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
Posted on 2019-07-26 - 04:25
Abstract Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6âmonths and frequent leptomeningeal dissemination. A recent study has revealed that 50% of epithelioid GBMs harbor three genetic alterations â 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.
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Kanemaru, Yu; Natsumeda, Manabu; Okada, Masayasu; Saito, Rie; Kobayashi, Daiki; Eda, Takeyoshi; et al. (2019). 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. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4590446.v1
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AUTHORS (18)
YK
Yu Kanemaru
MN
Manabu Natsumeda
MO
Masayasu Okada
RS
Rie Saito
DK
Daiki Kobayashi
TE
Takeyoshi Eda
JW
Jun Watanabe
SS
Shoji Saito
YT
Yoshihiro Tsukamoto
MO
Makoto Oishi
HS
Hirotake Saito
MN
Masayuki Nagahashi
TS
Takahiro Sasaki
RH
Rintaro Hashizume
HA
Hidefumi Aoyama
TW
Toshifumi Wakai
AK
Akiyoshi Kakita
YF
Yukihiko Fujii