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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.

Publication ,  Journal Article
Halvorson, KG; Barton, KL; Schroeder, K; Misuraca, KL; Hoeman, C; Chung, A; Crabtree, DM; Cordero, FJ; Singh, R; Spasojevic, I; Berlow, N ...
Published in: PLoS One
2015

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.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

3

Start / End Page

e0118926

Location

United States

Related Subject Headings

  • Triazines
  • Survival Rate
  • Pyrazoles
  • Mice, Inbred C57BL
  • Mice
  • High-Throughput Screening Assays
  • Glioma
  • General Science & Technology
  • Disease Models, Animal
  • Brain Stem Neoplasms
 

Citation

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Chicago
ICMJE
MLA
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Halvorson, K. G., Barton, K. L., Schroeder, K., Misuraca, K. L., Hoeman, C., Chung, A., … Becher, O. 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), e0118926. https://doi.org/10.1371/journal.pone.0118926
Halvorson, Kyle G., Kelly L. Barton, Kristin Schroeder, Katherine L. Misuraca, Christine Hoeman, Alex Chung, Donna M. Crabtree, et al. “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, no. 3 (2015): e0118926. https://doi.org/10.1371/journal.pone.0118926.
Halvorson, Kyle G., et al. “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, vol. 10, no. 3, 2015, p. e0118926. Pubmed, doi:10.1371/journal.pone.0118926.
Halvorson KG, Barton KL, Schroeder K, Misuraca KL, Hoeman C, Chung A, Crabtree DM, Cordero FJ, Singh R, Spasojevic I, Berlow N, Pal R, Becher OJ. 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. 2015;10(3):e0118926.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

3

Start / End Page

e0118926

Location

United States

Related Subject Headings

  • Triazines
  • Survival Rate
  • Pyrazoles
  • Mice, Inbred C57BL
  • Mice
  • High-Throughput Screening Assays
  • Glioma
  • General Science & Technology
  • Disease Models, Animal
  • Brain Stem Neoplasms