Article
Gene-expression profiling of sporadic and NF2 associated vestibular schwannomas reveals molecular homogeneity and a possible mutual therapeutic target
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Published: | May 13, 2014 |
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Objective: The transcriptome of schwannoma remains poorly understood as inappropriate control tissues or insufficient sample numbers were used in a few published studies investigating the gene expression. As such identification of novel recurring alterations in schwannoma is limited leading to a poor fundamental understanding of core signaling pathways that are activated, which may serve as therapeutic targets. To address this issue, we conducted a large vestibular schwannoma transcriptome study to identify differentially expressed genes and activated pathways
Method: Tissue samples were collected during the surgical excision from 36 patients with sporadic VS and 13 patients with a history of NF2. Seven controls of postmortem tissue of the vestibulocochlear nerve were obtained. All samples were analyzed on the Affymetrix Human HG219 array. Several distinct technologies were used for clustering (NMF, k means, hierarchical). A pre-clinical cell line model (HEI 293) was used for compound testing.
Results: We could not reproducibly identify distinct vestibular subtypes or significant differences between sporadic and NF2 associated schwannomas suggesting that vestibular schwannoma comprises of a highly similar entity. We identified over-expression of PI3K/AKT/mTOR signaling networks in our gene expression study, 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. 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.
Conclusions: Our findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in vestibular schwannoma and suggest inhibition of this pathway as a potential treatment strategy.