摘要Ⅰ型神经纤维瘤病(Neurofibromatosis type 1,NF1)是一组常在儿童时期起病的常染色体显性遗传病.NF1基因编码的蛋白质产物为神经纤维瘤素,是一种Ras-GTP酶,通过将有活性的Ras-GTP形式水解为无活性的Ras-GDP形式,从而下调Ras下游通路活性达到抑制细胞增殖的作用.NF1患儿由于神经纤维瘤素不足导致Ras通路的活化,主要表现为Ras下游的两条通路Raf-MEK-ERK和PI3K-AKT-mTOR的异常活化;因此针对这两条通路上的靶点,如MEK,mTOR的抑制剂成为NF1肿瘤的主要靶向治疗药物.其中MEK抑制剂司美替尼及mTOR抑制剂西罗莫司已进入临床试验阶段,均被证实有缩小肿瘤体积及延长疾病进展时间的效果.另外瘤体与微环境的信号传导也是NF1肿瘤的靶向治疗热点,其中肿瘤微环境中基质细胞上的c-kit络氨酸激酶抑制剂伊马替尼是首个在临床上证实有效抑制NF1肿瘤的靶向治疗药物.本综述总结了与NF1相关的丛状神经纤维瘤、恶性外周神经鞘瘤和视通路胶质瘤的基础实验以及临床试验的最新进展.

abstractsNeurofibromatosis type 1 (NF1) is an autosomal dominant syndrome occurring predominantly in children.Neurofibromin encoded by NF1 gene is a kind of Ras-GTPase capable of transforming active Ras-GTP into inactive Ras-GDP.Thus neurofibromin can decrease the downstream Ras signaling.NF1 patients have two major Ras downstream pathways of abnormal high level activity,namely Raf-MEK-ERK and PI3K-AKT-mTOR.The inhibitors of MEK and mTOR have proved effective in reducing tumor volume and prolonging time to progress.In addition,c-kit signaling in microenviroument is essential for tumor progression.As a kind of inhibitor of c-kit,Irnatinib is the first drug of targeted therapy proved clinically effective in NF1 tumor.This review will highlight the advances on preclinical researches and clinical trials of targeted therapy for NF1 associated tumors,including plexiform neurofibromas (PNTs),malignant peripheral nerve sheath tumors (MPNSTs) and optic pathway glioma.