Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
Pediatric Neurology, Pediatric Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Italy.
Acta Biomed. 2020 Jun 30;91(7-S):101-114. doi: 10.23750/abm.v91i7-S.9961.
Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofibromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most frequent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumorigenesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results.
神经纤维瘤病 1 型（NF1）是一种常染色体显性遗传的肿瘤易感性疾病，由 NF1 基因的杂合功能丧失变异引起，该基因编码一种称为神经纤维瘤蛋白的蛋白质。神经纤维瘤蛋白的缺失导致 Rat sarcoma 蛋白（RAS）信号通路活性增加，从而导致生长和细胞增殖增加。因此，肿瘤和非肿瘤合并症都会导致这些患者的高发病率和死亡率。视神经通路胶质瘤、丛状神经纤维瘤和恶性外周神经鞘瘤（MPNST）是最常见的 NF1 相关肿瘤。由于这些肿瘤的位置、大小和浸润性，手术可能不可行，而且标准的化疗或放疗存在显著的毒性和继发恶性肿瘤的风险，因此这些并发症的治疗常常具有挑战性。出于这些原因，在发现导致 NF1 患者细胞增殖和肿瘤发生的病理生理机制的新发现后，已经开发出针对特定信号通路（即 MEK/ERK 级联）的靶向药物，取得了有希望的结果。
