Cysteinyl Leukotriene Receptor Signalling: Novel therapeutic targets to improve patient outcomes in metastatic Uveal Melanoma

Dr. Kayleigh Slater

Dr. Kayleigh Slater was awarded with Breakthrough Cancer Research Project Grant, enabling her to conduct research under the supervision of Prof. Breandan Kennedy at University College Dublin.

Uveal melanoma (UM for short) is a rare form of ocular or eye cancer that will spread or metastasise to the liver in half of all patients. Although it is a rare disease, Ireland has one of the highest incidence rates of this cancer in the world. Once UM spreads to the liver, patients are faced with an extremely poor prognosis as there are currently no treatments that stop UM spreading from the eye to the liver. This means that as few as 8% of patients diagnosed with metastatic UM will survive beyond 2 years.
In this project, we will establish a pipeline to access precious tumour biopsies and blood samples from patients being monitored for, or diagnosed with, metastatic UM across Ireland. This will allow us to work closely with our colleagues in hospitals across Ireland to better understand and treat this disease. Studying patient samples gives us the best opportunity of discovering how exactly this cancer grows and spreads within the body. We will analyse blood samples to identify markers in the blood that will tell us how likely the cancer is to spread outside of the eye, and whether a patient may respond to treatment. Our lab has identified drugs that stop the growth of UM cells in a dish. Throughout this project, we will collect tumour biopsies from patients diagnosed with metastatic UM and treat them with these drugs to see if they have the same effect on patient tumours.

Clinical Challenge being addressed: Metastatic uveal melanoma is an extremely poor prognosis cancer and unfortunately, Ireland has one of the highest incidence rates of this cancer in the world. Identifying new therapeutic targets in this disease are critical to improving patient prognoses. Very few patients  present  with  detectable  metastases  upon  primary  treatment,  yet  half  of UM patients  will ultimately develop  metastatic  disease. Through analysing differentially expressed transcripts and proteins in patient blood samples, we may be able to develop a method of detecting dissemination faster than currently used imaging techniques.

In addition, this project will seed sustainable growth of a collaborative Uveal Melanoma Research Group in Ireland. During  this  research  we  move  towards  personalised  treatments  for  UM  patients,  identifying  which patient  cohorts  respond  best  to  new  drug  therapies  and  currently  available  chemotherapeutics.  This will  impact  patients  in  the  future  by  identifying  which  patients  are  likely  to  respond  best  to  specific treatments.

RESEARCH FINDINGS

Publications:

Slater K, Heeran AB, Garcia-Mulero S, Kalirai H, Sanz-Pamplona R, Rahman A, Al-Attar N, Helmi M, O’Connell F, Bosch R, Portela A, Villanueva A, Gallagher WM, Jensen LD, Piulats JM, Coupland SE, O’Sullivan J, Kennedy BN. High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells. Cancers (Basel). 2020 Oct 13;12(10):2950. doi: 10.3390/cancers12102950. PMID: 33066024; PMCID: PMC7600582. doi: 10.3390/cancers12102950

Mahon N, Slater K, O’Brien J, Alvarez Y, Reynolds A, Kennedy B. Discovery and Development of the Quininib Series of Ocular Drugs. J Ocul Pharmacol Ther. 2022 Jan-Feb;38(1):33-42. doi: 10.1089/jop.2021.0074. PMID: 35089801.

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.

Slater K, Bosch R, Smith KF, Jahangir CA, Garcia-Mulero S, Rahman A, O’Connell F, Piulats JM, O’Neill V, Horgan N, Coupland SE, O’Sullivan J, Gallagher WM, Villanueva A, Kennedy BN. 1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model. Front Med (Lausanne). 2023 Jan 9;9:1036322. doi: 10.3389/fmed.2022.1036322. PMID: 36698840; PMCID: PMC9868667.

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.