title: Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas.
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.
authors.affiliation: Aix-Marseille Université, CNRS CRN2M UMR 7286, 13344, Marseille edex 15, France, tom.graillon@free.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graillon
authors.forename: Céline
authors.initials: C
authors.lastname: Defilles
authors.forename: Amira
authors.initials: A
authors.lastname: Mohamed
authors.forename: Christophe
authors.initials: C
authors.lastname: Lisbonis
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Germanetti
authors.forename: Olivier
authors.initials: O
authors.lastname: Chinot
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: Pierre-Hugues
authors.initials: PH
authors.lastname: Roche
authors.forename: Tarek
authors.initials: T
authors.lastname: Adetchessi
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fuentes
authors.forename: Philippe
authors.initials: P
authors.lastname: Metellus
authors.forename: Henry
authors.initials: H
authors.lastname: Dufour
authors.forename: Alain
authors.initials: A
authors.lastname: Enjalbert
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy*; D008579:Meningioma / Q000188:drug therapy*; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage; D025581:Neurofibromin 2 / Q000378:metabolism; D015282:Octreotide / Q000008:administration & dosage*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage; D017481:Receptors, Somatostatin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D007093:Imidazoles; D009025:Morpholines; C571178:NVP-BKM120; D025581:Neurofibromin 2; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D017481:Receptors, Somatostatin; D000068338:Everolimus; C093733:somatostatin receptor 2; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D015282:Octreotide