Oncotarget

Research Papers:

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

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

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Oncotarget. 2018; 9:36530-36541. https://doi.org/10.18632/oncotarget.26370

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Abstract

Hazel Anne Rogers1, Rebecca Chapman1, Holly Kings1, Julie Allard1, Jodie Barron-Hastings1, Kristian W. Pajtler2,3,4, Martin Sill2,3, Stefan Pfister2,3,4 and Richard Guy Grundy1

1Children’s Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, UK

2Hopp Children’s Cancer Centre at the NCT (KiTZ), Heidelberg, Germany

3German Cancer Research Centre (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

4Department of Haematology and Oncology, University Hospital, Heidelberg, Germany

Correspondence to:

Richard Guy Grundy, email: richard.grundy@nottingham.ac.uk

Keywords: ependymoma; brain tumor; epigenetics; pediatric

Received: May 16, 2018     Accepted: November 01, 2018     Published: November 23, 2018

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.


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