Abstract
Abstract Background Glioblastoma is the most aggressive subtype of brain tumors. Antiangiogenic compounds are being tested in clinical trials, for this pathology, mostly in combination with other molecules. The availability of an imaging biomarker of efficacy could help optimize the dosing and scheduling of these combinations. The aim of this study was to validate DCE-MRI, using two contrast agents of different molecular weight, as an imaging biomarker of the efficacy of sorafenib (Nexavar®, BAY 43-9006) in an orthotopic glioma model in Nude rats. Methods U-87 MG human glioma cells were inoculated by stereotactic injection in the right caudate nucleus of 24 Nude rats. All rats were first imaged 10 days after cell injection to measure their baseline tumor volume (TV) using T2-weighted MRI (Bruker Pharmascan, 4.7T). Based on their TV, 20 rats were selected and imaged at D-1 (14 days after cell injection). The rats were then randomized into 2 groups of 8 rats according to their tumor vascular status following a full DCE-MRI protocol using either Gd-DTPA (Magnevist®) or P846 (two parameters: Ktrans from pharmaco-kinetic modeling of the contrast agent uptake curve, and iAUC60, the initial area under the gadolinium concentration time curve after 60 seconds). P846 is a medium-molecular weight, gadolinium-based contrast agent provided by Dr P. Robert (Guerbet). In both subgroups of 8 rats, each animal received a daily per os administration of either sorafenib (100 mg/kg/adm) or its vehicle. All 16 rats were then imaged at D1, D3 and D7. At each time point, voxelwise maps of DCE-MRI parameters were derived from imaging data and their distribution analyzed within regions of interest within the tumor and the contralateral lesion-free tissue. Results Sorafenib was well tolerated and it increased the median survival of tumor-bearing rats by 20%. At D7, despite no difference in tumor growth kinetics, DCE-MRI parameters (Ktrans and iUAC60) showed significant differences between sorafenib-treated and control groups using either Magnevist® or P846. Visual assessment showed that the heterogeneity of contrast agent uptake was reduced by antiangiogenic treatment with sorafenib. The quantification of this phenomenon by statistical analysis of the parameter distributions within the ROIs is pending. Conclusions In conclusion, we have shown that DCE-MRI, with either Magnevist® or P846 contrast agents, is a suitable non-invasive imaging technique to show changes of tumor vasculature integrity induced by antiangiogenic treatment such as sorafenib in orthotopically-implanted glioma in Nude rats. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2447. doi:1538-7445.AM2012-2447
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