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

• Published in: PloS one 2015-03, Vol.10 (3), p.e0118926
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: AKT protein; Animal models; Animals; Anticancer properties; Antineoplastic Agents - therapeutic use; Antitumor activity; Brain; Brain cancer; Brain research; Brain Stem Neoplasms - drug therapy; Brain Stem Neoplasms - pathology; Cancer treatment; Chemical compounds; Clinical trials; Computer engineering; Consortia; Cytotoxicity; Disease Models, Animal; Dosage and administration; Drug delivery; Drug delivery systems; Drug screening; Drug therapy; Enzyme inhibitors; Gene expression; Genetic aspects; Genetic engineering; Glioma; Glioma - drug therapy; Glioma - pathology; Gliomas; High-throughput screening (Biochemical assaying); High-Throughput Screening Assays; In vivo methods and tests; Inhibition; Insulin; Insulin-like growth factors; Kinases; Laboratories; Medical prognosis; Medical research; Medical screening; Methods; Mice; Mice, Inbred C57BL; Mutation; Oncology; p53 Protein; Pathology; Pediatrics; Pharmacology; Platelet-derived growth factor; Pyrazoles - therapeutic use; Signaling; Survival; Survival Rate; Triazines - therapeutic use; TrkA protein; TrkB receptors; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0118926

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.