Journal article

Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase

Hui-Ming Lin, Blossom Mak, Nicole Yeung, Kevin Huynh, Thomas G Meikle, Natalie A Mellett, Edmond M Kwan, Heidi Fettke, Ben Tran, Ian D Davis, Kate L Mahon, Alison Zhang, Martin R Stockler, Karen Briscoe, Gavin Marx, Megan Crumbaker, Phillip D Stricker, Pan Du, Jianjun Yu, Shidong Jia Show all

EBIOMEDICINE | ELSEVIER | Published : 2021

Abstract

BACKGROUND: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. METHODS: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free sur..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by Cancer Institute New South Wales


Awarded by Prostate Cancer Foundation of Australia


Awarded by Cancer Council New South Wales


Awarded by Cancer Council South Australia (Beat Cancer Project Principal Cancer Research Fellowship)


Awarded by Victorian Cancer Agency Clinical Research Fellowship


Funding Acknowledgements

We gratefully acknowledge Lisa Graham (Chris O'Brien Lifehouse), Anne-Maree Hayes (Garvan Institute of Medical Research), Daniela Barreto (Garvan Institute of Medical Research) and research nurses for collection of blood/tissue specimens and clinical data; Gillian Lehrbach for assistance with tissue culture; Anaiis Zaratzian and Garvan Histopathology staff for assistance with immunostaining of tissue; and Tony Maxwell as our consumer representative.We also thank our funders: National Health and Medical Research Council of Australia (GNT0614296 & APP1196225 to L.G.H, GNT1098647 to A.A.A); Cancer Institute New South Wales (10/TPG/104 & 2018/TPG001 to L.G.H); 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 and L. G.H); Cancer Council New South Wales (PG 10-01 to L.G.H); Cancer Council South Australia (Beat Cancer Project Principal Cancer Research Fellowship, PRF1117 to L.M.B); The Victorian Government's Operational Infrastructure Support Program; NHMRC Postgraduate Scholarship (E.M.K), Monash University Postgraduate Publications Award (E.M.K & H.F); Cancer Council Victoria Postdoctoral Fellowship (E.M.K); Australian Government Research Training Program Scholarship (H.F); Victorian Cancer Agency Clinical Research Fellowship (CRF14009 to A.A.A); Astellas Investigator-Initiated Grant (A.A.A); Australian and New Zealand Urogenital and Prostate Cancer Trials Group's Noel Castan Fellowship (H.M.L); Twin Towns Services Community Foundation (L.G.H).