Everolimus improves the efficacy of dasatinib in the treatment of PDGFRA-driven glioma
Vivek Nand Yadav,
Chase C. Thomas,
Jessica R Cummings,
Amy K. Bruzek,
Patricia L. Robertson,
Daniel R Wahl,
Jann N. Sarkaria,
Sarah E.S. Leary,
Pai P. Manjunath,
Timothy N. Phoenix,
Bernard L. Marini,
Posted 02 Jan 2020
medRxiv DOI: 10.1101/2019.12.28.19015974
Posted 02 Jan 2020
BackgroundPediatric 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. MethodsDose 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. ResultsDasatinib 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 dasatinib and extended survival of PPK tumor bearing mice. Two children with recurrent PDGFRA-driven HGG treated with dasatinib and everolimus survived six months and nine months after progression. A paired CSF sample from the patient with PDGFRA-amplified HGG showed 50% increase in CSF dasatinib levels after the addition of everolimus. ConclusionEfficacy of dasatinib treatment of PDGFRA-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population. Trial RegistrationClinicalTrials.gov NCT03352427 FundingThe authors thank the patients and their families for participation in this study. CK is supported by NIH/NINDS K08-NS099427-01, the University of Michigan Chad Carr Pediatric Brain Tumor Center, the Chad Tough Foundation, Hyundai Hope on Wheels and Catching up with Jack. The PEDS-MIONCOSEQ study was supported by grant 1UM1HG006508 from the National Institutes of Health Clinical Sequencing Exploratory Research Award (PI: Arul Chinnaiyan).
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