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BACKGROUND Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In our preclinical model on meningioma primary cell culture, the combination of the mTOR inhibitor, everolimus and the somatostatin analog, octreotide decreased cell viability and proliferation without inducing apoptosis. The interest of the combined treatment everolimus plus octreotide were clinically validated by the CEVOREM clinical trial demonstrating a decrease in growth rate of meningiomas in most treated patients. Nevertheless, everolimus induced an increase in Akt activity in vitro, which probably limited everolimus efficiency. We hypothesized that targeting Pi3K could prevent this positive feedback on Akt phosphorylation, induced by mTOR inhibition. The involvement of MAPKinase pathway in meningioma tumorigenesis was recently demonstrated. Our aim was to decipher the effect of the Pi3k α inhibitor Alpelisib (BYL719) and the specific inhibitor of MEK1,2 Mekinist (Trametinib) alone or in combination, in comparison to the mTor inhibitor everolimus on human meningioma primary cell cultures. MATERIAL AND METHODS The impact of the drugs was studied on 40 meningiomas, well characterized at clinical, histological and molecular level. The cell viability, cell proliferation and apoptosis were analyzed under drugs. RESULTS BYL719 induced a dose dependent decrease in cell viability (maximal effect -90%, IC50 10-6M) in all tested meningiomas (n=30). This effect was stronger than those of everolimus (maximal effect -50%, n=24, IC50 10-8M). 22 tumors were sensitive to Trametinib (maximal effect &lt;-50%, IC50 10–5 M), 14 were partially sensitive (maximal effect between -20 and -40% IC50 10–5 M) and 3 were resistant. An apoptotic effect was observed under BYL719 in 6/18 tested tumors whereas no apoptosis was observed under Trametinib and Everolimus. Combination of BYL719 and Trametinib induced a significant stronger decrease in cell viability than each drug alone. Correlation analysis between these functional results, the tumor genomic profile and the activation of ERK/MEK kinase pathway is ongoing. CONCLUSION PI3K-Akt-mTOR and ERK/MEK kinase pathways constitute relevant targets in aggressive meningioma therapy. In our preclinical model, previously validated by CEVOREM clinical trial, co-targeting Pi3k-Akt-mTOR and MAPkinase pathways improved cell proliferation inhibition in comparison to the target of each pathway alone. BYL719 induced apoptosis which was not achieved by everolimus. These results support the ongoing clinical trial ALTREM combining Alpelisib and Trametinib on patients harboring aggressive recurrent meningiomas.

OS8.7 Targeting Pi3k-Akt-mTOR and MAPKinase pathways in aggressive meningiomas: in vitro study