated in VS tumorigenesis. 2,5 Our results imply that this pathway may be more important in VSs lacking mutational hits in the NF2 gene.…”

“…In recent years, several transcriptome studies using microarray techniques have also added to the understanding of this disease. 1,2,11,61,66 6,19,24,65 The predominant view regarding sVS pathobiology is that loss of function of merlin, encoded by the NF2 gene, is the main driver of tumorigenesis. However, controversies exist because several reports indicate that a proportion of tumors have an intact NF2 gene and normal mRNA and protein levels.…”

Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis

“…However, the inactivation of the NF2 gene is not found in every VS, which possibly indicates additional mechanisms that might be involved in tumorigenesis [3,32]. Gene expression profiling and pathway analysis in other studies have identified a high range of tumor-related candidate genes and pathways that contribute to the biology of VS [19,26,[33][34][35][36][37][38][39]. None of these studies, however, have investigated differences between irradiated tumors and their controls.…”

Editorial: Therapeutic targeting based on gene-expression profiling in vestibular schwannomas

“…Gelareh zaDeh, M.D., Ph.D., 7 saMeer aGnihotri, Ph.D., 1 isabel GuGel, M.D., 2 Marc reMke, M.D., 1,3,4 antje borneMann, M.D., Ph.D., 5 GeorGios Pantazis, M.D., 6 stePhen c. We are grateful to Drs. Peruzzi and Lonser for their positive review of our work and for highlighting some of the key points arising from the results we obtained in our study.…”

“…Agnihotri and colleagues analyzed the differential gene expression between vestibular schwannomas (VSs) and normal control vestibular nerve tissue. 1 They uncovered a rather striking pattern of gene dysregulation in VSs. More than 1400 and 2800 genes were downregulated or upregulated, respectively, in VSs compared to vestibular nerves.…”