Potential Therapies and Biomarkers for Uveal Melanoma

Dr Clare Quigley Reports

A preclinical study highlights the potential utility of a candidate drug and biomarker in treating uveal melanoma. The international study of Irish and Spanish patients revealed the potential diagnostic utility of CysLT1 and ATP51F1B as biomarkers of uveal melanoma and the therapeutic potential of 1,4-dihydroxy quininib with ATP5F1B as a companion diagnostic to treat metastatic uveal melanoma.

“This research builds on our previous work evaluating compounds that can interfere with CysLT receptors in UM cells in the laboratory,” said Dr Kayleigh Slater, first author on the study, published in the January 2023 issue of Frontiers in Medicine.

“We developed a laboratory model of primary uveal melanoma from patient samples and a preclinical model of metastatic uveal melanoma. Then, we used biochemical and pharmacological tests to gather a range of data,” she explained. “This preclinical data shows us firstly that higher CysLT receptor levels in primary uveal melanoma tumours indicate poor prognosis. Secondly, our candidate drug affects the molecular hallmarks of the disease that enable the cancer to grow and spread in uveal melanoma models. Thirdly, we identified a biomarker that appears to predict which patients will not develop metastatic disease.”

Uveal melanoma is a rare cancer with an annual incidence of five per million in the United States, rising to as high as nine per million in Ireland. It is the most common intraocular malignancy, and death from metastatic disease occurs in up to half of patients affected. For uveal melanoma, as for cutaneous melanoma, the cancer arises from melanocytes. While fair complexion is an important risk factor in melanoma, an association with exposure to UV radiation for uveal melanoma is limited to iris melanoma and less well described in more posterior ciliary body and choroidal melanoma.

Current standard treatment is radiotherapy or enucleation. Despite this treatment, the melanoma will metastasize, usually to the liver, in one out of every two patients. There are limited treatment options once the disease spreads to the liver, with as few as 8% of patients surviving beyond two years.

Led by Professor Breandán Kennedy, this team used patient samples and experimental models to see if levels of these molecules, CysLT receptors, are linked to patient survival and what effect the candidate drug (1,4-dihydroxy quininib) has on them. CysLTs are involved in inflammation and known for playing a role in allergic diseases such as asthma. More recently, they have been implicated in many diseases, including central nervous system diseases and cancer.

“These are positive findings using an Irish and a Spanish cohort of patient samples in a disease that is the primary cause of eye cancer in Ireland,” Prof Kennedy said. “We have shown this candidate drug can act on the tumour and that the biomarkers could be valuable prognostic tools for clinicians to assess which patients are unlikely to develop metastatic disease.”

“Unfortunately, effective treatment for advanced stage (metastatic) uveal melanoma remains elusive in many cases,” said Mr Noel Horgan, consultant ophthalmologist, Royal Victoria Eye and Ear Hospital, Dublin. “Research continues to advance our understanding of this type of melanoma.”

For more information, visit https://www.frontiersin.org/articles/10.3389/fmed.2022.1036322/full

Breandán N Kennedy PhD is a Professor at the UCD Conway Institute and the UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland. brendan.kennedy@ucd.ie

Kayleigh Slater PhD was a post-doctoral scientist in the UCD Conway Institute and the UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland.