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- Title
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma.
- Authors
Miklja, Zachary; Yadav, Viveka Nand; Cartaxo, Rodrigo T; Siada, Ruby; Thomas, Chase C; Cummings, Jessica R; Mullan, Brendan; Stallard, Stefanie; Paul, Alyssa; Bruzek, Amy K; Wierzbicki, Kyle; Yang, Tao; Garcia, Taylor; Wolfe, Ian; Leonard, Marcia; Robertson, Patricia L; Garton, Hugh Jl; Wahl, Daniel R; Parmar, Hemant; Sarkaria, Jann N
- 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.
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 10, p5313
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI133310