Oral Presentation 46th Lorne Genome Conference 2025

Unveiling Epigenomic Vulnerabilities in Diffuse Midline Glioma: Paving the Way for Innovative Therapeutic Approaches (114885)

Yolanda Colino Sanguino 1 2 , Laura Rodriguez de la Fuente 1 2 3 , Sarah Fox 2 , Afraah Cassim 2 3 , Dana Kisswani 1 2 , Evangeline Jackson 4 5 , Ryan Duchatel 4 5 , Holly Holliday 1 6 , Anjana Gopalakrishnan 6 , Maria Tsoli 1 6 , Emily Dowling 2 , David Ziegler 1 6 , David Gallego Ortega 3 , Matthew Dun 4 5 , Fatima Valdes Mora 1 2
  1. School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Kensington, New South Wales, Australia
  2. Cancer Epigenetic Biology and Therapeutics, Children's Cancer Institute, Randwick, NSW, Australia
  3. School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, NSW, Australia
  4. Cancer Signalling Research Group, University of Newcastle, Callaghan, New South Wales, Australia
  5. Precision Medicine Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
  6. Brain Tumour Group, Children's Cancer Institute. Therapeutic Discovery Theme, Kensington, NSW, Australia

Diffuse midline glioma (DMG) is the most aggressive brain tumour in children, with a median survival of less than one year and with no cure. DMG is an epigenetically driven cancer, where more than 85% of the cases are characterised by a global loss of the repressive epigenetic mark, histone 3 trimethylation at the lysine 27 (H3K27me3). This is caused by a single somatic mutation in the histone H3, called H3K27M, or by the overexpression of the developmental gene EZHIP, a natural mimic of H3K27M, and subclassifies these DMGs as “H3K27-altered”. Unfortunately, the epigenomic landscape of H3K27-altered DMG is far from been completed and thus epigenetic therapies tested in DMG to date have not been rationalized based on such information. Our group’s mission is to complete the epigenomic landscapes on H3K27-altered DMGs, not only in the cancer cells but also in the cells from the tumour microenvironment (TME). Ultimately, we aim to use research-informed epigenetic therapy to target both the cancer cells and the cells from the TME as a novel therapeutic strategy for H3K27-altered DMG. Using epigenomic and single cell approaches, our group has defined the epigenomic changes that are specific of DMG malignancy. Our proteomic studies have also showed that the chromatin landscape in H3K27-altered DMG is chromatin permissive with an increase of overall histone acetylation. Using ChIP-seq for histone marks and ATACseq, we identified changes in enhancer activation for neural differentiation and stemness, and epigenetic erosion, respectively. Single-cell ATACseq has also revealed the epigenome landscape of infiltrated immune cells involved in tumour immunosuppression. Finally, a combinatorial epigenetic therapy based on the aforementioned molecular characteristics results in significant reduction of cancer growth both in in vivo and ex vivo DMG models. In conclusion, targeting the downstream epigenomic changes caused by H3K27M/EZHIP provides a promising therapeutic strategy in DMG.