Slater, Kayleigh, Bosch, Rosa, Smith, Kaelin Francis, Jahangir, Chowdhury Arif, Garcia-Mulero, Sandra, Rahman, Arman, O'Connell, Fiona, Piulats, Josep M, O'Neill, Valerie, Horgan, Noel et al (show 5 more authors)
(2023)
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, 9.
1036322-.
Abstract
Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84-1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT<sub>1</sub>) expression associates with poor outcomes. CysLT<sub>1</sub> antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines <i>in vitro</i>. Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical <i>in vivo</i> orthotopic xenograft models and <i>ex vivo</i> patient samples. Immunohistochemical staining of an independent cohort (<i>n</i> = 64) of primary UM patients confirmed high CysLT<sub>1</sub> expression significantly associates with death from metastatic disease (<i>p</i> = 0.02; HR 2.28; 95% CI 1.08-4.78), solidifying the disease relevance of CysLT<sub>1</sub> in UM. In primary UM samples (<i>n</i> = 11) cultured as <i>ex vivo</i> explants, 1,4-dihydroxy quininib significantly alters the secretion of IL-13, IL-2, and TNF-α. In an orthotopic, cell line-derived xenograft model of MUM, 1,4-dihydroxy quininib administered intraperitoneally at 25 mg/kg significantly decreases ATP5B expression (<i>p</i> = 0.03), a marker of oxidative phosphorylation. In UM, high <i>ATP5F1B</i> is a poor prognostic indicator, whereas low <i>ATP5F1B</i>, in combination with disomy 3, correlates with an absence of metastatic disease in the TCGA-UM dataset. These preclinical data highlight the diagnostic potential of CysLT<sub>1</sub> and <i>ATP5F1B</i> in UM, and the therapeutic potential of 1,4-dihydroxy quininib with <i>ATP5F1B</i> as a companion diagnostic to treat MUM.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | cysteinyl leukotriene, uveal melanoma (UM), xenograft model, tumour metabolism, inflammation, immunohistochemistry, tumour microenvironment, ATP5B ATP synthase |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 18 Apr 2023 08:39 |
| Last Modified: | 18 Apr 2023 08:39 |
| DOI: | 10.3389/fmed.2022.1036322 |
| Open Access URL: | https://doi.org/10.3389/fmed.2022.1036322 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169640 |
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