Graillon Thomas, Defilles Céline, Mohamed Amira, Lisbonis Christophe, Germanetti Anne-Laure, Chinot Olivier, Figarella-Branger Dominique, Roche Pierre-Hugues, Adetchessi Tarek, Fuentes Stéphane, Metellus Philippe, Dufour Henry, Enjalbert Alain, Barlier Anne
Aix-Marseille Université, CNRS CRN2M UMR 7286, 13344, Marseille edex 15, France,
J Neurooncol. 2015 Aug;124(1):33-43. doi: 10.1007/s11060-015-1812-3. Epub 2015 May 27.
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.
复发性侵袭性脑膜瘤的治疗仍然是神经肿瘤学中尚未满足的医疗需求，而化疗即便有临床活性也很有限。由NF2基因编码的Merlin表达在大多数脑膜瘤中缺失，且Merlin是mTORC1的负调节因子。奥曲肽靶向的sst2生长抑素受体在脑膜瘤中高度表达。为了研究新的治疗策略，我们分别评估了依维莫司（mTOR抑制剂）、BKM-120和BEZ-235（新型Pi3K/Akt/mTOR抑制剂）、奥曲肽以及联合治疗（奥曲肽加依维莫司）对细胞增殖、信号通路和细胞周期蛋白的作用。体外研究在从新鲜肿瘤中提取的人脑膜瘤原代细胞上进行，从而能够评估患者使用浓度水平的生长抑素类似物。结果与世界卫生组织（WHO）分级相关。此外，依维莫司降低了人脑膜瘤的细胞活力，但同时诱导了Akt激活，降低了药物的抗增殖作用。新型Pi3K抑制剂并不比单独使用依维莫司更具活性，限制了它们的临床相关性。相反，在所有测试的脑膜瘤（包括WHO II - III级）中，观察到奥曲肽和依维莫司对细胞增殖有明显的协同抑制作用。奥曲肽不仅逆转了依维莫司诱导的Akt磷酸化，还与依维莫司在参与翻译的下游蛋白（4EB-P1）以及控制细胞周期的蛋白（p27Kip1和细胞周期蛋白D1）上表现出相加和互补作用。我们已经证明依维莫司和奥曲肽在人脑膜瘤（包括侵袭性脑膜瘤）的细胞增殖上有协同作用，为临床试验奠定了基础。
