Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin

SIMPLE SUMMARY: Men with metastatic castration-resistant prostate cancer (mCRPC) have shorter overall survival and resist therapy faster if their blood have a poor lipid profile. This poor lipid profile includes high levels of sphingolipids, thus reducing these sphingolipids may slow prostate cancer growth. The aim of our study is to determine if simvastatin can change a poor lipid profile (high sphingolipids) into a better profile (low sphingolipids) in mCRPC. Twenty-seven men with mCRPC were given simvastatin together with their standard treatment for 12 weeks. We found that 11 men had the poor lipid profile at the start of the study. After 12 weeks of treatment, 40% of these 11 men no longer had the poor lipid profile and their sphingolipids were reduced, regardless of changes in their blood cholesterol, LDL or triglycerides. In conclusion, simvastatin can modify the poor lipid profile in some men with mCRPC. ABSTRACT: Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23–52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate.