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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

45 Downloads (Pure)

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.

Original language	English
Article number	4792
Pages (from-to)	1-15
Number of pages	15
Journal	Cancers
Volume	14
Issue number	19
DOIs	https://doi.org/10.3390/cancers14194792
Publication status	Published - 30 Sept 2022

Bibliographical note

Copyright the Author(s) [include year if part of copyright statement]. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

ceramides
lipidomic
metabolic therapy
prostate cancer
sphingolipids
statins

Access to Document

10.3390/cancers14194792Licence: CC BY

Publisher version (open access)Final published version, 2.71 MBLicence: CC BY

Cite this

Mak, B., Lin, H.-M., Duong, T., Mahon, K. L., Joshua, A. M., Stockler, M. R., Gurney, H., Parnis, F., Zhang, A., Scheinberg, T., Wittert, G., Butler, L. M., Sullivan, D., Hoy, A. J., Meikle, P. J., & Horvath, L. G. (2022). Modulation of plasma lipidomic profiles in metastatic castration-resistant prostate cancer by simvastatin. Cancers, 14(19), 1-15. Article 4792. https://doi.org/10.3390/cancers14194792

@article{caf4ba3626a8490db5c96cfa8ac00295,

title = "Modulation of plasma lipidomic profiles in metastatic castration-resistant prostate cancer by simvastatin",

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",

author = "Blossom Mak and Hui-Ming Lin and Thy Duong and Mahon, {Kate L.} and Joshua, {Anthony M.} and Stockler, {Martin R.} and Howard Gurney and Francis Parnis and Alison Zhang and Tahlia Scheinberg and Gary Wittert and Butler, {Lisa M.} and David Sullivan and Hoy, {Andrew J.} and Meikle, {Peter J.} and Horvath, {Lisa G.}",

note = "Copyright the Author(s) [include year if part of copyright statement]. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2022",

month = sep,

day = "30",

doi = "10.3390/cancers14194792",

language = "English",

volume = "14",

pages = "1--15",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "19",

}

Mak, B, Lin, H-M, Duong, T, Mahon, KL, Joshua, AM, Stockler, MR, Gurney, H, Parnis, F, Zhang, A, Scheinberg, T, Wittert, G, Butler, LM, Sullivan, D, Hoy, AJ, Meikle, PJ & Horvath, LG 2022, 'Modulation of plasma lipidomic profiles in metastatic castration-resistant prostate cancer by simvastatin', Cancers, vol. 14, no. 19, 4792, pp. 1-15. https://doi.org/10.3390/cancers14194792

TY - JOUR

T1 - Modulation of plasma lipidomic profiles in metastatic castration-resistant prostate cancer by simvastatin

AU - Mak, Blossom

AU - Lin, Hui-Ming

AU - Duong, Thy

AU - Mahon, Kate L.

AU - Joshua, Anthony M.

AU - Stockler, Martin R.

AU - Gurney, Howard

AU - Parnis, Francis

AU - Zhang, Alison

AU - Scheinberg, Tahlia

AU - Wittert, Gary

AU - Butler, Lisa M.

AU - Sullivan, David

AU - Hoy, Andrew J.

AU - Meikle, Peter J.

AU - Horvath, Lisa G.

N1 - Copyright the Author(s) [include year if part of copyright statement]. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2022/9/30

Y1 - 2022/9/30

N2 - 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.

AB - 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.

KW - ceramides

KW - lipidomic

KW - metabolic therapy

KW - prostate cancer

KW - sphingolipids

KW - statins

UR - http://www.scopus.com/inward/record.url?scp=85139946582&partnerID=8YFLogxK

UR - https://purl.org/au-research/grants/nhmrc/1196225

U2 - 10.3390/cancers14194792

DO - 10.3390/cancers14194792

M3 - Article

C2 - 36230715

AN - SCOPUS:85139946582

SN - 2072-6694

VL - 14

SP - 1

EP - 15

JO - Cancers

JF - Cancers

IS - 19

M1 - 4792

ER -

Modulation of plasma lipidomic profiles in metastatic castration-resistant prostate cancer by simvastatin

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this