Modulation of the plasma lipidomic profile with simvastatin in metastatic castration-resistant prostate cancer (mCRPC).
Bibliographic record
Abstract
154 Background: Elevated circulating sphingolipids are associated with poorer outcomes across the natural history of prostate cancer (PC), including metastatic relapse in localised PC, earlier androgen deprivation failure in metastatic hormone-sensitive PC, and shorter overall survival (OS) in mCRPC. We have derived and validated a poor prognostic 3-lipid signature (3LS) [consisting of ceramide Cer(d18:1/24:1), sphingomyelin SM(d18:2/16:0) and phosphatidylcholine PC(16:0/16:0)], which was independently associated with shorter radiographic progression-free survival (rPFS) and OS in men with mCRPC commencing taxanes or androgen receptor signaling inhibitors (ARSI). Statins significantly reduce plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease. We hypothesised that this therapy could change the poor prognostic lipid profile of patients with mCRPC. This study assessed whether the addition of simvastatin to standard treatment for mCRPC modulates the circulating lipidomic profile. Methods: This investigator-initiated, multi-centre, single arm, pilot study enrolled men with mCRPC commencing taxanes or ARSI for disease progression, who were not on a lipid-lowering agent. Men were treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of treatment for mCRPC. Plasma was taken at baseline and after 12 weeks of simvastatin, and underwent lipidomic profiling of ̃800 lipids. Differences in lipid levels between baseline and post-simvastatin samples and between those with and without the 3LS were assessed using t-tests. Results: 27 men (74% on taxanes, 26% on ARSI) were recruited between May 2018 to March 2021. 46% of the men had the poor prognostic 3LS at baseline, of whom 45% lost the 3LS after simvastatin. Comparison between all paired baseline and post-simvastatin samples showed significant reduction (p < 0.05) in free cholesterol, cholesteryl esters and some sphingolipids (sphingomyelins, hexosylceramides) with simvastatin treatment. Baseline profiles with the 3LS displayed significantly higher levels (p < 0.05) of ceramides, hexosylceramides and sphingomyelins, relative to baseline profiles without the 3LS. Men who lost the 3LS after treatment (n = 5) demonstrated significant reductions in ceramides (23-45%, p≤0.046), hexosylceramides (27-52%, p≤0.049) and sphingomyelins (28-44%, p≤0.047). These changes were not seen in men with persistent 3LS after treatment (n = 6). Conclusions: Simvastatin in addition to standard treatment for mCRPC can modulate the circulating lipidomic profile and eliminate the presence of a poor prognostic 3LS in 45% of participants with the 3LS. Further prospective randomised control studies are required to determine if modulation of the 3LS by simvastatin can improve clinical outcomes. Clinical trial information: ACTRN12617000965303.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".