For the thousands of British men each year who develop the most aggressive form of prostate cancer, the treatment options have generally been exhausted.

Most will have had surgery and radiotherapy, as well as chemical castration, the drug therapy that stops them from producing the male hormones that prostate tumours need to grow. Should their cancers return, and they receive a diagnosis of castration-resistant prostate cancer (CRPC), there is little more that medicine can do.

The promise of abiraterone acetate is that it might provide these men with a further alternative. Like all cancers, prostate tumours owe their origins to a biological domino effect, and preliminary results have suggested that this drug can prevent a critical stage. “With this drug we believe we can stop the first domino falling and stop the cancer growth and survival,” said Johann de Bono, who led the research team at the Institute of Cancer Research in London.

For a cancer to begin, a cell must acquire a mutation in a tumour-pro-moting gene, or “oncogene”, which allows it to divide unchecked. Further mutations must then disable “tumour suppressor” genes, which usually ensure that such abnormal cells are destroyed. Cancerous cells must then be fed by nutrients and growth factors, such as hormones, which enable them to develop and sometimes to spread through the body. Prostate cancer is especially reliant on this stage, as it is generally driven by male hormones.

This explains why chemical castration is the frontline treatment for this type of tumour. Deprived of the male hormones (or androgens), prostate cancers usually wither and die.

Tumours that kill, however, fail to respond to chemical castration as they should, or regress before returning. Even when the testes are making few androgens, CRPC tumours continue to grow and spread to other tissues.

These cancers are very difficult to treat, and they kill about 10,000 men in Britain each year. It is thought that they keep growing because they have developed a way of making androgens themselves, probably as a result of the cascade of genetic mutation that afflicts cancer cells.

Abiraterone is an encouraging option for these men because it represents an alternative, more powerful way of eliminating the hormones that prostate cancer needs to thrive. Instead of cutting off the circulation of androgens from the testes, the drug knocks out an enzyme, CYP17, which is essential to androgen production.

This means that not only are the testes incapable of making male hormones, such as testosterone, but so are any mutant cancerous tissues that might be able to produce them.

It effectively denies even self-sustaining tumours the raw materials they need to grow. Dr de Bono said: “The ability of cancer to survive and grow depends on its power supply, which in this case are the hormones.”

Scientists are keen to improve understanding of the genetic processes that promote CRPC, to identify which patients will respond best to abiraterone or other drugs, and perhaps to find other steps of the prostate cancer pathway that might be attacked.

Research has identified that many castration-resistant cancers are characterised by an oncogene, ERG, which drives the cancer. The cancerous cells’ genomes become rearranged so that the ERG gene is stuck to the activating switch or promoter of a different gene which is sensitive to hormones.

“In normal patients, this gene makes an innocent enzyme that is present in men’s semen,” said Ger-hardt Attard, another leader of the study team. “When it is stuck to ERG, it becomes an oncogenic [cancer-caus-ing] switch that drives the tumour causing it to divide, to grow and to spread.”

Abiraterone worked well in five of six patients in the study group who tested positive for the ERG rearrangement, Dr Attard said. “By looking at this genetic abnormality, we may be able to identify a subgroup of patients with a higher response rate,” he said.

Other oncogenes that are reliant on hormones, however, also allow abiraterone to work. “The caveat is that many patients who do not have the rearrangement also respond,” he said.

“In the short term, we do not have sufficient knowledge to select patients, but as we understand this disease better, I am confident we will find other genetic signatures.”

In the longer term it should become possible to screen prostate cancer patients to determine which ones are likely to respond well to abiraterone.

Gaining time

70% of newly diagnosed prostate cancer patients now survive beyond five years. In the 1970s it was 30 per cent

12-18 months life expectancy after chemotherapy of patient with most aggresive forms of the disease

34 months current survival of some patients on abiraterone in continuing trials

Source: Prostate Cancer Charity; Institute of Cancer Research

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