Understanding prostate cancer response to the hormone therapy bicalutamide

University of UlsterProfessor Stephanie McKeown£96,4012009 - 2012

Why we funded it

By selecting different drugs to use at different times during this treatment regime Professor McKeown hopes to design new methods for treating androgen-dependent prostate cancer that should improve survival times. Other information gained from the study will be used to identify new targets for killing prostate cancer cells.

 

Scientific title

Understanding prostate tumour response to bicalutamide can lead to improved treatment regimens

Research project summary

When men are first diagnosed with prostate cancer they often have a tumour that requires a hormone (androgen) to stimulate their growth. Consequently the patients are often treated with a drug that blocks the effects of androgen on the tumour cells; this is called androgen ablation therapy (AAT). Unfortunately we know that it will only be successful in a proportion of patients before the tumour returns in a form that is no longer sensitive to androgens. This type of 'advanced' tumour is much less sensitive to a wide range of treatments and has often spread to other parts of the patient's body. This research project is to investigate new combination drug therapies for their effectiveness against hormone-dependent prostate cancer.

The drug bicalutamide is a form of AAT treatment during which the tumours become hypoxic (have very low oxygen levels), which leads to development of resistance to treatment and re-growth of cancer cells (link to further info below). Currently bicalutamide is rarely used in combination with other drugs except Zoladex which has severe side effects. Our studies aim to prove that prostate tumour control is achievable using bicalutamide combined with other less toxic drugs. We propose to test a number of different schedules using our knowledge of the physiological changes caused by bicalutamide to inform new methods to trial drug combinations in patients.

Professor McKeown and her research team have well characterised animal models which demonstrate the changes in oxygen levels as described, they will use a carefully planned regime of drugs to target the tumour specific changes as they take place. (link to further info below) This project will investigate a number of new methods designed to treat androgen-dependent prostate cancer that should enhance average survival for some considerable time.

Understanding the physiological and molecular changes caused by bicalutamide could lead to the design of new treatment combinations that could significantly improve tumour control. With the correct schedule it could add several months (possibly even years) to the effective life span of treatments - the drug combinations should be much more effective in killing the tumour cells before they become insensitive to treatment.  Both of the drugs that the study will combine with bicalutamide act on characteristics only found in tumours. This means that they have very few side effects, so it is likely that the combinations proposed would only show a limited increase in toxicity to the patient as compared to bicalutamide alone.

For further info read here...

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Further info...

Recently the team have shown that prostate tumours become very hypoxic (i.e. have extremely low levels of oxygen) within the first 3 days of AAT using the drug bicalutamide. This continues for about 11 days before oxygen returns to more normal levels over days 14 - 21. Many cells will die during this period of oxygen deprivation however those that remain will be 'stress-resistant'. When the oxygen levels increase at day 14 these 'stress-resistant' cells will cause regrowth of the tumour. This selection of 'stress-resistant' cells may explain why bicalutamide treated tumours eventually become insensitive to hormones. Our results are consistent with other published studies although they also show some completely new findings which strongly support the reasons for our proposed study.

The researchers propose to kill as many cells as possible during the first phase of treatment by using bicalutamide and including a drug called Banoxantrone (at day 7) that is specifically toxic to hypoxic cells. When oxygen levels start to increase (at about day 14) we would propose to use a drug called Avastin that interferes with blood vessel growth (we also provide evidence to show that the increase in oxygen is caused by new blood vessels growing into the tumour).