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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.

Al's Comment:

 This is only in mice right now but if you happen to have these 3 mutations, which signify a pretty much hopeless situation, it might be worth trying this combination of drugs.


Posted on: 07/29/2019

  Acta Neuropathol Commun. 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.
Kanemaru Y1, Natsumeda M2, Okada M1, Saito R3, Kobayashi D1, Eda T1, Watanabe J1, Saito S1, Tsukamoto Y1, Oishi M1, Saito H4, Nagahashi M5, Sasaki T6, Hashizume R6, Aoyama H4, Wakai T5, Kakita A3, Fujii Y1.
 
Author information:
1. From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan.
2. From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan. mnatsumeda@bri.niigata-u.ac.jp.
3. Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
4. Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
5. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
6. Department of Neurosurgery, Northwestern University, Chicago, IL, USA.
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.
Free Article
PMID: 31345255
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