HG-10HYPOXIA PATHWAY DRIVEN BY HIF-1ALPHA ARE PREDOMINANTLY INVOLVED IN PEDIATRIC HIGH GRADE GLIOMA AND REPRESENT PROMISING THERAPEUTIC TARGETS.

Hypoxia is frequently involved in cancer progression and is a way for tumor cells to escape to conventional therapies. In hypoxic conditions, the induction of Hypoxia Inducible Factor-1 alpha (HIF-1alpha) will favor the tumor cell adaptation. This transcription factor is a global regulator of oxygen homeostasis and plays a crucial role in angiogenesis, cell metabolism and migration. In the pediatric high grade gliomas (HGGs), few data are available on hypoxia pathways. Therefore, in an unicentric cohort of pediatric HGGs, we studied in tumor samples and in tumor-derived cell lines the role and therapeutic value of HIF-1alpha and its upstream regulators. 25 pediatric HGGs and 8 DIPGs (diffuse intra-pontine gliomas), mutated in 14 cases for histone H3.3) were explored. Transcriptomic analyses were performed in 8 HGGs comparatively to 20 low grade astrocytomas (LGGs). All samples were analyzed at protein level in a TMA focusing on HIF-1alpha and HIF-2 proteins and their upstream regulators. The 2 patient-derived cell lines (1 thalamic pediatric high grade glioma and 1 DIPG) were analyzed in in vitro normoxic and hypoxic conditions and in orthotopic animal models (striatum). Several drugs targeting MEK, mTor and HIF-1alpha were tested. To identify hypoxia markers, we queried the microarray profiling and discovered that HIF-1alpha, but also VHL, MAPK1, H- and K-RAS, VEGFA and PARP1, are particularly overexpressed, which was confirmed on tumors' TMA. In the cell lines, we confirmed the crucial role of hypoxia induction in in vitro and in vivo conditions. Moreover, the inhibition of MEK, mTor and/or HIF-1alpha in cell lines show in a single drug approach or in combination an impact on cell proliferation. This observation was confirmed with mTor/HIF-1 alpha targeting in animal models. Our results suggest that targeting hypoxia pathway might be a therapeutic strategy potentially effective in pediatric DIPGs and HGGs.