Introduction: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Patient Care: 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.
Learning Objectives: 1. In vitro drug assays demonstrating promising new targets in treating DIPG are potentially plagued by poor translation to clinical benefit.
2. Preclinical models of DIPG including the H3.3K27M mutation are critical for accurate representation of the biology of this disease as well as selection of potential therapeutics to advance to clinical trials.
3. Poor drug delivery paradigms limit in vivo efficacy of novel therapeutics in treating DIPG.