Signaling inhibitors in the treatment of prostate cancer.

Inhibiting androgen receptor (AR) activation through medical or surgical castration and blockade of AR-androgen binding is the cornerstone of treatment for advanced prostate cancer. However, in most cases tumor growth eventually becomes androgen independent. Alternative mechanisms of AR activation, some of which involve growth factor receptor signaling, have been demonstrated in prostate cancer models, and it is likely that a number of autocrine and paracrine growth factor ligand-receptor interactions such as those of epidermal growth factors, fibroblast growth factors, and insulin-like growth factors contribute to the androgen independent phenotype by promoting cell proliferation and survival. Blocking activation and signaling through growth factor receptors and upstream signaling proteins has emerged as a credible approach to cancer treatment. Successful application of this approach in prostate cancer using a growing array of small molecule kinase inhibitors, antibodies, and antisense oligonucleotides will be greatly accelerated by elucidation of the key signaling pathways that maintain the androgen independent phenotype.