Accelerating The Route Towards Metastatic Uveal Melanoma Diagnosis And Treatment

Dr. Valentina Tonelotto

Dr. Valentina Tonelotto was awarded an IRC Enterprise Partnership Scheme Post-Doctoral Award 2022. Dr Tonelotto will work in the lab of Prof. Breandan Kennedy at UCD.  The full title of her research is: “Accelerating the route towards metastatic uveal melanoma diagnosis and treatment: cysteinyl leukotriene receptor signalling & uveal melanoma extracellular vesicles as novel therapeutic targets and biomarkers”.

This research investigates the disease relevance and therapeutic potential of a protein called “cysteinyl leukotriene receptors (CysLT)” in uveal melanoma (UM). UM is a cancer arising within the eye, which frequently spreads to the liver, with up to 50% of patients developing metastatic UM (MUM). Unfortunately, once MUM occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. No effective therapies are available for MUM.  Prof Kennedy’s group has recently identified that increased levels of these receptors in UM tumours are associated with reduced patient survival. In preclinical models, drugs targeting CysLT receptors were seen to affect UM cell growth and other hallmarks of cancer. Valentina will investigate whether drugs specific to CysLT receptors block the growth of UM in the liver. She will do this on patient samples and pre-clinical mouse models of liver UM.  She will also investigate patient blood to identify factors associated with better/worse patient survival and to reveal new therapeutic targets for UM. Together, these novel studies will evaluate the therapeutic efficacy of CysLT drugs and allow me to stratify patients most likely to benefit from this intervention.

RESEARCH FINDINGS

Publications

Sundaramurthi H, Tonelotto V, Wynne K, O’Connell F, O’Reilly E, Costa-Garcia M, Kovácsházi C, Kittel A, Marcone S, Blanco A, Pallinger E, Hambalkó S, Piulats Rodriguez JM, Ferdinandy P, O’Sullivan J, Matallanas D, Jensen LD, Giricz Z, Kennedy BN. Ergolide mediates anti-cancer effects on metastatic uveal melanoma cells and modulates their cellular and extracellular vesicle proteomes. Open Res Eur. 2023 Nov 13;3:88. doi: 10.12688/openreseurope.15973.2. PMID: 37981907; PMCID: PMC10654492.

Sundaramurthi H, García-Mulero S, Tonelotto V, Slater K, Marcone S, Piulats JM, Watson RW, Tobin DJ, Jensen LD, Kennedy BN. Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor. Cancers (Basel). 2022 Feb 3;14(3):782. doi: 10.3390/cancers14030782. PMID: 35159049; PMCID: PMC8833954.

Tonelotto V, Costa-Garcia M, O’Reilly E, Smith KF, Slater K, Dillon ET, Pendino M, Higgins C, Sist P, Bosch R, Passamonti S, Piulats JM, Villanueva A, Tramer F, Vanella L, Carey M, Kennedy BN. 1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature. Cell Death Discov. 2024 Feb 10;10(1):70. doi: 10.1038/s41420-023-01773-8. PMID: 38341410.

Swords E, Kennedy BN, Tonelotto V. Assessment of ferroptosis as a promising candidate for metastatic uveal melanoma treatment and prognostication. Front Pharmacol. 2024 Oct 1;15:1466896. doi: 10.3389/fphar.2024.1466896. PMID: 39411069; PMCID: PMC11473310.

Conference Presentations

Extracellular Vesicle Workshop 2023, Conway Institute, Dublin, Ireland. Title: “Accelerating the route towards metastatic uveal melanoma diagnosis and treatment: uveal melanoma extracellular vesicles as novel therapeutic targets and biomarkers”.

Irish Melanoma Forum 2024, Dublin, Ireland. Title: “Ferroptosis and Extracellular Vesicles as Potential Biomarkers for Uveal Melanoma Progression” and “Ferroptosis and CysLT antagonists: new opportunities for the treatment and prognosis of challenging cancer types”.

Association for Research in Vision and Ophthalmology (ARVO) 2024. Seattle, USA. Title: “Ferroptosis, Extracellular Vesicles and Circulating Tumor DNA as Potential Biomakers for Uveal Melanoma Prognostication”