Abstract 1409P
Background
Using comprehensive lipidomic profiling of pre-treatment plasma from men with metastatic castration resistant prostate cancer (mCRPC), we have previously identified and validated that circulating sphingolipids, especially ceramides, are associated with shorter progression-free and overall survival (OS) (Lin et al, 2021). Furthermore, Inhibition of the ceramide-sphingosine-1-phosphate axis with sphingosine kinase (SPHK) inhibitors overcomes enzalutamide resistance in prostate cancer cell lines (Lin et al, 2021). We hypothesise that the clinical outcomes of men with this poor prognostic circulating lipid profile can be improved by therapy targeting lipid metabolism such as SPHK inhibitors. To identify men with this metabolically actionable lipid profile, we require a clinically accessible and regulatory approved plasma lipid biomarker assay.
Methods
Using liquid chromatography-mass spectrometry, we optimised a single assay capable of accurately quantifying a panel of candidate lipids according to National Association of Testing Authorities (NATA) guidelines. We performed the assay on plasma samples from two cohorts of men with mCRPC prior to starting taxane or androgen receptor signalling inhibitor therapy, and developed a cox regression-based risk-model capable of predicting men with poor prognostic mCRPC.
Results
Within both the discovery and validation cohorts, men who were lipid biomarker positive had significantly shorter OS compared to those who were biomarker negative (discovery: median OS 12.0 months (mo) vs 24.2 mo, hazard ratio (HR) 3.75 [95% confidence interval (CI) 2.29 – 6.15], p<0.001, validation: median OS 13.0 mo vs 25.7 mo, HR = 2.13 [95% CI 1.46 – 3.12], p<0.001).
Conclusions
We have developed a lipid biomarker assay capable of prospectively identifying men with mCRPC with a poor prognostic plasma lipid profile. This lipid biomarker assay will allow us to identify men for prospective clinical trials of therapeutic agents targeting lipid metabolism, such as the SPHK2 inhibitor opaganib.
Clinical trial identification
Ethics and Governance: All participants provided written informed consent (Monash Health Institutional Review Board (15571X), Royal Prince Alfred Hospital Human Research Ethics Committee (X14-0406, X19-0320), Australia-New Zealand Clinical Trials Registry ACTRN12607000077460, ACTRN12611000540910).
Editorial acknowledgement
Legal entity responsible for the study
Chris O'Brien Lifehouse.
Funding
National Health and Medical Research Council of Australia (GNT1196225 to LGH, GNT1098647 to AAA ); Cancer Institute New South Wales (10/TPG/1-04, 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); Cancer Council New South Wales (PG 10-01); The Victorian Government’s Operational Infrastructure Support Program; Australian Government Research Training Program (RTP) Scholarship and University of Sydney Merit Award to BM; Australian Government Research Training Program (RTP) Scholarship and Sydney Catalyst Research Top-up Award to TS; Victorian Cancer Agency Clinical Research Fellowship (CRF14009) and Astellas Investigator-Initiated Grant to AAA; ANZUP Noel Castan Fellowship to HML; Twin Towns Services Community Foundation to LGH.
Disclosure
M. Fitzpatrick: Financial Interests, Institutional, Full or part-time Employment: New South Wales Health Pathology. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Personal, Invited Speaker, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Invited Speaker, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Invited Speaker, AMG160 Phase 1AMG509 Phase 1: Amgen; Financial Interests, Institutional, Invited Speaker, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Invited Speaker, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Invited Speaker, C344102: Pfizer; Financial Interests, Institutional, Invited Speaker, JPCM: Eli Lilly; Financial Interests, Institutional, Invited Speaker, DASL-HiCAP: ANZUP; Financial Interests, Institutional, Invited Speaker, GALAHADACISPrevalence: Janssen-Cilag; Financial Interests, Institutional, Invited Speaker, GSK204697: GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker, XL184-021: Exelexis; Financial Interests, Institutional, Invited Speaker, BGB-A317BGB-283BGB-A317-290: Beigene; Financial Interests, Institutional, Invited Speaker, FPT155-001: Five Prime; Financial Interests, Institutional, Invited Speaker, AB928CSP0003: ARCUS; Financial Interests, Institutional, Invited Speaker, ENZAMETENZARAD: ANZUP; Financial Interests, Institutional, Invited Speaker, ATG-017: Antagene. All other authors have declared no conflicts of interest.