1. Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
- Author
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Sabine Mueller, Rodrigo Cartaxo, Viveka Nand Yadav, Rajen Mody, Cassie Kline, Alyssa Paul, Zachary Miklja, Brendan Mullan, Patricia L. Robertson, Ruby Siada, Marcia Leonard, Sriram Venneti, Taylor Garcia, Amy K. Bruzek, Stefanie Stallard, Hugh J. L. Garton, Bernard L. Marini, Carl Koschmann, Chase Thomas, Kyle Wierzbicki, Jann N. Sarkaria, Arul M. Chinnaiyan, Theodore Nicolaides, Daniel R. Wahl, Sarah Leary, Chandan Kumar-Sinha, Chana Glasser, Hemant Parmar, Jessica R. Cummings, Ian Wolfe, Tao Yang, Timothy N. Phoenix, and Manjunath P. Pai
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_treatment ,Dasatinib ,Gene Expression ,Tyrosine-kinase inhibitor ,Targeted therapy ,Mice ,0302 clinical medicine ,Pregnancy ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Medicine ,Molecular Targeted Therapy ,Child ,0303 health sciences ,Brain Neoplasms ,Drug Synergism ,Glioma ,General Medicine ,3. Good health ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Research Article ,medicine.drug ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Adolescent ,medicine.drug_class ,PDGFRA ,Receptor, Platelet-Derived Growth Factor beta ,03 medical and health sciences ,Pharmacokinetics ,In vivo ,Internal medicine ,Animals ,Humans ,Everolimus ,Adverse effect ,Cell Proliferation ,030304 developmental biology ,business.industry ,medicine.disease ,030104 developmental biology ,Drug Screening Assays, Antitumor ,business - Abstract
BackgroundPediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-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. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus.ResultsDasatinib 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 reduction in mTOR signaling that persists after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Pediatric patients (n=6) with glioma tolerated this combination without significant adverse events. Recurrent patients (n=4) demonstrated median overall survival of 8.5 months.ConclusionEfficacy of dasatinib treatment of PDGFRα-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population.Trial RegistrationClinicalTrials.gov NCT03352427FundingThe 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, Catching up With Jack, Prayers from Maria Foundation, U CAN-CER VIVE FOUNDATION, Morgan Behen Golf Classic, and the DIPG Collaborative. The PEDS-MIONCOSEQ study was supported by grant 1UM1HG006508 from the National Institutes of Health Clinical Sequencing Exploratory Research Award (PI: Arul Chinnaiyan).
- Published
- 2020
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