Poster Presentation 46th Lorne Genome Conference 2025

Harnessing epigenetic vulnerabilities for the treatment of H3K27-altered diffuse midline glioma (#133)

Sarah L Fox 1 , Yolanda Colino Sanguino 1 2 , Afraah Cassim 1 , Evangeline R Jackson 3 , Ryan J Duchatel 3 4 , Laura Rodriguez de la Fuente 1 2 , Emily Dowling 1 , Anjana Gopalakrishnan 5 , Maria Tsoli 5 , David Ziegler 5 , David Gallego-Ortega 6 , Matthew Dun 3 4 , Fatima Valdes Mora 1 2
  1. Cancer Epigenetic Biology and Therapeutics, Children's Cancer Institute, Randwick, NSW, Australia
  2. Faculty of Medicine and Health, UNSW, School of Clinical Medicine, Sydney, NSW, Australia
  3. Cancer Signalling Research Group, University of Newcastle, Callaghan, NSW, Australia
  4. Precision Medicine Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  5. Molecular Targets and Cancer Therapeutics, Children's Cancer Institute, Sydney, NSW, Australia
  6. Faculty of Engineering and Information Technology, UTS, School of Biomedical Engineering, Sydney, NSW, Australia

Diffuse midline glioma (DMG) is a lethal paediatric brain cancer with less than 10% of patients surviving beyond 2 years from diagnosis1. It is an epigenetically driven cancer with more than 80% of DMG cases containing a somatic mutation at the lysine 27 to methionine in histone H3 (H3K27M)2.  Studies have shown that this mutation causes major epigenomic alterations with an overall increase in histone acetylation and decrease in histone lysine K27 trimethylation, yet targeting the genetic mutation H3K27M directly is currently not possible3.We hypothesised that targeting the epigenomic alterations driven by H3K27M may be an alternative approach to target the pro-oncogenic features of this mutation and, therefore, have studied inhibitors of two major epigenetic factors, one that writes histone acetylation, p300, and one that erases H3K27 methylation, JMJD3/UTX. We investigated the effects of various epigenetic drugs that target different p300 protein domains, GNE-049 and A-485, as well as GSK-J4, a drug that inhibits H3K27 demethylation, either as single or combination treatments in several DMG cellular models. Our data reveals that combinatorial treatment with GNE-049 and GSK-J4 is more effective than single treatments, and it inhibits DMG cell growth in both in vitro and ex vivo models. We are currently investigating the transcriptomic consequences of this combinatorial epigenetic therapy to advance our understanding of the mechanism of action. This ongoing study provides pre-clinical evidence for the use of p300 inhibitors in combination with H3K27 demethylase inhibitors as an epigenetic therapy for DMG.

  1. Warren, K., Diffuse intrinsic pontine glioma: poised for progress. Front Oncol. 2012; 2: 205. 2012, Epub 2013/01/08.
  2. Khuong-Quang, D.A., et al., K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol, 2012. 124(3): p. 439-47.
  3. Chan, K.M., et al., The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev, 2013. 27(9): p. 985-90.