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INTRODUCTION

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With a heightening awareness of the molecular signalling pathways responsible for the development and progression of prostate cancer has come a paradigm shift in the identification of targets for new therapeutic endeavours. The use of targeted therapies at different stages of the disease is leading to new concepts in how the activity of these agents may be measured in terms of the design of clinical trials and the progression of the use of new molecules from the laboratory setting to the clinic.

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In recent years the pivotal role of the androgen receptor in prostate cancer progression has been confirmed [1] (Figure 13.1). In the hormone-sensitive disease stages the receptor is stimulated by androgens and possibly also by oestrogens and other steroid molecules, whereas in the more advanced disease, particularly in the so-called hormone-refractory state, the androgen receptor at very low levels of androgen is stimulated by a series of growth factors and cytokines.

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Figure 13.1

The role of the androgen receptor (AR).

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The hope for the future is the identification of specific targets at different stages of the disease and in individual patients, which will lead to tailored therapy for prostate cancer, an important step on the way to truly personalized medicine [2]. In order to establish the value of an individual therapy it is important to be certain that at a given clinical stage of prostate cancer or even in a particular cancer that the target for that new therapy is present, that the expression of that target is a reflection of the disease process and that therefore a proof of principle and proof of concept will undoubtedly be followed by a specific and beneficial therapeutic effect for a given treatment [3].

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Prostate cancer is a heterogeneous tumour and, because of this, it is likely that identification of a single target and therapeutic inhibition of that target will not result in complete ablation of a tumour. Rather, targeted therapies will be used in conjunction with other more established therapeutic options in combination therapy, a more multidisciplinary approach to the management of this disease.

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UNDERSTANDING THE BIOLOGY OF PROSTATE CANCER

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As the prostate gland is a secondary sexual organ, rather like the breast, proliferating epithelium is largely under the control of hormones produced by the primary sex organ, the testicle. In addition, androgenic hormones are produced by the adrenal gland and converted in the periphery to testosterone. The androgens arrive on the prostate cell in the bloodstream bound to sex hormone-binding globulin. On reaching the prostate epithelium, testosterone diffuses passively into the cytoplasm of the cell where it is converted to dihydrotestosterone by 5-alpha-reductase. This more active androgen attaches to the androgen receptor and, by a process of dimerization, sheds heat shock proteins ...

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