Endocrine Abstracts

Androgens are required for normal development and fertility. They have a vital role in tissues such as the reproductive tract, the brain, muscle and bone. Prostate cancer (PCa) is the most prevalent malignancy in western males: it is dependent upon circulating androgens and the therapies currently available aim to reduce synthesis of circulating androgens and/or inhibit the pathway using antiandrogens. Therapies inhibiting androgen signalling, and in particular the androgen receptor (AR) can result in dangerous and/or debilitating side effects, including liver toxicity, impotence, osteoporosis. There is a wide interest in developing tissue-selective AR inhibitors (Selective Androgen Receptor Modulators, SARMs) which ideally should inhibit androgen action in the prostate but not affect or activate AR in other tissues. We developed a transgenic mouse model that expresses luciferase when the endogenous AR is activated. This model is extremely useful because AR activity can be assayed in both reproductive (testes, prostate) and non-reproductive (brain, gut) tissues, during the lifetime of the animals. In this study ARE-Luc mice are used to assess side effects of approved and novel agents that affect androgen signalling. Compounds were tested in cell lines first, to assess their effect on androgen activation. Subsequently, intact and castrated mice were treated with SARMs, imaged in vivo and ex vivo and tissues were collected for analysis. Our results identified novel tissues targeted by SARMs in vivo and characterise tissue-specific action of compounds that affect androgen signalling. Moreover in order to assess the role of AR signalling in the disease context, the compounds were tested in a transgenic mouse derived from the crossing of the ARE-Luc with a prostate cancer model. Overall this project will help predict possible side effects of treatments and their suitability for PCa treatment, as well as elucidate the role of the AR signalling in the progression of PCa.