Limitations of current in vitro models for testing the clinical potential of epigenetic inhibitors for treatment of pediatric ependymoma

Rogers, Hazel Anne; Chapman, Rebecca; Kings, Holly; Allard, Julie; Barron-Hastings, Jodie; Pajtler, Kristian W.; Sill, Martin; Pfister, Stefan; Grundy, Richard Guy

Abstract

Background: Epigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target.

Results: Agents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses. Additionally, DNA methylation profiling revealed a lack of similarity to primary ependymomas suggesting alterations were induced during culture. Toxicity to fetal neural stem cells was also seen at similar drug concentrations

Conclusions: Agents targeting epigenetic modifications were able to inhibit the growth and induced the death of ependymoma cells grown in vitro. However, many agents were only active at high doses, outside clinical ranges, and also resulted in toxicity to normal brain cells. The lack of similarity in DNA methylation profiles between cultured cells and primary ependymomas questions the validity of using in vitro cultured cells for pre-clinical analysis of agents targeting epigenetic mechanisms and suggests further investigation using models that are more appropriate should be undertaken before agents are taken forward for clinical testing.

Materials and Methods: The effects of agents targeting epigenetic modifications on the growth and death of a panel of ependymoma cell lines was investigated, as well as toxicity to normal fetal neural stem cells. The ependymoma cell lines were characterized using DNA methylation profiling.

Citation

Rogers, H. A., Chapman, R., Kings, H., Allard, J., Barron-Hastings, J., Pajtler, K. W., …Grundy, R. G. (2018). Limitations of current in vitro models for testing the clinical potential of epigenetic inhibitors for treatment of pediatric ependymoma. Oncotarget, 9(92), 36530-36541. https://doi.org/10.18632/oncotarget.26370

• Journal Article Type: Article
• Acceptance Date: Nov 1, 2018
• Online Publication Date: Nov 12, 2018
• Publication Date: Nov 23, 2018
• Deposit Date: Feb 14, 2019
• Publicly Available Date: Feb 14, 2019
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 92
• Pages: 36530-36541
• DOI: https://doi.org/10.18632/oncotarget.26370
• Keywords: Ependymoma; Brain tumor; Epigenetics; Pediatric
• Public URL: https://nottingham-repository.worktribe.com/output/1548547
• Publisher URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26370&path[]=82126