Brendan Mullan
Research Subjects
Research Interests
Brendan Mullan has a total of 32 co-authors. Here are the top co-authors by number of shared publications:
- Alyssa Paul
Department of Pediatrics
1 shared publication - Amy K. Bruzek
Department of Neurosurgery
1 shared publication - Arul M. Chinnaiyan
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
1 shared publication - Bernard Lawrence Marini
University of Michigan College of Pharmacy, University of Michigan Health
1 shared publication - Carl Koschmann
Department of Pediatric Hematology and Oncology, Michigan Medicine, Ann Arbor, MI, United States
1 shared publication - Cassie Kline
Division of Oncology The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA
1 shared publication
Latest Publications
- 1 October 2020
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 130 (10) , 5313-5325
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
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.
- 1 October 2020
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 130 (10) , 5313-5325
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
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.