Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy
Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy
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DOI：
10.1186/s40478-019-0774-7
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发表时间：
2019-07-25
影响因子：
7.1
通讯作者：
Fujii, Yukihiko
中科院分区：
文献类型：
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作者：
Kanemaru, Yu;Natsumeda, Manabu;Fujii, Yukihiko
上皮样胶质母细胞瘤是胶质母细胞瘤的一种罕见的侵袭性变异，其特征是预后差，约6个月，经常发生软脑膜播散。最近的一项研究表明，50%的上皮样GBM具有三种遗传改变- BRAF V600 E突变、TERT启动子突变和CDKN 2A/2B纯合缺失。新出现的证据支持靶向治疗对BRAF V600 E突变脑肿瘤的有效性。在这里，我们描述了一个戏剧性的放射学反应与BRAF和MEK抑制剂联合治疗的患者与上皮样GBM窝藏BRAF V600 E突变，其特点是厚的脊柱传播。从尸检时获得的复发肿瘤中，我们建立了保留BRAF V600 E突变、TERT启动子突变和CDKN 2A/2B缺失的细胞系。将这些细胞颅内植入小鼠体内导致与原始细胞非常相似的肿瘤，其特征在于上皮样肿瘤细胞和播散，以及侵入血管周围空间。然后，我们在体外和体内证实了用BRAF和MEK抑制剂治疗的功效。具有BRAF V600 E突变的上皮样GBM可以被认为是精确医学的良好治疗适应症，并且这种患者来源的细胞系应该有助于预测肿瘤反应和澄清其生物学特性。
Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6months and frequent leptomeningeal dissemination. A recent study has revealed that 50% of epithelioid GBMs harbor three genetic alterations - BRAF V600E mutation, TERT promoter mutations, and homozygous deletions of CDKN2A/2B. Emerging evidence support the effectiveness of targeted therapies for brain tumors with BRAF V600E mutation. Here we describe a dramatic radiographical response to combined therapy with BRAF and MEK inhibitors in a patient with epithelioid GBM harboring BRAF V600E mutation, characterized by thick spinal dissemination. From relapsed tumor procured at autopsy, we established a cell line retaining the BRAF V600E mutation, TERT promoter mutation and CDKN2A/2B loss. Intracranial implantation of these cells into mice resulted in tumors closely resembling the original, characterized by epithelioid tumor cells and dissemination, and invasion into the perivascular spaces. We then confirmed the efficacy of treatment with BRAF and MEK inhibitor both in vitro and in vivo. Epithelioid GBM with BRAF V600E mutation can be considered a good treatment indication for precision medicine, and this patient-derived cell line should be useful for prediction of the tumor response and clarification of its biological characteristics.