Biomarkers and Lipids in Localised Prostate Cancer

Abstract

In practice, despite using existing clinicopathological biomarkers to predict outcomes, many localised prostate cancers are still over-treated. Hence improved markers in localised prostate cancer (PC) are urgently required. The aim of this thesis was to validate potential prognostic markers of localised PC, with an emphasis on zinc-alpha 2-glycoprotein (AZGP1) as a lipid-based biomarker. The thesis also explores the contributions of lipids in PC progression using various pre-clinical platforms. AZGP1 is putative biomarker in PC. Data from our prospective phase III validation study demonstrates that AZGP1 status at radical prostatectomy (RP) is predictive of outcomes. Samples from 347 patients undergoing RP were analysed for AZGP1 expression. Absent/low AZGP1 expression was an independent predictor of shorter metastasis-free survival. AZGP1 also improved the discriminatory value of existing prognostic risk models. Over decades, our research group has also contributed to other studies of molecular biomarkers in PC. These candidate biomarkers have been re-analysed in discovery and validation cohorts to examine for more clinically meaningful endpoints of metastasis and PC death. Out of 12 evaluable markers, AZGP1 and Ki67 were the key predictors of these clinically relevant outcomes. Importantly, this thesis demonstrates that PSA relapse is a poor surrogate for metastasis and death. AZGP1 is a known lipid-mobilising factor. Using an in vitro spheroid model and a novel ex vivo platform, we investigated the relationship between lipids and PC cells. With fatty acid co-culture, we demonstrated that there is gross uptake of fatty acids from the tumour microenvironment. We identified the role of external fatty acid uptake as the dominant component of energy transfer over de novo lipid synthesis from glucose and glutamine utilisation in PC. The resultant lipid uptake led to increased PC growth and proliferation.