Assessment of bevacizumab resistance increased by expression of BCAT1 in IDH1 wild-type glioblastoma: application of DSC perfusion MR imaging.

Hye Rim Cho,Chul-Kee Park,Sunghyouk Park,Seung Hong Choi,Bora Hong,Hyeonjin Kim,Sung-Hye Park

doi:10.18632/oncotarget.11901

Abstract

BCAT1 (branched-chain amino acid trasaminase1) expression is necessary for the progression of IDH1 wild-type (WT) glioblastoma multiforme (GBM), which is known to be associated with aggressive tumors. The purpose of our study is to investigate the bevacizumab resistance increased by the expression of BCAT1 in IDH1 WT GBM in a rat model, which was evaluated using DSC perfusion MRI. BCAT1 sh#1 inhibits cell proliferation and limits cell migration potential in vitro. In vivo MRI showed that the increase in both tumor volume and nCBV after bevacizumab treatment in IDH1 WT tumors was significantly higher compared with BCAT1 sh#1tumors. In a histological analysis, more micro-vessel reformation by bevacizumab resistance was observed in IDH1 WT tumors than BCAT1 sh#1 tumors. These findings indicate that BCAT1 expression in IDH1 WT GBM increases resistance to bevacizumab treatment, which could be assessed by DSC perfusion MRI, and that nCBV can be a surrogate imaging biomarker for the prediction of antiangiogenic treatment in GBM.

Highlights

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults
Proliferation and migration of BCAT1 sh#1 cells were significantly slower than isocitrate dehydrogenase 1 (IDH1) WT cells (Supplementary Figure S3A and S3B)
The glutamate concentration was lower in the BCAT1 sh#1 GBM compared to the IDH1 WT and Nt shRNA

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The tumor is generally treated with surgical resection, chemotherapy, and radiation, recurrence is common, and the mean progression-free survival is just over 6 months [1]. Various molecular subclassifications have been proposed based on the genetic makeup of these tumors, with the hope that a better understanding of the origin of tumor cells and molecular pathogenesis may allow the prediction of the response to targeted therapies [2,3,4,5]. Bevacizumab (Avastin; Genentech, South San Francisco, Calif), which is an antiangiogenic monoclonal antibody that binds vascular endothelial growth factor (VEGF), has been shown to increase progression-free survival in patients with newly diagnosed or recurrent GBM, presumably by inhibiting both the formation of vessels dependent on VEGF and the vascular permeability of these highly vascular tumors [1, 7, 9, 10]

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