mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models

• Published in: Clinical cancer research Vol. 19; no. 5; pp. 1180 - 1189
• Main Authors: PACHOW, Doreen, ANDRAE, Nadine, KLIESE, Nadine, ANGENSTEIN, Frank, STORK, Oliver, WILISCH-NEUMANN, Annette, KIRCHES, Elmar, MAWRIN, Christian
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2013
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Blotting, Western; Cell Adhesion; Cell Proliferation; Disease Models, Animal; Genes, Neurofibromatosis 2 - physiology; Humans; Immunoenzyme Techniques; Male; Mechanistic Target of Rapamycin Complex 1; Medical sciences; Meningeal Neoplasms - metabolism; Meningeal Neoplasms - pathology; Meningeal Neoplasms - prevention & control; Meningioma - metabolism; Meningioma - pathology; Meningioma - prevention & control; Mice; Mice, Nude; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neoplasm Grading; Neurology; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumor Cells, Cultured; Tumors of the nervous system. Phacomatoses; Animal model; Nervous system diseases; Vertebrata; Mammalia; Mouse; Growth; Rodentia; Inhibitor; Benign neoplasm; Meningioma
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-1904

To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models. Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls. All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors. mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival.