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.
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.
Type
Journal articleSubject
AnimalsAntineoplastic Agents
Brain Stem Neoplasms
Disease Models, Animal
Glioma
High-Throughput Screening Assays
Mice
Mice, Inbred C57BL
Pyrazoles
Survival Rate
Triazines
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https://hdl.handle.net/10161/12567Published Version (Please cite this version)
10.1371/journal.pone.0118926Publication Info
Halvorson, Kyle G; Barton, Kelly L; Schroeder, Kristin; Misuraca, Katherine L; Hoeman,
Christine; Chung, Alex; ... Becher, Oren J (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 https://hdl.handle.net/10161/12567.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Oren Josh Becher
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
Javi Cordero
Research Program Leader
Kristin M. Schroeder
Associate Professor of Pediatrics
I have a strong belief that all children diagnosed with cancer should have the same
chance of cure regardless of where they live. Since 2014, i have spent six or more
months per year in Mwanza, Tanzania, at the Bugando Medical Centre as part of the
Duke Global Cancer Program. In addition to developing capacity for pediatric cancer
care, my research focuses on creating interventions to improve outcomes and reducing
treatment abandonment in low resource settings. As a trained pedi
Ivan Spasojevic
Associate Professor in Medicine
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