1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model.

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) expression associates with poor outcomes. CysLT antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines . Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical orthotopic xenograft models and patient samples. Immunohistochemical staining of an independent cohort ( = 64) of primary UM patients confirmed high CysLT expression significantly associates with death from metastatic disease ( = 0.02; HR 2.28; 95% CI 1.08-4.78), solidifying the disease relevance of CysLT in UM. In primary UM samples ( = 11) cultured as 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 ( = 0.03), a marker of oxidative phosphorylation. In UM, high is a poor prognostic indicator, whereas low , 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 and in UM, and the therapeutic potential of 1,4-dihydroxy quininib with as a companion diagnostic to treat MUM.