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J Clin Invest ; 130(10): 5313-5325, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32603316

ABSTRACT

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Dasatinib/administration & dosage , Everolimus/administration & dosage , Glioma/drug therapy , Glioma/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Adolescent , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Brain Neoplasms/metabolism , Cell Proliferation/drug effects , Child , Child, Preschool , Dasatinib/pharmacokinetics , Drug Screening Assays, Antitumor , Drug Synergism , Everolimus/pharmacokinetics , Female , Gene Expression , Glioma/metabolism , Humans , Male , Mice , Molecular Targeted Therapy , Pregnancy , Tumor Cells, Cultured
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