Until the middle of the 20th century, prostate cancer was perceived as a death sentence, and there was little understanding of the disease or its reliance on hormones. But things turned around when researchers found that metastatic prostate cancer – where the cancer has spread – responded when the production of male sex hormones (androgens) was blocked or their effects inhibited. This signalled the emergence of an entirely new way of thinking about prostate cancer and heralded the beginning of a new era of prostate cancer therapy – much of which The Institute of Cancer Research here in London had a part to play in.
Prostate cancer gland
The androgen – male hormone – story started back in 1941 with Charles Huggins and colleagues at the University of Chicago. They discovered that in men with prostate cancer, reducing androgen concentrations by orchiectomy – removing the testes – or administering the female hormone oestrogen, appeared to restore the health of patients with widespread metastases. Showing that cancer cells were not autonomous and self-perpetuating as previously believed, but were dependent on chemical signals such as hormones to grow and survive, was an incredible revelation. But it wasn’t until the late 1960s, when three independent groups of researchers – led by Anderson, Bruchovsky and Mainwaring – discovered and characterised the androgen receptor, that the race to design effective hormone treatments began. First generation drugs targeted against the androgen receptor were effective, but had unwanted side-effects such as loss of libido and impotence, so the search for alternative non-steroidal ‘pure’ anti-androgens continued.
Professor Johann de Bono – Professor of Experimental Cancer Medicine at the ICR and Honorary Consultant at The Royal Marsden – has written two papers overviewing androgen receptor-targeted therapy, one focussed on the progresses and prospects, and the other on the evolution. It seems that although initial response rates to androgen-deprivation therapy are good – exceeding 80% – most prostate tumours become resistant and transform to a more aggressive form called castration-resistant prostate cancer. I managed to catch up with Professor de Bono to see what the next steps are in targeting the androgen receptor. “Accumulating evidence shows that prostate cancers develop adaptive mechanisms for maintaining androgen receptor signalling through a myriad of changes at various levels – from androgen synthesis to receptor binding on DNA,” says Professor de Bono. “To add to the complexity, several mechanisms of resistance are likely to exist in different patients or even in the same patient. For many years, the only effective treatment for men with castration-resistant prostate cancer was the chemotherapy agent docetaxel, and palliative therapies that managed pain.”
In recent years, a better understanding of the mechanisms that drive resistance to castration has led to the approval of the next-generation androgen receptor targeting agents abiraterone and enzalutamide. The ICR discovered and developed the first, and had a hand in developing the second, too. Abiraterone is an androgen biosynthesis inhibitor, and inhibits CYP17 – an enzyme essential for the biosynthesis of androgens and adrenal hormones. Enzalutamide is a second-generation anti-androgen. “The significant survival advantage demonstrated with abiraterone and enzalutamide in patients with metastatic castration-resistant prostate cancer has provided the clinical evidence that targeting androgen receptor signalling is still a rational approach,” says Professor de Bono.
As with most cancer types, it seems that the identification of biomarkers to help select treatments for individual patients is becoming a top priority for maximising treatment benefit and minimising toxicity and costs. To date, no molecular subtype has shown to predict treatment response or resistance to androgen receptor-targeted agents. But researchers envision that the molecular characterisation of patients will help to unravel the mechanisms of resistance, and help to identify tissue and circulating biomarkers to allow selection of patients for specific treatment.
Over the past decade we have witnessed a phenomenal shift in the diagnosis and treatment for men with prostate cancer. Before Huggins’s discovery, prostate cancer was perceived as a fatal disease, and wasn’t diagnosed until the advanced stage, meaning the average life expectancy was 1-2 years. Now, as shown by a study conducted by the ICR and The Royal Marsden, patients with incurable prostate cancer treated at leading cancer hospital The Royal Marsden now live for about two extra years on average than they did just 10 years ago. Much of this improvement is down to the increased understanding of the underlying biology of castration-resistant prostate cancer in concert with progress in translational research and better ways to appropriately develop drugs to treat this disease. The fruits of these efforts are unmistakable and the challenge now is to continue this pace of progress.
But perhaps we should go back to the founder of androgen depletion therapy – Huggins. In his official University of Chicago obituary, Huggins is quoted as remembering distinctly how he felt on the day of his discovery: “I was excited, nervous, happy,” he recalled. “That night I walked home – one mile – and I had to sit down two or three times, my heart was pounding so. I thought: “This will benefit man forever… a thousand years from now people will be taking this treatment.” To date, 80 years after his discovery, that prediction may well prove to be correct.
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