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

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 J Meikle; Lisa G Horvath

doi:10.3390/cancers14194792

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

Cancers (Basel). 2022 Sep 30;14(19):4792. doi: 10.3390/cancers14194792.

Authors

Blossom Mak^{1

2

3}, Hui-Ming Lin^{2

4}, Thy Duong⁵, Kate L Mahon^{1

2

3

6}, Anthony M Joshua^{2

4

7}, Martin R Stockler^{3

8}, Howard Gurney⁹, Francis Parnis¹⁰, Alison Zhang^{1

3

9}, Tahlia Scheinberg^{1

2

3}, Gary Wittert^{11

12}, Lisa M Butler^{11

12}, David Sullivan^{6

13}, Andrew J Hoy¹⁴, Peter J Meikle^{5

15}, Lisa G Horvath^{1

2

3

4

6}

Affiliations

¹ Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW 2050, Australia.
² Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
³ Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia.
⁴ St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW 2010, Australia.
⁵ Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
⁶ Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
⁷ Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
⁸ Concord Cancer Centre, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
⁹ Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia.
¹⁰ Adelaide Cancer Centre, Kurralta Park, SA 5037, Australia.
¹¹ South Australian Immunogenomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA 5005, Australia.
¹² South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
¹³ NSW Health Pathology, Department of Chemical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
¹⁴ School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW 2050, Australia.
¹⁵ Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, VIC 3086, Australia.

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.

Keywords: ceramides; lipidomic; metabolic therapy; prostate cancer; sphingolipids; statins.

Abstract

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