| ANDROGEN
RECEPTOR MUTATIONS IN ADVANCED PROSTATE CANCER.
Dr Charlotte Bevan Imperial College London, Department of Oncology |
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Prostate tumours, like the prostate itself, grow in response to the male hormones androgens (the major one of these is testosterone). Androgens exert their effects on growth via the androgen receptor, which is hence a key molecule in prostate cancer research.
"Antiandrogen" therapies (e.g. bicalutamide, flutamide) are commonly used to treat prostate cancer. They work by blocking the androgen receptor and are very effective for a limited period of time. Unfortunately, eventually they stop working and tumours recur, often in an aggressive form. Currently there is no effective therapy for such advanced stages of the disease, hence we need to understand what drives this progression. Often, prostate tumours at this stage have mutations in the androgen receptor gene that allow the receptor to become "activated" instead of blocked by antiandrogens. Activated androgen receptor can then cause growth of prostate cancer cells – in other words, the therapies themselves may in these cases contribute towards growth of advanced tumours. There is substantial evidence that specific mutations arise in response to specific antiandrogens. We are proposing to study the association between the type of antiandrogen therapy a prostate cancer patient undergoes, and mutations that subsequently arise in the androgen receptor and/or associated genes. Next, we will undertake study of how the mutations affect growth of prostate cancer cells and their response to different therapies.
Previously, such studies have been difficult as biopsies (samples of tumour) are not routinely taken when a man with prostate cancer relapses. Now we have the technology and expertise to extract tumour DNA from blood, allowing us to study a significant number of patients to test this hypothesis. This is important because our previous work has suggested that prostate tumours may behave differently dependent upon which (if any) androgen receptor mutation is present and what hormone is driving growth, as different subsets of genes seem to be regulated. Hence if we know a man has a particular androgen receptor mutation, we may be able to predict which of the current and developing therapies would be the best to use, and which to avoid.
We believe that this study will improve and increase the options for men with advanced prostate cancer. Screening for mutations at relapse by a painless and non-invasive method (blood sampling) could allow tailoring of currently available therapies to maximise their effectiveness and prolong the relapse-free period. In future, novel therapies specific for men with a given mutation or change in androgen signalling could arise from this research. Thus changes in androgen receptor signalling could act as a biomarker to facilitate personalised therapy for advanced cancer.
Research summary, 25 March 2008.
Project 2007/06