gms | German Medical Science

57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

12. - 15.09.2012, Erlangen

Banner: 57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie

Targeting mTORC1 is an effective strategy to inhibit meningioma cell tumorigenicity

Meeting Abstract

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  • presenting/speaker Doreen Pachow - Universitätsklinikum Magdeburg, Neuropathologie, Magdeburg, Germany
  • Elmar Kirches - Universitätsklinikum Magdeburg, Neuropathologie, Magdeburg, Germany
  • Christian Mawrin - Universitätsklinikum Magdeburg, Neuropathologie, Magdeburg, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnPP3.10

DOI: 10.3205/12dgnn054, URN: urn:nbn:de:0183-12dgnn0547

Veröffentlicht: 11. September 2012

© 2012 Pachow 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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Background: The mammalian target of Rapamycin (mTOR) regulates cell growth, proliferation, and motility. Since enhanced activity is frequently observed in malignant cells, mTORC1 inhibition has become an attractive strategy to treat cancer. Rapamycin analogues, like temsirolimus and everolimus, have demonstrated clinical efficiency in various cancers.

Over fifty percent of meningiomas display alterations in the neurofibromatosis type 2 (NF2) gene. The tumors exhibit a high recurrence rate, especially those of high WHO-grade. There is no standard chemotherapy available to control residual tumor cells. We analyzed mTORC1 as a potential target in meningiomas.

Methods: mTORC1-activity (S6K-phosphorylation) in meningioma cell lines and phospho-S6K in meningioma samples of all WHO grades were measured by Western blotting and immunohistochemistry. Cells with intact or downregulatedNF2(stable knockdown) and tumor-bearing mice were tested for their sensitivity towards rapamycin analogues.

Results: We found that mTORC1 is generally active in meningiomas. The percentage of tumors with strong phospho-S6K immunoexpression was significantly higher in atypical and anaplastic meningiomas compared to benign meningiomas (n=52). Using meningioma cell cultures, cell growth signal transduction appeared to be mediated partly via mTORC1, since FCS and insulin enhanced mTORC1 activity (S6K phosphorylation). All tested benign and malignant cell lines had significantly reduced cell viability following treatment with temsirolimus or everolimus. Meningioma cells with stable siRNA-mediated NF2knockdown showed significantly decreased sensibility to mTORC1-Inhibitors. Temsirolimus treatment (i.p.) of mice carrying malignant meningioma cells significantly reduced the tumor volume (267±52 mm3 vs. 674±124 mm3 [S.E.M.]) reached within three weeks, intratumoral proliferation (12.5% vs. 35.7% [Ki-67 rate]), and phosphorylation of S6K. The same treatment significantly reduced meningioma growth in an intracranial orthotopic mouse model as detected by magnetic resonance imaging after 2nd and 9th day, respectively.

Conclusions: Our data suggest that targeting mTORC1 in meningiomas by substances already used for other cancers will be an effective option to treat aggressive meningiomas.