Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide

Tailored approaches targeting crucial oncogenes and pathways have shown successful results in a number of cancer types and offer exciting perspective in neuro-oncology. IDH (Isocitrate dehydrogenase) wild-type (IDHwt) glioblastoma (GBM) (10%) present a unique and homogenous energetic metabolism which is specifically dependent on the oxidative phosphorylation (OXPHOS) rather than on the aerobic glycolysis. OXPHOS+ IDHwt GBMs overexpress mitochondrial markers and can be specifically inhibited by mitochondrial inhibitors in vitro and in vivo. Metformin is an oral inhibitor of mitochondrial complex I and is a widely used drug in diabetic and non-diabetic patients, safe and well tolerated in association with radiotherapy and chemotherapy. Basing on drastic effect, the investigators have observed in vivo (reduction of \>50% of tumor growth) and hypothesize that metformin could be specifically efficient to treat up-front patients affected by OXPHOS+ GBM, in association with the standard first-line treatment with radiotherapy and temozolomide (RT-TMZ). The investigators set up a dedicated molecular analysis including RNA assay and expression of OXPHOS markers for formalin-fixed paraffin-embedded tumors (FFPE), which allows to detect OXPHOS+ GBM at diagnosis. Here a phase II, open label, non-randomized multicenter trial including five French neurooncology centers (H. Foch-Suresnes, Pitié-Salpêtrière-Paris, Saint Louis-Paris, Lyon, Marseille) and one in Italy (Istituto Besta, Milan) is proposed. Newly diagnosed IDH wild-type GBM patients with the OXPHOS+ signature will be eligible for inclusion in this trial. The investigators expect to screen 640 patients and to include 64 patients over a period of 24 months with 24 months of follow-up.