HGG-03. EVEROLIMUS TREATMENT IMPROVES THE CNS PENETRATION AND EFFICACY OF DASATINIB IN THE TREATMENT OF PDGFRA-DRIVEN PEDIATRIC HIGH-GRADE GLIOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA

ABSTRACT: Abstract Pediatric high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG) frequently harbor alterations in PDGFRA. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp in non-tumor models, would increase CNS penetration and efficacy of dasatinib in PDGFRA-driven HGG and DIPG. Dasatinib effectively treated mouse DIPG cells generated from an intra-uterine electroporation (IUE) model (TP53, PDGFRA and H3K27M mutations), with an IC50 of 100 nM and a dose-dependent reduction in PDGFRA and pPDGFRA by western blot. Using an in vitro P-gp inhibitor assay, we confirmed that everolimus strongly blocks P-gp activity at 1 uM (p=0.0028

SUBMITTER: Miklja Z 

PROVIDER: S-EPMC6477298 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature