Growth factor receptor tyrosine kinase inhibitors; Clinical development and potential for prostate cancer therapy

Purpose: The development of effective, novel, targeted cancer therapies with minimal side effects has long been a goal in cancer research. A key group of targets identified for drug development consists of the receptor tyrosine kinases, which have pivotal roles in the growth factor signaling that is subverted in carcinogenesis and in the host processes, such as angiogenesis, involved in tumor progression. Materials and Methods: A literature review of the role of receptor tyrosine kinases in human malignancies is followed by a discussion of the potential use of inhibitors of receptor tyrosine kinases as anticancer therapy, focusing on the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839, AstraZeneca, Macclesfield, United Kingdom). Results: Several small molecule inhibitors that are specific to individual receptor tyrosine kinases have been developed and a number of these potential anticancer agents are progressing through clinical trials. Various surrogate end points are being assessed to demonstrate the activity of these inhibitors against their targets. Results from studies of gefitinib alone and with the antiandrogen bicalutamide in both hormone dependent and independent prostate tumor xenografts suggested that gefitinib may have potential as monotherapy and combination therapy in the treatment of both forms of the disease. Gefitinib is currently undergoing further preclinical and clinical evaluation for the treatment of prostate cancer. Conclusions: A number of tyrosine kinase inhibitors, including gefitinib, are progressing through clinical development and are beginning to provide new treatment options for a range of malignancies.