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Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

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Abstract

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.

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Acknowledgments

Tumor specimens were stored in the AP-HM tumor bank AC 2013-1786. We thank Gary Burkhart and Enago for proofreading. The study was partially supported by Novartis International.

Financial support for this study

Novartis France, Centre National de la Recherche Scientifique (CNRS UMR 7286), Aix Marseille University and Association pour le Développement des Recherches Biologiques et Médicales au Centre Hospitalier Régional de Marseille (ADEREM). Amira MOHAMED was a recipient of a fellowship from the Association pour le Developpement des Recherches Biologiques et Medicales au Centre Hospitalier Régional de Marseille (2010/2011) through funding from Novartis.

Funding Source

Novartis funding was used for a fellowship for a PhD student (A. Mohamed).

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Authors and Affiliations

  1. Aix-Marseille Université, CNRS CRN2M UMR 7286, 13344, Marseille edex 15, France

    Thomas Graillon, Céline Defilles, Amira Mohamed, Christophe Lisbonis, Alain Enjalbert & Anne Barlier

  2. Neurosurgical Department, APHM, Hôpital La Timone, 13005, Marseille, France

    Thomas Graillon, Tarek Adetchessi, Stéphane Fuentes, Philippe Metellus & Henry Dufour

  3. Molecular Biology Laboratory, APHM, Hôpital Conception, 13385, Marseille, France

    Anne-Laure Germanetti, Alain Enjalbert & Anne Barlier

  4. Neurooncology Department, APHM, Hôpital La Timone, 13005, Marseille, France

    Olivier Chinot

  5. Neuropathology Department, APHM, Hôpital La Timone, 13005, Marseille, France

    Dominique Figarella-Branger

  6. Neurosurgical Department, APHM, Hôpital Nord, 13011, Marseille, France

    Pierre-Hugues Roche

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  1. Thomas Graillon
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Correspondence to Thomas Graillon.

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Graillon, T., Defilles, C., Mohamed, A. et al. Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas. J Neurooncol 124, 33–43 (2015). https://doi.org/10.1007/s11060-015-1812-3

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  • DOI: https://doi.org/10.1007/s11060-015-1812-3

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