Abstract
BackgroundRadiotherapy plays a major role in the management of high grade glioma. However, the radioresistance of glioma cells limits its efficiency and drives recurrence inside the irradiated tumor volume leading to poor outcome for patients. Stereotactic hypofractionated radiotherapy is one option for recurrent high grade gliomas. Optimization of hypofractionated radiotherapy with new radiosensitizing agents requires the identification of robust druggable targets involved in radioresistance.MethodsWe generated 11 xenografted glioma models: 6 were derived from cell lines (1 WHO grade III and 5 grade IV) and 5 were patient derived xenografts (2 WHO grade III and 3 grade IV). Xenografts were treated by hypofractionated radiotherapy (6x5Gy). We searched for 89 biomarkers of radioresistance (39 total proteins, 26 phosphoproteins and 24 ratios of phosphoproteins on total proteins) using Reverse Phase Protein Array.ResultsBoth type of xenografted models showed equivalent spectrum of sensitivity and profile of response to hypofractionated radiotherapy. We report that Phospho-EGFR/EGFR, Phospho-Chk1/Chk1 and VCP were associated to resistance to hypofractionated radiotherapy.ConclusionsSeveral compounds targeting EGFR or CHK1 are already in clinical use and combining them with stereotactic hypofractionated radiotherapy for recurrent high grade gliomas might be of particular interest.
Highlights
Radiotherapy plays a major role in the management of high grade glioma
The aim of this study was to search for predictive biomarkers of radioresponse on nude mice engrafted with high grade glioma cell lines and patient-derived tumor samples irradiated with a hypofractionated stereotactic RT (HFRT) regimen
Xenograft models Xenografts derived from cell lines (CDX) were obtained by injecting 4 × 106 cells of each cell line described above into the flank of adult female nude mice (Swiss nu/nu, Janvier, Le Genest Saint Isle, France)
Summary
Radiotherapy plays a major role in the management of high grade glioma. Stereotactic hypofractionated radiotherapy is one option for recurrent high grade gliomas. First line adjuvant therapy is based on systematic normofractionated radiotherapy (RT) (total dose of 60Gy; 5 fractions of 2Gy/week over 6 weeks), with daily temozolomide-based chemotherapy [7, 8]. Despite these treatments, median survival remains very low around 14 months. Treatment options for recurrent high grade glioma are limited and hypofractionated stereotactic RT (HFRT) is one option with limited efficacy [10,11,12,13,14].
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