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.
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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.
Brain Stem Neoplasms
Disease Models, Animal
High-Throughput Screening Assays
Mice, Inbred C57BL
Published Version (Please cite this version)10.1371/journal.pone.0118926
Publication InfoBarton, KL; Becher, Oren J; Berlow, N; Chung, A; Cordero, FJ; Crabtree, DM; ... Spasojević, Ivan (2015). 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. PLoS One, 10(3). pp. e0118926. 10.1371/journal.pone.0118926. Retrieved from http://hdl.handle.net/10161/12567.
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Associate Professor of Pediatrics
My laboratory interests are to apply genetic mouse models of pediatric brain tumors to prioritize the translation of novel agents into clinical trials. In particular, my laboratory is using a genetic mouse model of Diffuse Intrinsic Pontine Gliomas to determine therapeutic targets, mechanisms of resistance to targeted agents, unravel new ways to bypass the blood-brain-barrier, and investigate region-specific differences between gliomagenesis in the brainstem and the cortex. My laboratory
Assistant Professor of Pediatrics
Associate Professor in Medicine
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