Everolimus improves the efficacy of dasatinib in PDGFR[alpha]-driven glioma

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFR[alpha] alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFR[alpha]-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 PDGFR[alpha]-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 PDGFR[alpha] 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 PDGFR[alpha], 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 PDGFR[alpha]-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.
Introduction High-grade gliomas (HGGs) are common and aggressive pediatric and adult brain tumors. The median overall survival (OS) of adult patients diagnosed with glioblastoma (GBM), grade IV glioma, is 12.6 [...]