gms | German Medical Science

65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

11. - 14. Mai 2014, Dresden

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Gene-expression profiling of sporadic and NF2 associated vestibular schwannomas reveals molecular homogeneity and a possible mutual therapeutic target

Meeting Abstract

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  • Boris Krischek - Klinik für Allgemeine Neurochirurgie, Universitätsklinikum Köln; Klinik für Neurochirurgie, Universitätsklinikum Tübingen
  • Sameer Agnihotri - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada
  • Isabel Gugel - Klinik für Neurochirurgie, Universitätsklinikum Tübingen
  • Marc Remke - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • Antje Bornemann - Abteilung für Neuropathologie, Universitätsklinikum Tübingen
  • Georgios Pantazis - Abteilung für Neuropathologie, Universitätsklinikum Marburg
  • Stephen Mack - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • David Shih - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • Sanjay K. Singh - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada
  • Nesrin Sabha - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada
  • Michael D. Taylor - Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • Gelareh Zadeh - Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Canada
  • Marcos Tatagiba - Klinik für Neurochirurgie, Universitätsklinikum Tübingen

Deutsche Gesellschaft für Neurochirurgie. 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC). Dresden, 11.-14.05.2014. Düsseldorf: German Medical Science GMS Publishing House; 2014. DocDI.09.01

doi: 10.3205/14dgnc160, urn:nbn:de:0183-14dgnc1608

Veröffentlicht: 13. Mai 2014

© 2014 Krischek et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.

Gliederung

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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.