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Neuro Oncol. 2014 Apr;16(4):493-504. doi: 10.1093/neuonc/not242. Epub 2014 Jan 10.

mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma.

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  • 1House Research Institute, Center for Neural Tumor Research, Los Angeles, CA, USA (M.G., N.-X.B., J.V., F.C., K.T., R.A., L.M.F.); Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, California (M.G.); Département de Dermatologie, Centre de référence des neurofibromatoses, Hôpital Henri-Mondor, AP-HP and EA 4393 LIC, Université Paris Est Créteil, Créteil, France (L.V.-A., P.W.); Department of Neurosurgery, AP-HP, Hopital Beaujon, Clichy, France (S.G); Department of Neurosurgery, AP-HP, Hôpital Pitié Salpêtrière, Paris Cedex 13, France (M.K.); Université Pierre et Marie Curie, Faculté de Médecine, Paris Cedex 13, France (M.K.); Unité Inserm U674, Fondation Jean Dausset, Paris, France (S.G., M.K.).



Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach.


We studied in vitro cell models, cohorts of mice allografted with Nf2(-/-) Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2.


We found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest.


Taken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors.


neurofibromatosis type 2; rapamycin; schwannoma

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