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

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.

Increased Antiangiogenic Effect by Blocking CCL2-dependent Macrophages in a Rodent Glioblastoma Model: Correlation Study with Dynamic Susceptibility Contrast Perfusion MRI

“…In a previous study, we injected the bevacizumab on the same days as in current study and assessed resistance by DSC perfusion MRI, without CCL2 inhibition treatment. Based on these results, we used bevacizumab before treating with a CCL2 inhibitor in the current study 37 . Furthermore, several studies have shown that bevacizumab does not work effectively alone, as mentioned in relationship to bevacizumab resistance and macrophage recruitment 30,38,39 .…”

“…We believe that a future study is warranted to determine the level of VEGF that is required for preventing or delaying this unwanted effect as well as to investigate the potential role of rodent VEGF on human cancer cells. Moreover, the concentration of bevacizumab used in this study to induce the bevacizumab resistance was determined according to our previous study 37 . However, the concentration was higher compared to the human dose.…”

“…mNOX-E36 and bevacizumab were injected intraperitoneally (i.p.) four times and two times, respectively, for one week 37,53–56 . The concentrations of bevacizumab 40,57 and mNOX-E36 58,59 used in this study were determined according to a previous study.…”

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy

“…Further work is needed to clarify where in the spectrum of other described mechanisms of resistance to anti-angiogenic therapy our mechanism falls. These other mechanisms include vessel co-option 42 driven by actin-related protein 2/3 complex (Arp2/3); 43 tumor cell invasion driven by c-Met 14 , 44 and β1 integrin; 15 hypoxia-driven expression of hyaluronic acid and sulfated glycosaminoglycans (sGAGs); 45 increased angiopoietin-2 expression by endothelial cells; 46 upregulation of tumor cell DLL4-Notch signaling; 47 increased tumor cell expression of VEGFR-2; 48 increased tumor cell expression of branched-chain amino acid transaminase1; 49 Tie2-expressing monocytes; 5 , 6 , 44 evolution of a mesenchymal phenotype; 5 , 14 , 50 and increased hypoxia-inducible protein 2 (HIG2). 51 It remains unclear if these multiple mechanisms occur in parallel or if resistance to anti-angiogenic therapy is heterogeneous.…”

Efficacy of Asparaginase Erwinia chrysanthemi With and Without Temozolomide Against Glioma Cells and Intracranial Mouse Medulloblastoma

“…Our study adds evidence justifying further research on amino acid manipulation for development of brain tumor therapeutics. Amino acid effects may be studied not only by depletion of these nutrients in brain tumors, but also by inhibition of upregulated enzymes, such as branched chain amino acid transaminase 1 (35,40,41).…”