Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.
Background:Biomarkers of therapeutic response and prognosis are needed to assist in the sequencing of treatments for metastatic castration-resistant prostate cancer (CRPC). Previously in a Phase 1 discovery study, we identified 14 circulating microRNAs that were associated with response to docetaxel chemotherapy or overall survival. We performed a Phase 2 validation study to verify these findings.Methods:Using real-time PCR, the levels of the 14 microRNAs were measured in plasma collected before and after the first cycle of docetaxel from a Phase 2 cohort of 89 patients.Results:The microRNAs were not associated with docetaxel response in the Phase 2 cohort. Higher baseline levels of six microRNAs, predominantly of the miR-200 family, were confirmed to be associated with shorter overall survival. A microRNA signature comprising these six microRNAs predicted high-risk patients in the Phase 2 cohort with a hazard ratio of 4.12 (95% CI 2.20–7.70, P=0.000001). The signature was an independent predictor in multivariable analysis with clinicopathological factors.Conclusions:The association of circulating microRNAs with overall survival suggests their involvement in CRPC progression.
Our findings suggest that co-administration of the FAK inhibitor, VS-6063, with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in prostate cancer.
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