Chen Zhihua,Ji Xinting,Gu Shuo.Application of BRAF mutations and targeted therapy in pediatric brain gliomas: successes and challenges[J].Journal of Clinical Pediatric Surgery,2023,22(07):601-606.[doi:10.3760/cma.j.cn101785-202201049-001]
BRAF突变及其靶向治疗在儿童脑胶质瘤中的应用与挑战
- Title:
- Application of BRAF mutations and targeted therapy in pediatric brain gliomas: successes and challenges
- 关键词:
- 原癌基因蛋白质B-raf; 突变; 弥漫性内生型桥脑胶质瘤; 分子靶向治疗; 外科手术; 儿童
- Keywords:
- Proto-Oncogene Proteins B-raf; Mutation; Diffuse Intrinsic Pontine Glioma; Molecular Targeted Therapy; Surgical Procedures; Operative; Child
- 摘要:
- 胶质瘤是儿童以及青少年最常见的脑肿瘤，常规治疗方法往往无法延长患者无进展生存期，部分难治性、复发性、无法手术治疗的胶质瘤患者5年生存率仅10%左右。研究发现，部分胶质瘤患者存在B型迅速加速性纤维肉瘤（B-type rapidly accelerated fibrosarcoma，BRAF）基因突变，这为BRAF靶向治疗提供了一定契机，也使BRAF靶向治疗在脑胶质瘤中的应用成为研究热点。多项国际多中心临床试验结果表明，单用或联合使用BRAF抑制剂和细胞外信号调控激酶（extracellular signal-regulated kinase，MEK）抑制剂能显著延长儿童脑胶质瘤患者的无进展生存期，其治疗效果已获得广泛认可。多种BRAF抑制剂已获得美国食品药品监督管理局（Food and Drug Administration，FDA）的批准用于治疗复杂、难治性、复发性胶质瘤，司美替尼作为MEK1/MEK2的强效抑制剂，可显著延长神经纤维瘤1（Neurofibromin 1，NF1）基因相关低级别胶质瘤（pediatric low-grade glioma，PLGG）的无进展生存期，该药已于2020年获美国FDA批准用于NF1突变的神经纤维瘤病患儿，2023年5月中国国家药监局也批准了该药用于中国市场。目前仍有多种BRAF抑制剂处于临床试验阶段。本文介绍了BRAF突变概况及其在儿童脑胶质瘤中的突变特征，同时总结BRAF靶向治疗在儿童脑胶质瘤中的临床试验成果，并对其不良反应和耐药问题进行评述。
- Abstract:
- Glioma is the most common brain tumor in children and adolescents.Conventional treatments have failed to prolong its progression-free survival.For some refractory, recurrent and unresectable gliomas, 5-year survival rate was merely 10%.Studies have demonstrated that some gliomas harbor mutations in B-type rapidly accelerated fibrosarcoma (BRAF) gene, providing an opportunity for BRAF-targeted therapy and creating a research hotspot in pediatric gliomas.Several international multicenter clinical trials have indicated that monotherapy or combination therapy with BRAF and extracellular signal-regulated kinase (MEK) inhibitors could significantly extend progression-free survival.Their therapeutic effects have been widely recognized.Several BRAF inhibitors have been approved by the US Food and Drug Administration (FDA) for treating complex, refractory and recurrent gliomas.Selumetinib, as a potent inhibitor of MEK1/MEK2, could significantly delay the progression of neurofibromin 1 (NF1)-related PLGG.And it has been approved by FDA in 2020 for children with NF1-mutated neurofibromas.In May 2023, China National Medical Products Administration also approved the use of this drug for domestic market.Currently, multiple BRAF inhibitors are still going through clinical trials.This review introduced the general profiles of BRAF mutation in pediatric gliomas and summarized the clinical trials of BRAF-targeted therapy.It was intended to provide references for clinical applications and researches of pediatric neurogliomas in China.
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备注/Memo
收稿日期:2023-02-28。
基金项目:海南省重点研发计划科技合作方向项目（ZDYF2020225）；海南省临床医学中心建设项目资助（琼卫医函〔2021〕75号）
通讯作者:顾硕,Email:gushuo007@163.com