Below the Belt Award

It has been found that certain levels of specific circulating lipids (naturally occurring molecules) in blood are associated with a worse prognosis in men with metastatic castrate-refractory prostate cancer (cancer which has spread to other parts of the body and is able to grow despite hormone therapy). The purpose of this study is to find out if a course of a drug called simvastatin (commonly used to treat high cholesterol, heart disease and diabetes) will lower the specific circulating lipids in blood associated with a worse prognosis. To date, biomarker studies in CRPC have mainly focused on changes in the cancer and their effects on therapeutic resistance and prognosis. However, the host environment (i.e. the patient) and its interactions with cancer is increasingly important, in light of the association of prostate cancer and obesity. Our exploratory study was the first to profile the plasma lipidome of men with metastatic CRPC, and to identify and validate plasma lipidomic profiles that are associated with survival in CRPC (Lin et al, Int J Cancer, 2017). Unsupervised analysis of baseline lipidomic profiles classified patients of a Phase 1 discovery cohort into two groups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, p=0•0005), independent of chemotherapy response. The baseline levels of 46 lipids were individually prognostic, and predominantly sphingolipids. A prognostic three-lipid signature was derived, consisting of ceramide, sphingomyelin and phosphatidylcholine. This signature was associated with shorter overall survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, p=0.0003), and was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics (Lin et al, Int J Cancer, 2017). Therefore, a key question is whether therapeutic modulation of a patient’s lipid profile will improve prognosis. However, the first step is to see if lipid modulation therapy can change the circulating lipidomic profile in CRPC patients. Statins significantly reduces the plasma levels of ceramides, sphingomyelin and cholesterol in those with cardiovascular disease or metabolic syndrome, suggesting that this therapy could change the high risk circulating lipid profile of CRPC patients. The aim of this study is to assess whether treatment with simvastatin during docetaxel chemotherapy for metastatic CRPC can reverse a poor prognostic circulating lipid signature.