Journal Article

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

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

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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 / Brain tumors / 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 / Pharmacokinetics / Pharmacology / Platelet-derived growth factor / Pyrazoles - therapeutic use / Signaling / Survival / Survival Rate / Triazines - therapeutic use / TrkA protein / TrkB receptors / Tumors