Abstract
Gliomas are the most common type of pediatric brain tumors. One third of them are high grade gliomas (pHGG) with a significant dismal prognosis and a very poor therapeutic arsenal. So, new therapeutic ideas are needed to counterpart the high resistance to current treatments. Therefore, our team focused recently on the glutaminolysis switch, which was previously described in our work targeting mTor and HIF1 in pHGG cell lines. Therefore, to go further and understand its role in pHGG, we started with metabolomics analyses in our monocentric cohort of 34 pediatric high grade gliomas (14 DIPG, 10 thalamic and 10 sus-tentoriel high grade gliomas). First, we were testing 14 appropriate fresh-frozen samples at diagnosis for metabolomics and used the 34 FFPE specimens for validations. A second step of in vitro experimentation was performed to target specifically the different metabotropic glutamate receptors (mGluR) involved in pHGG glutamine metabolism. We used 6 HGG cell lines mutated or not for H3.3 K27M variant. In terms of results, metabolomics, done by HRMAS NMR, confirmed in tumors and in cell lines a high level of glutaminolysis, which is currently confirmed in all tumors by immunohistochemistry. This specific metabolic switch was also significantly observed by RNAsequencing analyses in our primary derived cell lines cultured in hypoxic conditions. Multiple genes, like mGluR8, mGluR2/3 and several subunits of the glutamate ionotropic receptors, were highly expressed. The in vitro blockade with mGluR2/3 NAM showed, finally, in our cell lines a significant decrease of proliferation, when using them as a single drug therapy, but also in association with temozolomide. This first in vitro work will be confirmed in our PDX mouse models of pHGG. Nevertheless, taking together, these promising results seem to be a scientifically-based rationale for testing mGluR antagonists as adjuvant therapy in pHGGs.