Background: Chronic inflammation is associated with an elevated risk of developing lung cancer. Inhibition of the inflammasome has emerged as a promising preventive and therapeutic strategy. Among inflammatory mediators, the cysteinyl leukotrienes and their receptors (CysLTR1 and CysLTR2) are well-established drivers of pro-inflammatory gene expression in asthma and allergic disorders. Notably, CysLTR1 and in some cases CysLTR2, has been reported to be overexpressed in malignancy, where their presence is linked to poorer clinical outcomes. However, the contribution of these inflammatory signalling pathways to non-small cell lung cancer (NSCLC) remains largely unexplored.
Preliminary Findings: Recent studies in the laboratory demonstrate that CysLTR1 and CysLTR2 mRNA levels are markedly elevated in NSCLC cell lines compared with normal bronchial epithelial cells. Furthermore, pharmacological inhibition of the receptors using 1,4-dihydroxy quininib, significantly decreased tumour cell viability and oxygen consumption rate. Furthermore, analysis of a tissue microarray from 175 NSCLC patients resected at St James’s Hospital showed that protein expression of both receptors is significantly altered in tumour tissue and correlates with gender and smoking history, suggesting clinical relevance and potential patient-specific patterns.
Hypothesis: CysLTR1 and CysLTR2 expression is significantly increased in NSCLC and may represent therapeutic targets for intervention with the novel CysLTR antagonist 1,4-dihydroxy quininib.
Aims: This project aims to investigate the translational potential of CysLTR1 and CysLTR2 by quantifying their protein levels in a retrospective cohort of blood sera from patients with advanced NSCLC, as well as in previously collected culture supernatants from NSCLC cells treated with 1,4-dihydroxy quininib. A panel of pro-inflammatory cytokines will be measured in the same samples to determine whether CysLTR modulation influences broader inflammatory signalling.
Expected Outcomes: This study will enhance our understanding of the use of CysLTRs as clinically relevant biomarkers in NSCLC and lay the foundations for future pre-clinical studies and biomarker-driven clinical trial development.