Oral Presentation Australasian Melanoma Conference 2026

Targeting Epigenetic Enzymes in Metastatic Uveal Melanoma (#97)

Emilie Jaune-Pons 1 , Kirill Orlov 1 , Joyce Tang 1 , Greg Kelly 2 , Michele Madigan 3 4 , Helen Rizos 5 6 , Anthony Joshua 7 8 , Nicholas Hayward 2 , Jason S Lee 1 9
  1. Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
  2. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  3. Save Sight Institute, The University of Sydney, Sydney, NSW, Australia
  4. School of Optometry and Vision Science, University of New South Wales, Sydney, NSW, Australia
  5. Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
  6. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
  7. Kinghorn Cancer Centre, St. Vincent's Hopital, Sydney, NSW, Australia
  8. Garvan Institute of Medical Research, University of New South Wales, Sydney, NSW, Australia
  9. School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

Uveal melanoma (UM) is a rare ocular melanoma with a marked propensity for metastasis and poor survival once advanced disease develops, underscoring a major unmet clinical need. In contrast to cutaneous melanoma, UM has an exceptionally low tumour mutational burden (0.51 mutations/Mb), limiting the number of actionable genomic alterations and likely contributing to the limited efficacy of current immunotherapies and targeted therapies. These features highlight epigenetic dysregulation as a plausible and potentially targetable driver of UM progression and therapeutic resistance.

Using The Cancer Genome Atlas Uveal Melanoma PanCancer Atlas, we identified a panel of epigenetic regulators, including a histone methyltransferase, that were overexpressed in more than 50% of UM tumours. Pharmacological inhibition of this enzyme induced robust cell death in UM cell lines and suppressed tumour growth in UM-bearing mice without overt toxicity, supporting its therapeutic relevance. To further define its role in UM biology, we analysed a published single-cell RNA-sequencing dataset (Durante et al., 2020) and found that expression of this enzyme was enriched in malignant UM cells relative to non-malignant ocular cells. Expression was further increased in metastatic UM samples and in PRAME-positive UM cells, linking this target to biologically aggressive disease states with high translational relevance.

Notably, this histone methyltransferase was also expressed across multiple immune cell populations within the UM microenvironment. In cytotoxic T cells, higher expression was associated with increased expression of exhaustion markers, suggesting that this enzyme may contribute not only to tumour-intrinsic survival programs but also to immune dysfunction that limits effective anti-tumour responses.

Ongoing studies are evaluating the therapeutic impact of enzyme inhibition in orthotopic metastatic UM models and using multicolour flow cytometry to define treatment-induced changes in immune cell composition and T cell exhaustion states. Together, these findings identify this histone methyltransferase as a promising therapeutic target in metastatic UM and provide a strong rationale for epigenetic therapy as a strategy to both suppress tumour growth and remodel the immune microenvironment. This work may guide the development of next-generation epigenetic therapies for UM and other low-mutation, therapy-resistant malignancies.