期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 10, 页码 5313-5325出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI133310
关键词
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资金
- National Institute of Neurological Disorders and Stroke (NINDS), NIH [K08-NS099427-01]
- University of Michigan Chad Carr Pediatric Brain Tumor Center
- Chad Tough Foundation
- Hyundai Hope on Wheels
- Catching up With Jack
- Prayers from Maria Foundation
- U CAN-CER VIVE Foundation
- Morgan Behen Golf Classic
- DIPG Collaborative
- Clinical Sequencing Exploratory Research Award from the NIH [1UM1HG006508]
Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA 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 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 PDGFR alpha-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.
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