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Case Reports
. 2019 Jul 25;7(1):119.
doi: 10.1186/s40478-019-0774-7.

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

Yu Kanemaru  1 , Manabu Natsumeda  2 , Masayasu Okada  1 , Rie Saito  3 , Daiki Kobayashi  1 , Takeyoshi Eda  1 , Jun Watanabe  1 , Shoji Saito  1 , Yoshihiro Tsukamoto  1 , Makoto Oishi  1 , Hirotake Saito  4 , Masayuki Nagahashi  5 , Takahiro Sasaki  6 , Rintaro Hashizume  6 , Hidefumi Aoyama  4 , Toshifumi Wakai  5 , Akiyoshi Kakita  3 , Yukihiko Fujii  1
Affiliations
Case Reports

"VSports手机版" 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

Yu Kanemaru et al. Acta Neuropathol Commun. .

Abstract

Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6 months 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 VSports手机版. 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. .

Keywords: BRAF V600E; Epithelioid glioblastoma; Precision medicine; Targeted therapy. V体育安卓版.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Clinicopathologic features of the patient. Preoperative (a) and postoperative (b) brain MR images of the lesion. Spinal cord MR images before (d) and after (e) combination therapy with BRAF and MEK inhibitor. Histopathologic features of the surgical (c, f, g, h, i; frontal lobe) and autopsy (j; second segment of the cervical cord) samples. T1-weighted gadolinium-enhanced image demonstrating enhancement of the well circumscribed tumor in the left frontal lobe (a) and confirming the subtotal resection except for enhancement of the lateral ventricle (b). Before targeted treatment, thick leptomeningeal dissemination (arrow) and syringomyelia are evident in the upper cervical cord on post-contrast MR images and T2-weighted images (d). After 4 weeks of treatment, T1-weighted gadolinium-enhanced images and T2-weighted images (e) reveal a dramatical radiological response to the therapy. The tumor cells are composed of discohesive, rounded cells with rhabdoid morphology, showing brisk mitotic activity (c). MIB-1 labeling index 36% (f). Positive immunoreactivity for BRAF V600E (g) and nuclear positivity for pERK (h). Ultrastructure of the tumor cells. A few foot processes (arrow) are not interwoven (i). Spinal cord invasion by the tumor cells with leptomeningeal dissemination (j). Scale bars c: 20 μm; f-h: 150 μm, i: 2 μm, j: 500 μm
Fig. 2
Fig. 2
Morphological similarity of the tumor cells between those in the orthotopic xenograft (a, b, c) and those from the patient (d, e, f). The orthotopic xenografts share strikingly similar characteristics to those of the autopsy specimen, including the mode of tumor infiltration (a, d) and the light microscopic (b, e) and ultrastructural (c, f) morphology of the tumor cells. Scale bars a, d: 200 μm; b, e: 50 μm; c, F: 2 μm
Fig. 3
Fig. 3
Effectiveness of dabrafenib and trametinib against BRAF V600E-mutant GBM cell lines in vitro. Targeted treatment reduced the viability of NGT41 and other BRAF V600E-mutant glioma cell lines (AM38, DBTRG-05MG) relative to BRAF-wildtype glioma cell lines (U87MG, T98G). (n ≧6, *p < 0.05, **p < 0.01, †p < 0.001, ‡p < 0.0001; Two-way ANOVA) (a). Marked inhibition of phosphorylated MEK and ERK was observed in BRAF V600E-mutant cell lines. The expression of phosphorylated ERK was suppressed by trametinib treatment, regardless of BRAF status (b)
Fig. 4
Fig. 4
Efficacy of combined treatment against subcutaneous and intracranial xenograft models. In the combined treatment group, tumor volume was significantly suppressed relative to the control group. (n = 4, error bars represent ± SEM, **p = 0.0021, ‡p < 0.0001; Two-way ANOVA) (a). Representative macro and micro images of the tumors from mice implanted subcutaneously with NGT41 cells (b). Western blot analysis demonstrated that expression of phosphorylated ERK was drastically inhibited by the combined treatment (c). Combined dabrafenib and trametinib treatment significantly prolonged the survival of mice in the intracranial model relative to the control (p = 0.0299, Log Rank test) (d). Scale bars a: 10 mm; b: 50 μm
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