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

Kyle G. Halvorson, Kelly L. Barton, Kristin Schroeder, Katherine L. Misuraca, Christine Hoeman, Alex Chung, Donna M. Crabtree, Francisco J. Cordero, Raj Singh, Ivan Spasojevic, Noah Berlow, Ranadip Pal, Oren J. Becher

Research output: Contribution to journalArticle

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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-PLOS 754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.

Original languageEnglish (US)
Article numbere0118926
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 6 2015

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Glioma
animal models
Throughput
drugs
therapeutics
Pharmaceutical Preparations
Bearings (structural)
inhibitory concentration 50
Therapeutics
neoplasms
Inhibitory Concentration 50
mice
Aurora Kinase A
in vitro studies
pharmacokinetics
cytotoxicity
Pediatrics
Pharmacokinetics
clinical trials
phosphotransferases (kinases)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Halvorson, Kyle G. ; Barton, Kelly L. ; Schroeder, Kristin ; Misuraca, Katherine L. ; Hoeman, Christine ; Chung, Alex ; Crabtree, Donna M. ; Cordero, Francisco J. ; Singh, Raj ; Spasojevic, Ivan ; Berlow, Noah ; Pal, Ranadip ; Becher, Oren J. / 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. In: PloS one. 2015 ; Vol. 10, No. 3.
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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-PLOS 754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.",
author = "Halvorson, {Kyle G.} and Barton, {Kelly L.} and Kristin Schroeder and Misuraca, {Katherine L.} and Christine Hoeman and Alex Chung and Crabtree, {Donna M.} and Cordero, {Francisco J.} and Raj Singh and Ivan Spasojevic and Noah Berlow and Ranadip Pal and Becher, {Oren J.}",
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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 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, vol. 10, no. 3, e0118926. https://doi.org/10.1371/journal.pone.0118926

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. / Halvorson, Kyle G.; Barton, Kelly L.; Schroeder, Kristin; Misuraca, Katherine L.; Hoeman, Christine; Chung, Alex; Crabtree, Donna M.; Cordero, Francisco J.; Singh, Raj; Spasojevic, Ivan; Berlow, Noah; Pal, Ranadip; Becher, Oren J.

In: PloS one, Vol. 10, No. 3, e0118926, 06.03.2015.

Research output: Contribution to journalArticle

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T1 - 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

AU - Halvorson, Kyle G.

AU - Barton, Kelly L.

AU - Schroeder, Kristin

AU - Misuraca, Katherine L.

AU - Hoeman, Christine

AU - Chung, Alex

AU - Crabtree, Donna M.

AU - Cordero, Francisco J.

AU - Singh, Raj

AU - Spasojevic, Ivan

AU - Berlow, Noah

AU - Pal, Ranadip

AU - Becher, Oren J.

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Y1 - 2015/3/6

N2 - 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-PLOS 754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.

AB - 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-PLOS 754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.

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