Modulation of the plasma lipidomic profile with simvastatin in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mak Blossom , Lin Hui-Ming , Mahon Kate Lynette , Joshua Anthony M. , Stockler Martin R. , Gurney Howard , Parnis Francis , Zhang Alison Yan , Scheinberg Tahlia , Wittert Gary , Butler Lisa , Hoy Andrew , Meikle Peter , Horvath Lisa 
Published: February 2022

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Background: Elevated circulating sphingolipids are associated with poorer outcomes across the natural history of prostate cancer (PC), including metastatic relapse in localised PC, earlier androgen deprivation failure in metastatic hormone-sensitive PC, and shorter overall survival (OS) in mCRPC. We have derived and validated a poor prognostic 3-lipid signature (3LS) [consisting of ceramide Cer(d18:1/24:1), sphingomyelin SM(d18:2/16:0) and phosphatidylcholine PC(16:0/16:0)], which was independently associated with shorter radiographic progression-free survival (rPFS) and OS in men with mCRPC commencing taxanes or androgen receptor signaling inhibitors (ARSI). Statins significantly reduce plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease. We hypothesised that this therapy could change the poor prognostic lipid profile of patients with mCRPC. This study assessed whether the addition of simvastatin to standard treatment for mCRPC modulates the circulating lipidomic profile. Methods: This investigator-initiated, multi-centre, single arm, pilot study enrolled men with mCRPC commencing taxanes or ARSI for disease progression, who were not on a lipid-lowering agent. Men were treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of treatment for mCRPC. Plasma was taken at baseline and after 12 weeks of simvastatin, and underwent lipidomic profiling of ̃800 lipids. Differences in lipid levels between baseline and post-simvastatin samples and between those with and without the 3LS were assessed using t-tests. Results: 27 men (74% on taxanes, 26% on ARSI) were recruited between May 2018 to March 2021. 46% of the men had the poor prognostic 3LS at baseline, of whom 45% lost the 3LS after simvastatin. Comparison between all paired baseline and post-simvastatin samples showed significant reduction (p < 0.05) in free cholesterol, cholesteryl esters and some sphingolipids (sphingomyelins, hexosylceramides) with simvastatin treatment. Baseline profiles with the 3LS displayed significantly higher levels (p < 0.05) of ceramides, hexosylceramides and sphingomyelins, relative to baseline profiles without the 3LS. Men who lost the 3LS after treatment (n = 5) demonstrated significant reductions in ceramides (23-45%, p≤0.046), hexosylceramides (27-52%, p≤0.049) and sphingomyelins (28-44%, p≤0.047). These changes were not seen in men with persistent 3LS after treatment (n = 6). Conclusions: Simvastatin in addition to standard treatment for mCRPC can modulate the circulating lipidomic profile and eliminate the presence of a poor prognostic 3LS in 45% of participants with the 3LS. Further prospective randomised control studies are required to determine if modulation of the 3LS by simvastatin can improve clinical outcomes. Clinical trial information: ACTRN12617000965303.