Study Uncovers Potential Biomarker and Candidate Drug for Uveal Melanoma

An international study involving Irish and Spanish patients has discovered a potential drug and biomarker for managing uveal melanoma (UM). UM, a rare form of eye cancer, starts in the melanocytes, cells responsible for eye color and is found in the back of the eye.

Ireland has one of the highest rates of this cancer, linked to factors such as fair skin, pale eyes, and increased risk of sunburn.

Current treatments for UM may involve the removal of the eye or direct radiotherapy. Despite these options, the cancer often spreads to the liver in half of all patients, leading to anxiety about the risk of metastasis even after life-altering surgery or local radiation therapy.

There is an increasing need for new treatments and ways to predict the spread of uveal melanoma (UM) to the liver as current options are limited and fewer than 8% of patients survive beyond two years. The study led by Professor Breandán Kennedy at the UCD School of Biomolecular & Biomedical Science and Fellow at the UCD Conway Institute aimed to address this need.

                                                                              Uveal Melanoma Credit: Nature.com 

The Research

The research initially focused on cysteinyl leukotriene (CysLT) receptors as potential biomarkers and drug targets for UM treatment. CysLT receptors are involved in inflammation and have been linked to a range of diseases, including cancer and asthma.

Using patient samples and experimental models, the team analyzed the relationship between CysLT receptor levels and patient survival, and evaluated the impact of a candidate drug, (1,4-dihydroxy quininib), on these levels.

According to Dr. Kayleigh Slater, the first author of the study, this research builds upon previous work evaluating compounds that can target CysLT receptors in UM cells.

"We developed a laboratory model of primary UM from patient samples and a preclinical model of metastatic UM. Then, we used biochemical and pharmacological tests to gather a range of data. This preclinical data shows us firstly that higher CysLT receptor levels in primary UM tumors is an indication of poor prognosis. Secondly, our candidate drug effects the molecular hallmarks of the disease that enable the cancer to grow and spread in UM models. Thirdly, we identified a biomarker that appears to predict which patients will not develop metastatic disease."

Professor Breandán Kennedy said, "These are positive findings using an Irish cohort of patient samples in a disease that is the primary cause of eye cancer in Ireland. We have shown that this candidate drug can act on the tumor and that the biomarkers could be valuable prognostic tools for clinicians to assess which patients are unlikely to develop metastatic disease. We are immensely grateful to the clinical team in the Royal Eye and Ear Hospital Dublin and the patients who agreed to partake in this study at a very difficult time in their lives."

Mr. Noel Horgan, consultant ophthalmologist, Royal Victoria Eye & Ear Hospital and St Vincent's University Hospital said, "Uveal melanoma, although uncommon, occurs more often in Ireland than in other parts of the world. Unfortunately, effective treatment for advanced-stage (metastatic) uveal melanoma remains elusive in many cases. Research continues to advance our understanding of this type of melanoma. Our team is delighted to collaborate with the research team at UCD in their efforts to make progress in the search for new and more effective treatments for this disease."

The research team, in collaboration with researchers from Spain and the U.K., has made patient involvement a priority from the beginning. Melody Buckley, a member of the patient support group Ocular Melanoma Ireland and a family member of a UM patient, expressed her excitement about the novel findings, saying "I am delighted that Irish researchers have published research that may lead to a future cure for this rare and deadly eye cancer."

The study is particularly significant as it suggests potential treatments for UM that have spread to the liver, a crucial need for patients who cannot use life-prolonging alternatives such as KIMMTRAK.

Reference: Kayleigh Slater et al, 1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model, Frontiers in Medicine (2023). DOI: 10.3389/fmed.2022.1036322