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

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posted on 2023-07-05, 05:38 authored by Blossom Mak, Hui-Ming Lin, Thy Duong, Kate L Mahon, Anthony M Joshua, Martin R Stockler, Howard Gurney, Francis Parnis, Alison Zhang, Tahlia Scheinberg, Gary Wittert, Lisa M Butler, David Sullivan, Andrew J Hoy, Peter MeiklePeter Meikle, Lisa G Horvath
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.

Funding

This work was supported by the National Health and Medical Research Council of Australia (GNT1196225 to L.G.H., L3 Investigator grant 2009965 to P.J.M.); Cancer Institute New South Wales (2018/TPG001); Australian Prostate Cancer Research Centre-New South Wales; Australian Department of Health and Aging; the Movember Foundation and the Prostate Cancer Foundation of Australia (Revolutionary Team Award MRTA3 to L.M.B., G.A.W., A.J.H., L.G.H.); Cancer Council New SouthWales (PG 10-01); Cancer Council South Australia (Beat Cancer Project Principal Cancer Research Fellowship, PRF1117 to L.M.B.); Australian Government Research Training Program (RTP) Scholarship and University of Sydney Merit Award to B.M.; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (Noel Castan Fellowship to H.M.L., ANZUP Below the Belt Research Fund to L.G.H.); Robinson Research Fellowship and University of Sydney funding to A.J.H.; and Twin Towns Services Community Foundation. This work was also supported by the Victorian Government's Operational Infrastructure Support Program.

History

Publication Date

2022-09-30

Journal

Cancers

Volume

14

Issue

19

Article Number

4792

Pagination

15p.

Publisher

Multidisciplinary Digital Publishing Institute

ISSN

2072-6694

Rights Statement

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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