Signalling pathways in prostate carcinogenesis: potentials for molecular-targeted therapy

Abstract

Prostate cancer represents a major health issue and its incidence is rising globally. In developed countries, prostate cancer is the most frequently diagnosed cancer and the second most common cause of death from cancer in men. Androgen deprivation reduces tumour activity in approx. 80% of patients with advanced disease, but most tumours relapse within 2 years to an incurable hormone-resistant state. Even for patients with early disease at the time of diagnosis, a proportion of patients will unfortunately develop relapsed disease following radical therapy. Treatment options for patients with hormone-resistant prostate cancer are very limited and, even with toxic therapy, such as docetaxel, the life expectancy is only improved by a median of 2 months. Advances in molecular oncology have identified key signalling pathways that are considered to be driving events in prostate carcinogenesis. The activation of multiple signalling pathways increases further the possibility of cross-talk among ‘linear’ signalling cascades. Hence signalling networks that may incorporate distinct pathways in prostate cancer, particularly in hormone-resistant disease, are increasingly appreciated in drug development programmes. With the development of potent small-molecule inhibitors capable of specifically suppressing the activities of individual ‘linear’ cascades, it may be that, by combining these agents as guided by the molecular signature of prostate cancer, a more efficient therapeutic regime may be developed. Therefore the present review focuses on evidence of abnormal signalling in prostate cancer and the potential of these targets in drug development, and incorporates key findings of relevant clinical trials to date.