Date Published: March 6, 2015
Publisher: Public Library of Science
Author(s): 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, Marta M. Alonso.
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.
An estimated 4,000 new malignant and non-malignant brain tumors are diagnosed annually in children in the United States [1, 2]. Up to 20% of malignant central nervous system (CNS) tumors in children arise in the brainstem, with the majority being the diffuse intrinsic pontine glioma (DIPG) subtype [1, 3]. DIPG is a high-grade glioma (HGG) that originates in the pons and is seen almost exclusively in children with a median age at diagnosis of 6 to 7 years [4, 5].
An in vitro high-throughput drug screen conducted in collaboration with the Children’s Oncology Group CNS-DVL committee preclinical consortium identified BMS-754807 as a drug of interest using cell-lines derived from our genetically engineered mouse models of DIPG. In the current study, we evaluated the efficacy of BMS-754807, a known multi-kinase inhibitor whose targets include IGF-1R, Insulin-R, MET, ALK, TRKA, TRKB, AURKA and AURKB both in vitro and in vivo using the PDGF-B; H3.3K27M; p53 deficient DIPG model. Advantages of this genetically engineered mouse model include the ability to generate tumors with well-defined genetic alterations in the brainstem of immunocompetent mice. The tumors developed in this model are infiltrative and invade the surrounding normal brain similar to human DIPG lesions. However, genetically engineered mouse models such as this one may not harbor the full complement of genetic alterations found in the human disease and so preclinical drug screenings should also be performed in parallel with human tumor derived cells or mouse models. Another potential limitation of this model is that PDGF signaling is activated by the PDGF-B ligand while in the human disease it is more often activated by the PDGFRA receptor through amplification or mutation .
Here we use a genetically engineered mouse model of DIPG that includes the H3.3K27M mutation as a novel platform through which in vitro and in vivo evaluations can help prioritize drug therapies for clinical trials for children with DIPG. These findings demonstrate that BMS-754807, a potent multi-kinase inhibitor, can significantly reduce both viability and proliferation of DIPG tumor cells at doses of 0.1 μM and higher in vitro. We also demonstrate BMS-754807-mediated inhibition of AKT. The efficacy of BMS-754807 in vitro did not translate to a survival benefit in vivo potentially due to the limited drug delivery to the brainstem. If given with additional agents or delivered locally to increase its delivery to the tumor, it has the potential to be efficacious in vivo. These results are promising and imply that BMS-754807 is a potential therapeutic agent for DIPG and future experiments aim to identify additional therapies that may synergize with BMS-754807.