Chun Brie M, Youngworth Sandra, Abtin Vicki, Stull David, Starkey Jay, Kummar Shivaani
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, United States.
Diagnostic Radiology, Oregon Health & Science University, Portland, OR 97239, United States.
Oncologist. 2025 May 8;30(5). doi: 10.1093/oncolo/oyaf093.
Diffuse leptomeningeal glioneuronal tumor (DL-GNT) is a rare disease which is more often diagnosed in children and adolescents than adults. Activation of the MAPK/ERK pathway is implicated in the majority of cases, and BRAF fusions are the most common genetic alteration. BRAF fusions result in dimerization and constitutive downstream MAPK/ERK activity, against which type I RAF inhibitors have limited efficacy. Type II RAF inhibitors stabilize RAF in an inactive conformation and inhibit both dimer protomers, thus inhibiting downstream MAPK/ERK activity in the setting of BRAF fusions.
A previously-healthy 33 year old man was diagnosed with DL-GNT, which harbored a pathogenic BRAF:KIAA1549 gene fusion. He was initially treated with a MEK inhibitor but developed drug-related cardiotoxicity. Without treatment, he developed significant functional limitations due to leptomeningeal disease. A compassionate use indication was pursued for an investigational CNS-penetrant type II BRAF inhibitor, tovorafenib. Within 3 months of initiating the medication, the patient experienced notable gains in functional status and with over 12 months of treatment has been able to rejoin recreational activities.
This case highlights the importance of tumor molecular characterization, particularly in rare tumors, whereby identification of the BRAF:KIAA1594 gene fusion led to an appropriate selection of a type II BRAF inhibitor.
弥漫性软脑膜胶质神经元肿瘤（DL-GNT）是一种罕见疾病，在儿童和青少年中比在成人中更常被诊断出来。丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路的激活在大多数病例中都有涉及，而BRAF融合是最常见的基因改变。BRAF融合导致二聚化和下游MAPK/ERK的组成性激活，I型RAF抑制剂对此疗效有限。II型RAF抑制剂使RAF稳定在非活性构象并抑制两个二聚体亚基，从而在BRAF融合情况下抑制下游MAPK/ERK活性。
一名既往健康的33岁男性被诊断为DL-GNT，其携带致病性BRAF:KIAA1549基因融合。他最初接受MEK抑制剂治疗，但出现了药物相关的心脏毒性。未经治疗，由于软脑膜疾病，他出现了明显的功能受限。为一种研究性的可穿透中枢神经系统的II型BRAF抑制剂托伐拉芬尼申请了同情用药。在开始用药的3个月内，患者的功能状态有显著改善，经过超过12个月的治疗，他已能够重新参加娱乐活动。
该病例强调了肿瘤分子特征的重要性，特别是在罕见肿瘤中，通过鉴定BRAF:KIAA1594基因融合，从而合理选择了II型BRAF抑制剂。
