by ecancer reporter Janet Fricker

Boosting gene methylation could help treat paediatric gliomas, suggests a US study published in Nature Medicine.

Currently few treatment options are available for children with diffuse intrinsic pontine gliomas, and surgery does not represent an option as tumours are dispersed through important regions of the brain.

Recent genetic studies have identified that many of these tumours have alterations in the H3F3A gene, which encodes histone variant H3.3.

The most commonly seen H3F3A mutation causes substitution of lysine-27 with methionine (K37M), abolishing a crucial site of regulatory post-translational methylation.

Such mutations are believed to drive tumour growth by causing reduced histone K27 methylation that alters gene expression in cells of the developing pons.

Rintaro Hashizume and colleague, from Northwestern University, Chicago, Illinois, hypothesised that pharmacologic reversal of brainstem glioma demyethylation might serve as an effective therapeutic strategy for glioma.

For the study the investigators explored GSKJ4, an inhibitor of the K27-demethylase, both invitro against K27M cell lines and in vivo against K27M mice xenografts.

For the invitro study the team found that GSKJ4 resulted in an increase in cellular H3F3A methylation.

In the in vivo study they showed intraperitoneal injection of GSKJ4 in mice for 10 consecutive days in comparison to untreated controls resulted in a significant reduction in the growth of tumours engrafted in mice brain stems (P=0.0418) and to increases in survival (P =0.0344).

Analysis of K27M tumours obtained from mice at the end of therapy showed significantly less Ki-67 staining (a measure of cell proliferation) (P<0.0001) and significantly higher TUNEL positivity (a measure of apoptotic activity), (P<0.0001).

“Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma,” write the authors, adding this approach warrants further investigation.

Reference

R Hashizume, N Andor, Y Ihara, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nature Medicine.