House 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.).
Neuro Oncol. 2014 Apr;16(4):493-504. doi: 10.1093/neuonc/not242. Epub 2014 Jan 10.
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.
神经纤维瘤病 2 型（NF2）是一种罕见的常染色体显性遗传疾病，导致多种神经肿瘤，以双侧前庭神经鞘瘤为最常见表现。最近，NF2 肿瘤抑制因子 Merlin 被鉴定为哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）的新型负调控因子； Merlin 的功能丧失导致 NF2 相关肿瘤中 mTORC1 信号的升高。因此，mTORC1 通路抑制可能是一种有用的靶向治疗方法。
我们研究了体外细胞模型、异体移植 Nf2(-/-)施万细胞的小鼠队列，以及 NF2 施万细胞瘤的遗传修饰小鼠模型，以评估针对 NF2 的拟议靶向治疗的疗效。
我们发现，mTORC1 抑制剂雷帕霉素的治疗减轻了 NF2 相关施万细胞瘤发生的严重程度，而没有明显的毒性。这些结果与在一名患有不断生长的前庭神经鞘瘤的 NF2 患者中的结果一致，雷帕霉素类似物西罗莫司诱导肿瘤生长停滞。
综上所述，这些结果构成了明确的证据，证明在选定的 NF2 患者和 NF2 相关散发性肿瘤患者中使用 mTORC1 靶向药物进行临床试验是合理的。
