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International audience; Recurrent or high-grade meningiomas are an unmet medical need. Recently, we demonstrated that targeting mTOR by everolimus was relevant both in vitro and in humans. However, everolimus induces an AKT activation that may impact the anti-proliferative effect of the drug. Moreover, the MAP kinase pathway was shown to be involved in meningioma tumorigenesis. We therefore targeted both the Pi3k-AKT-mTOR and MAP kinase pathways by using combinations of the Pi3k inhibitor alpelisib and the MEK inhibitor trametinib. Our study was performed in vitro on the human meningioma cell lines and on a large series of primary cultures providing from 63 freshly operated meningiomas including 35 WHO grade 1, 23 grade 2, and five grade 3, half of which presented a NF2 genomic alteration. Alpelisib induced a higher inhibitory effect on cell viability and proliferation than everolimus in all cell lines and 32 randomly selected tumors no matter the genomic status, the histological subtype or grade. Trametinib also strongly inhibited cell proliferation and induced AKT activation. Combined treatment with alpelisib plus trametinib reversed the AKT activation induced by trametinib and induced an additive inhibitory effect irrespective of the cell lines or tumor features. Co-targeting pathways seems promising and may be considered particularly for aggressive meningioma

International audience; Treatment for recurrent and aggressive meningiomas remains an unmet medical need in neuro-oncology, and chemotherapy exhibits limited clinical activity, if any. Merlin expression, encoded by the NF2 gene, is lost in a majority of meningiomas, and merlin is a negative regulator of mTORC1. The sst2 somatostatin receptor, targeted by octreotide, is highly expressed in meningiomas. To investigate new therapeutic strategies, we evaluated the activity of everolimus (mTOR inhibitor), BKM-120 and BEZ-235 (new Pi3K/Akt/mTOR inhibitors), octreotide and a combined treatment (octreotide plus everolimus), on cell proliferation, signaling pathways, and cell cycle proteins, respectively. The in vitro study was conducted on human meningioma primary cells extracted from fresh tumors, allowing the assessment of somatostatin analogs at the concentration levels used in patients. The results were correlated to WHO grades. Further, everolimus decreased cell viability of human meningiomas, but concomitantly, induced Akt activation, reducing the antiproliferative effect of the drug. The new Pi3K inhibitors were not more active than everolimus alone, limiting their clinical relevance. In contrast, a clear cooperative inhibitory effect of octreotide and everolimus was observed on cell proliferation in all tested meningiomas, including WHO grades II-III. Octreotide not only reversed everolimus-induced Akt phosphorylation but also displayed additive and complementary effects with everolimus on downstream proteins involved in translation (4EB-P1), and controlling cell cycle (p27Kip1 and cyclin D1). We have demonstrated a co-operative action between everolimus and octreotide on cell proliferation in human meningiomas, including aggressive ones, establishing the basis for a clinical trial.

International audience; Pasireotide is a somatostatin analog (SSA) that targets somatostatin receptor subtype 1 (SST1), SST2, SST3, and SST5 with a high affinity. Pasireotide has a better antisecretory effect in acromegaly, Cushing's disease, and neuroendocrine tumors than octreotide. In this study, we compared the effects of pasireotide to those of octreotide in vitro on meningioma primary cell cultures, both alone and in combination with the mTOR inhibitor everolimus. Significant mRNA expression levels of SST1, SST2, and SST5 were observed in 40.5%, 100%, and 35% of meningioma samples, respectively. Pasireotide had a significantly stronger inhibitory effect on cell proliferation than octreotide. The effect of pasireotide, but not of octreotide, was significantly stronger in the group expressing the highest level of SST1 mRNA. Combined treatment with pasireotide and everolimus induced a higher reduction in cell viability than that with octreotide plus everolimus. Moreover, pasireotide decreased Akt phosphorylation and reversed everolimus-induced Akt hyperphosphorylation to a higher degree than octreotide. Using 4E-BP1 siRNA (si4E-BP), we demonstrated that 4E-BP1 protein silencing significantly reversed the response to everolimus, both alone and in combination with SSAs. Moreover, si4E-BP completely reversed the inhibition of cyclin D1 expression level and the increase in p27kip1 induced by SSAs, both alone and in combination with everolimus. Our results strongly support the need for further studies on the combination of pasireotide and everolimus in medical therapy for meningiomas.

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 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.