Research 2007 Research Projects 2007 Research Charlotte Bevan | 2007 Research Charlotte Bevan |
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Inhibition of androgen signalling in prostate cancer using engineered repressors
Dr Charlotte Bevan and the team at Imperial College London The prostate grows in response to androgens, the male sex hormones, such as testosterone and dihydrotestosterone.
Prostate tumours also grow in response to androgens, hence therapies are aimed at inhibiting androgen signalling. The actions of androgens are mediated by one protein, the androgen receptor, and thus the androgen receptor pathway is key in prostate cancer. Current therapies, such as removing androgens by chemical castration and inhibiting the androgen receptor using antiandrogens, are initially successful but eventually fail and patients experience a recurrence of tumour growth, termed hormone-refractory prostate cancer. This hormone refractory growth is often aggressive and metastatic, and currently no effective therapies exist for this stage of the disease. The reasons why tumours stop responding to antiandrogens are not fully understood, but in many cases it seems to be due to mutations or increased levels of the androgen receptor, or alterations in the levels of accessory proteins called coactivators and corepressors. Under these conditions, existing antiandrogens are ineffective.
This project aims to create a new and more effective antiandrogen, in reality an engineered protein that binds to the androgen receptor very specifically and represses its activity, even in the presence of androgens. This is being designed to address many of the concerns over existing therapies, so it will (i) be specifically directed against the androgen receptor while not affecting other, related receptors; (ii) be effective against mutated as well as wild-type androgen receptor; (iii) be effective in conditions of altered cofactor levels; (iv) bind to the androgen receptor in response to androgens, so may not require androgen ablation as many antiandrogens do for maximum effect. As well as having the potential to be a more effective antiandrogen, this will at last provide a therapeutic option for men with advanced prostate cancer who have relapsed on current therapies
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