Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition
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Aurélia Nguyen1, François Marie Moussallieh2,*, Alan Mackay3,*, A. Ercument Cicek4,5, Andres Coca6, Marie Pierre Chenard7,8, Noelle Weingertner7, Benoit Lhermitte7, Eric Letouzé9, Eric Guérin1, Erwan Pencreach1, Sarah Jannier1,10, Dominique Guenot1, Izzie Jacques Namer2, Chris Jones3 and Natacha Entz-Werlé1,10
1Laboratory EA 3430, Progression Tumorale et Micro-Environnement, Approches Translationnelles et Epidémiologie, University of Strasbourg, Strasbourg, France
2Department of Nuclear Medicine, University Hospital of Strasbourg, Strasbourg, France
3Institute of Cancer Research, Sutton, Surrey, United Kingdom
4Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA
5Computer Engineering Department, Bilkent University, Cankaya, Ankara, Turkey
6Department of Neurosurgery, University Hospital of Strasbourg, Strasbourg, France
7Department of Pathology, University Hospital of Strasbourg, Strasbourg, France
8Centre de Ressources Biologiques, University Hospital of Strasbourg, Strasbourg, France
9Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France
10Department of Pediatric Onco-hematology, University Hospital of Strasbourg, Strasbourg, France
*These authors have contributed equally to this work
Natacha Entz-Werlé, email: [email protected]
Keywords: high grade glioma, pediatric, HIF1alpha, mTor, targets
Received: June 14, 2016 Accepted: January 16, 2017 Published: March 23, 2017
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.
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