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, Manabu Natsumeda, Masayasu Okada, Rie Saito, Daiki Kobayashi, Takeyoshi Eda, Jun Watanabe, Shoji Saito, Yoshihiro Tsukamoto, Makoto Oishi, Hirotake Saito, Masayuki Nagahashi, Takahiro Sasaki, Rintaro Hashizume, Hidefumi Aoyama, Toshifumi Wakai, Akiyoshi Kakita, Yukihiko Fujii

Research output: Contribution to journalArticle

1 Citation (Scopus)

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. 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.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Jul 25 2019

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Mitogen-Activated Protein Kinase Kinases
Glioblastoma
Heterografts
Cell Line
Mutation
Neoplasms
Therapeutics
Epithelioid Cells
Precision Medicine
Sequence Deletion
Brain Neoplasms
Autopsy

Keywords

  • BRAF V600E
  • Epithelioid glioblastoma
  • Precision medicine
  • Targeted therapy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Kanemaru, Yu ; Natsumeda, Manabu ; Okada, Masayasu ; Saito, Rie ; Kobayashi, Daiki ; Eda, Takeyoshi ; Watanabe, Jun ; Saito, Shoji ; Tsukamoto, Yoshihiro ; Oishi, Makoto ; Saito, Hirotake ; Nagahashi, Masayuki ; Sasaki, Takahiro ; Hashizume, Rintaro ; Aoyama, Hidefumi ; Wakai, Toshifumi ; Kakita, Akiyoshi ; Fujii, Yukihiko. / 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. In: Acta Neuropathologica Communications. 2019 ; Vol. 7, No. 1.
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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. 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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author = "Yu Kanemaru and Manabu Natsumeda and Masayasu Okada and Rie Saito and Daiki Kobayashi and Takeyoshi Eda and Jun Watanabe and Shoji Saito and Yoshihiro Tsukamoto and Makoto Oishi and Hirotake Saito and Masayuki Nagahashi and Takahiro Sasaki and Rintaro Hashizume and Hidefumi Aoyama and Toshifumi Wakai and Akiyoshi Kakita and Yukihiko Fujii",
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Kanemaru, Y, Natsumeda, M, Okada, M, Saito, R, Kobayashi, D, Eda, T, Watanabe, J, Saito, S, Tsukamoto, Y, Oishi, M, Saito, H, Nagahashi, M, Sasaki, T, Hashizume, R, Aoyama, H, Wakai, T, Kakita, A & Fujii, Y 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', Acta Neuropathologica Communications, vol. 7, no. 1. https://doi.org/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. / Kanemaru, Yu; Natsumeda, Manabu; Okada, Masayasu; Saito, Rie; Kobayashi, Daiki; Eda, Takeyoshi; Watanabe, Jun; Saito, Shoji; Tsukamoto, Yoshihiro; Oishi, Makoto; Saito, Hirotake; Nagahashi, Masayuki; Sasaki, Takahiro; Hashizume, Rintaro; Aoyama, Hidefumi; Wakai, Toshifumi; Kakita, Akiyoshi; Fujii, Yukihiko.

In: Acta Neuropathologica Communications, Vol. 7, No. 1, 25.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor

T2 - establishment and xenograft of a cell line to predict clinical efficacy

AU - Kanemaru, Yu

AU - Natsumeda, Manabu

AU - Okada, Masayasu

AU - Saito, Rie

AU - Kobayashi, Daiki

AU - Eda, Takeyoshi

AU - Watanabe, Jun

AU - Saito, Shoji

AU - Tsukamoto, Yoshihiro

AU - Oishi, Makoto

AU - Saito, Hirotake

AU - Nagahashi, Masayuki

AU - Sasaki, Takahiro

AU - Hashizume, Rintaro

AU - Aoyama, Hidefumi

AU - Wakai, Toshifumi

AU - Kakita, Akiyoshi

AU - Fujii, Yukihiko

PY - 2019/7/25

Y1 - 2019/7/25

N2 - 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. 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.

AB - 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. 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.

KW - BRAF V600E

KW - Epithelioid glioblastoma

KW - Precision medicine

KW - Targeted therapy

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