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Where did abiraterone come from?

Posted Sep 21 2011 12:00am

As we’ve reported on our news feed this morning, abiraterone – a cancer drug that we helped discover and develop – has been launched in the UK following licensing by the European authorities.

Men with advanced prostate cancer , who were treated with abiraterone along with a steroid as part of a large clinical trial , survived on average for four months longer than men given just the steroid.

The drug, developed at the Institute of Cancer Research and marketed by Janssen-Cilag , is currently only licensed for men whose prostate cancer has become resistant to chemotherapy, and still has yet to be approved by NICE (or its Scottish equivalent, the SMC) for use on the NHS.

If suitable, it may be available for men in England through the Cancer Drugs Fund  – there’s more about this process over on our CancerHelp UK website , where you can also find a detailed Q&A about abiraterone for patients.

We’ve been following abiraterone’s successes on this blog since 2008, when the results of the first major trials began to emerge . But we thought it would be timely to rewind back to the early 1990s, to the beginning of the story, and look at the invention of the chemical that ultimately became abiraterone.

By the 1990s, researchers and doctors had discovered that the key to managing prostate cancer was to shut off its supply of testosterone , the majority of which is made by a man’s testicles.

Over the years, they’d devised several strategies to do this – initially using castration (orchiectomy, or removal of the testicles), and latterly using hormones like stilboestrol or gonadotrophin-releasing hormone. None of these worked for long; a patient’s PSA levels would gradually start to rise again, and the disease would come back. This became called ‘castration-resistant’ or ‘hormone-refractory’ prostate cancer, and back then there was generally nothing more that could be done.

But measuring testosterone levels in these men’s blood during their treatment gave clues as to what was happening. Hormone treatment would cause a large drop in testosterone, but not to zero. Even though testosterone production by the testicles had been ‘turned off’ (so to speak), the small quantities made by other tissues, such as the adrenal glands, were enough to keep the cancer growing.

And so the hunt was on for a new drug that could completely shut off the body’s supply of testosterone.

Enter a team of chemists led by Professor Mike Jarman, working at what is now the Cancer Research UK Centre for Cancer Therapeutics at the Institute of Cancer Research in Surrey.

Jarman’s team had read about research from the early 1980s, involving a chemical found in fungus called ketoconazole , which was known to target a key early step in the body’s testosterone production line – an enzyme called cytochrome p450 17A1 , or CYP17. Theoretically, targeting this enzyme should shut down testosterone production anywhere in the body.

When given to men with advanced prostate cancer, ketoconazole worked reasonably well at shutting down testosterone production and slowing cancer growth. However, it caused serious side effects, didn’t work reliably and – worst of all – the body broke it down so quickly that men had to be treated three times a day or more.

Nevertheless, these small trials showed that targeting CYP17 was a promising idea. So, armed with a detailed understanding of the chemical reactions CYP17 carried out, the team set about trying to make a molecule in the lab that would mimic ketoconazole’s pros, but with none of its associated cons.

In the mid-nineties, the team published the fruits of their labours. In a paper in 1995, in the Journal of Medicinal Chemistry , they set out details of how they’d made a whole series of ketoconazole-like chemicals, using intricate and carefully controlled reactions.

All of these chemicals, to some degree, blocked the key reactions carried out by CYP17. In fact, as they wrote in the paper,

“The most inhibitory compounds in the present study were far more potent than any inhibitor of [CYP17] for which comparable data have previously been described”

Several of these compounds were extremely promising – they didn’t interfere with other key hormonal processes, and two of them could completely shut off testosterone production in mice. The most promising of them all was described in the paper simply as “3”:

“The evidence…provided here… makes 3 a strong candidate for further development as a potential candidate for the treatment of prostatic carcinoma in humans”

3 would eventually be developed into abiraterone acetate, or to give it its brand name, Zytiga.

It took sixteen more years of hard slog, and collaborative scientific and clinical research, to prove that abiraterone could treat prostate cancer.

First, the drug had to be ‘formulated’ into a pill that could be taken orally (this was done at our Strathclyde Formulation Unit ). Then, it had to be vigorously tested in clinical trials. We helped support the initial phase I and II studies , which took place at the Institute of Cancer Research and the Royal Marsden hospital, before the final, costly phase III trials were carried out with the help of the pharmaceutical industry.

We’re hoping that NICE makes a speedy appraisal of abiraterone, and that it can be made available to all men who are suitable for treatment. But that’s not the end of the story.

Abiraterone has only been proven effective in men with advanced disease that has stopped responding to chemotherapy. We don’t yet know if it will have the same effect when given to men with less advanced disease. This question is being answered in another trial ( which has now closed ) and we’re keenly awaiting the results.

And excitingly, abiraterone could be used to treat diseases other than prostate cancer. For example, we’re currently helping to support a trial looking at whether it can treat certain forms of breast cancer.

The story of abiraterone, from the earliest molecular twinkles in its inventors’ eyes through to a fully licensed pharmaceutical is one that exemplifies all the challenges of discovering new cancer drugs.

And even though the story of abiraterone ‘began’ in the 1990s, it wouldn’t have been possible without a prior understanding of prostate cancer’s intimate relationship with testosterone, or of the way the body makes this hormone.

That’s why we spend around 40 per cent of our research funding on the basic biology of cancer – so we can make more fundamental discoveries like this, and translate them into treatments that will ultimately benefit the people we’re all working for – people with cancer.

Henry


Reference:

Potter GA, Barrie SE, Jarman M, & Rowlands MG (1995). Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. Journal of medicinal chemistry, 38 (13), 2463-71 PMID: 7608911

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