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Neuro Oncol ; 16(4): 493-504, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24414536

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Multiprotein Complexes/antagonists & inhibitors , Neurilemmoma/prevention & control , Neurofibromatosis 2/prevention & control , Neurofibromin 2/physiology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Blotting, Western , Cell Proliferation/drug effects , Cell Size/drug effects , Enzyme-Linked Immunosorbent Assay , Humans , Immunoenzyme Techniques , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Nude , Mice, Transgenic , Multiprotein Complexes/metabolism , Neurilemmoma/metabolism , Neurilemmoma/pathology , Neurofibromatosis 2/metabolism , Neurofibromatosis 2/pathology , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/metabolism , Tumor Cells, Cultured
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