Lipidomic alterations in prostate cancer as mediators and markers of androgen responses to androgen receptor antagonists.

Prostate cancer (PCa) is the most commonly diagnosed cancer and is the second leading cause of cancer-related death in men in the developed world. Particularly management of metastatic cancer is challenging. Because prostate epithelial cells are exquisitely dependent on male sex hormones, called androgens, the primary treatment for men with metastatic PCa is suppression of androgen production, often combined with antagonists that directly inhibit the mediator of androgen action, the androgen receptor (AR). Whilst these treatments are initially effective, patients eventually relapse. Along with promising new developments in this therapy using a new generation of agents that more effectively target AR signalling, there is a strong need for more reliable clinical indicators of response to these hormonal therapies as well as for complementary targets for intervention. One of the pathways that may hold significant potential in this context is lipid metabolism, which is dramatically altered in PCa, is strongly affected by (anti)-androgens and is tightly linked with cancer biology. Using a unique explant culture system, complemented by mouse models and clinical samples we will carefully dissect alterations in lipid metabolism in PCa in response to new generation anti-androgens, we will examine the underlying enzymes, and explore the potential of this pathway as more reliable marker of responses to anti-androgens and as complementary target in the management of metastatic PCa.