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dc.contributor.author Halvorson, KG
dc.contributor.author Barton, KL
dc.contributor.author Schroeder, K
dc.contributor.author Misuraca, KL
dc.contributor.author Hoeman, C
dc.contributor.author Chung, A
dc.contributor.author Crabtree, DM
dc.contributor.author Cordero, FJ
dc.contributor.author Singh, R
dc.contributor.author Spasojevic, I
dc.contributor.author Berlow, N
dc.contributor.author Pal, R
dc.contributor.author Becher, OJ
dc.coverage.spatial United States
dc.date.accessioned 2016-08-01T21:58:26Z
dc.date.issued 2015
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/25748921
dc.identifier PONE-D-14-07346
dc.identifier.citation PLoS One, 2015, 10 (3), pp. e0118926 - ?
dc.identifier.uri http://hdl.handle.net/10161/12567
dc.description.abstract Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.
dc.format.extent e0118926 - ?
dc.language eng
dc.relation.ispartof PLoS One
dc.relation.isversionof 10.1371/journal.pone.0118926
dc.subject Animals
dc.subject Antineoplastic Agents
dc.subject Brain Stem Neoplasms
dc.subject Disease Models, Animal
dc.subject Glioma
dc.subject High-Throughput Screening Assays
dc.subject Mice
dc.subject Mice, Inbred C57BL
dc.subject Pyrazoles
dc.subject Survival Rate
dc.subject Triazines
dc.title A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.
dc.type Journal Article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/25748921
pubs.issue 3
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Faculty
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Medical Oncology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published online
pubs.volume 10
dc.identifier.eissn 1932-6203

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