Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition.
Fiche publication
Date publication
septembre 2017
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHENARD Marie-Pierre, Pr ENTZ-WERLE Natacha, Dr GUENOT Dominique, Dr GUERIN Eric, Pr NAMER Izzie-Jacques, Dr PENCREACH Erwan
Tous les auteurs :
Nguyen A, Moussallieh FM, Mackay A, Cicek AE, Coca A, Chenard MP, Weingertner N, Lhermitte B, Letouzé E, Guérin E, Pencreach E, Jannier S, Guenot D, Namer IJ, Jones C, Entz-Werlé N
Lien Pubmed
Résumé
Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. To establish, the crucial role of the hypoxic pathways in pHGGs, we, first, assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs and in pHGG's cell lines, cultured in both normoxic and hypoxic conditions. Secondly, based on the concept of a bi-therapy targeting in pHGGs mTORC1 (rapamycin) and HIF-1α (irinotecan), we hypothesized that the balanced expressions between RAS/ERK, PI3K/AKT and HIF-1α/HIF-2α/MYC proteins or genes may provide a modulation of the cell response to this double targeting. Finally, we could evidence three protein, genomic and metabolomic profiles of response to rapamycin combined with irinotecan. The pattern of highly sensitive cells to mTOR/HIF-1α targeting was linked to a MYC/ERK/HIF-1α over-expression and the cell resistance to a major hyper-expression of HIF-2α.
Mots clés
HIF1alpha, high grade glioma, mTor, pediatric, targets
Référence
Oncotarget. 2017 Sep 22;8(42):71597-71617