Targeting lipid metabolism in metastatic prostate cancer

Abstract

Despite key advances in the treatment of prostate cancer (PCa), a proportion of men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.

Keywords: high-fat diet; lipids; prostate cancer; targeted therapy.

Figure 1.

Intracellular lipid metabolism and targets for lipid therapy. Key: red colour indicates therapeutic targets and blue colour indicates drug therapies. ACACA, acetyl-coA carboxylase alpha; AR, androgen receptor; ARE, androgen response elements; ATP, adenosine triphosphate; CPT-1, carnitine palmitoyltransferase 1; FASN, fatty acid synthase; LDLR, Low density lipoprotein receptor; PCSK9, Proprotein convertase subtilisin/kexin type 9; SCD, stearoyl-CoA desaturase; SPHK, sphingosine kinase; S1P, sphingosine-1-phosphate; TCA, tricarboxylic acid.