Over 20,000 new cases of prostate are reported in the UK annually. Hormonally based therapies that deprive the tumour of the growth stimulatory androgens are usually effective, in the first instance. These work either by reducing the biosynthesis of androgens or by blocking the steroid hormone at the level of its protein receptor, the androgen receptor (AR). However, patients will invariably relapse with hormonally insensitive disease. As a result, prostate cancer accounts for 12% of all cancer deaths in UK males. Tumours which have relapsed usually contain higher than normal levels of the AR, or may contain mutated receptor. The action of coactivator proteins which further enhance AR transcriptional activity several fold may have an important role in tumour progression.
The histone acetyltransferase (HAT) enzyme Tip60 has been recently identified as a coactivator of the AR and is a novel target for the treatment of hormonally insensitive prostate cancer. In collaboration with OSI Pharmaceuticals, we are using structure-based drug design and high-throughput screening to identify inhibitors of Tip60 which can be developed into novel therapies for hormone independent prostate cancer.
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Key references:
1. Brady, M. E.; Ozanne, D. M.; Gaughan, L.; Waite, I.; Cook, S. et al. Tip60 is a nuclear hormone receptor coactivator. J. Biol. Chem. 1999, 274, 17599-17604.
2. Gaughan, L.; Brady, M. E.; Cook, S.; Neal, D. E.; Robson, C. N. Tip60 is a co-activator specific for class I nuclear hormone receptors. J. Biol. Chem. 2001, 276, 46841-46848.
3. Gaughan, L.; Logan, I. R.; Cook, S.; Neal, D. E.; Robson, C. N. Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. J. Biol. Chem. 2002, 277, 25904-25913.
4. Halkidou, K.; Gnanapragasam, V. J.; Mehta, P.; Logan, I. R.; Brady, M. E.; Cook, S.; Leung, H. Y.; Neal, D. E.; Robson, C.N. Expression of Tip60, an androgen receptor co-activator, and its role in prostate cancer development. Oncogene 2003, 22, 2466-2477. |
