Everolimus improves the efficacy of dasatinib in the treatment of PDGFRA-driven glioma

MedRxiv : the Preprint Server for Health Sciences
Z. MikljaCarl Koschmann


Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. Treatment of PDGFRA-driven HGG with targeted agents, such as the tyrosine kinase inhibitor dasatinib, has failed in the clinic. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRA-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. Methods: Dose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. De novo tumors were generated in mice using intra-uterine electroporation (IUE) by injecting PB plasmids of TP53 mutation, PDGFRA mutation and H3K27M mutation (PPK) in the lateral vertical of mice embryos. Two children with recurrent PDGFRA-driven HGG were treated with dasatinib and everolimus with correlate CSF analysis. Results: Dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a dose-dependent reduction of PDGFRA and pPDGFRA. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents. Prolonged exposure to everolimus significantly improved the CNS retention of das...Continue Reading

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