Lgg-15. Combined Suppression of the Mtor and Mapk Pathways Inhibits Cell Proliferation and Decreases Vascularity in Pediatric Low Grade Glioma
Year: 2019
Type: conference-abstract
Abstract: Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in five patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1NF1mut, BT66_SV40BRAF:KIAA1549, BT40BRAFV600E, Res186PTEN-/- and Res259CDKN2A-/-. In all cell lines, trametinib treatment led to suppression of phospho-ERK at low levels (1-5nM; Western Blot). TAK228 treatment led to inhibition of mTORC1/2 in low nanomolar range. Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). We tested trametinib and TAK228 against the mutant BT40BRAFV600E patient-derived xenograft cells in immunodeficient mice. Combination of TAK228 with trametinib showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide a strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.
Source: Neuro-Oncology
Authors: Antje Arnold, Lauren Harris, Ming Yuan, Fausto Rodriguez, Charles Eberhart, Eric Raabe
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2941425777