Every year at the start of November, scientists and doctors from every cancer speciality gather in Liverpool for the NCRI - the UK’s largest cancer conference.
This year we sponsored a session calling on the research community to think outside the box about the next big steps in treatments for advanced prostate cancer. The session was titled ‘beyond the androgen receptor’. In layman’s terms that means researchers were being asked to think beyond hormone therapies - the usual first defence against advanced prostate cancer.
Here we report on how some leading scientists in prostate cancer research responded and explain the interesting results they revealed.
The androgen receptor is a protein found inside prostate cells that becomes activated when it binds to the male hormone testosterone. Once activated, the androgen receptor moves from the main cell body into the nucleus – the cell’s control centre. There, it attaches to the DNA and controls the activity of certain genes by turning them on or off. In normal cells this process is tightly controlled, but in prostate cancer cells the control is lost and androgen receptor signaling starts to drive prostate cancer growth and spread.
The first line of defence against this is to stop the androgen receptor becoming activated by blocking its binding to testosterone. This is how most hormone therapies work, and is usually very effective at slowing or stopping tumour growth for a while. But almost inevitably the tumour eventually begins to grow again.
This is a problem that’s been puzzling scientists and doctors alike for years, and is still one of the biggest obstacles facing both men with advanced metastatic prostate cancer (prostate cancer that has spread outside the prostate) and the clinicians treating them.
We still don’t understand all the ins and outs of how or why prostate cancer eventually becomes resistant to hormone therapy, but there’s a huge amount of research going on in this area. Scientists are trying to understand how the androgen receptor works, and how it changes over time, in far greater detail than ever before. We’re also starting to learn how it interacts with other signaling systems inside cancer cells. Together, these approaches should help us investigate whether there are ways to treat advanced prostate cancer that will avoid coming up against the problem of hormone resistance.
The first speaker was Professor Karen Knudsen from Thomas Jefferson University in Philadelphia. It’s already well known that inherited mutations in genes controlling DNA damage repair (for example BRCA1 and BRCA2) increase a man’s risk of developing advanced prostate cancer. But in this talk Professor Knudsen presented new evidence suggesting that spontaneous (non-inherited) changes in genes controlling the way that cells repair damaged DNA are actually far more common in prostate cancer patients than previously thought.
She went on to reveal that early results from clinical trials of a drug that affects this DNA damage repair process were positive, with some patients with advanced, aggressive prostate cancer having an impressive response to the drug. Finally, she showed brand new data revealing that the androgen receptor plays a role in controlling how well cells repair their DNA. This suggests that the androgen receptor and the cells’ system for repairing damaged DNA may be more intertwined than previously expected. And it highlights promising new avenues of investigation.
By tracking the course of a man’s disease in real time...it may be possible to match treatment to how an individual man’s cancer is developing
Dr Gerhardt Attard shared updates from research he has recently published. He examined tumour DNA circulating in the blood of patients with advanced prostate cancer. Dr Attard looked at the tumour DNA at regular times during the men’s treatment and used it to study changes in the gene responsible for building the androgen receptor. He suggested that by tracking the course of a man’s disease in real time like this, it may be possible to match treatment to how an individual man’s cancer is developing. This would allow doctors to ensure men get the right treatment for them at the right time to get the most benefit.
Professor Kevin Prise from Queen’s University Belfast discussed the results of a Prostate Cancer UK funded project. The project was looking to find out whether loss of a gene called PTEN, which is often missing in patients with both early and advanced prostate cancer, affects the response to radiotherapy treatment. He used mice without a functioning PTEN gene for these experiments, and found that treating them with radiotherapy as well as with a drug that restored PTEN function led to a reduction of tumour growth, suggesting that this combination of treatments is worth exploring further.
Finally, Professor Tapio Visakorpi from the University of Tampere in Finland discussed how analysing prostate cancer DNA in depth could provide a way to track how the disease is developing and understand how and why it’s happening. This might help doctors to give men appropriate treatments at the time when they’d be of most benefit. It could also help scientists investigate possible options for new therapies.
Overall, we left this session thinking that while we’re unlikely to see a ‘miracle cure’, which makes the problem of hormone resistance irrelevant, we’re really at an important juncture for the treatment of advanced disease.
Our understanding of how the androgen receptor works, how it interacts with other systems within the cancer cell, and how one man’s cancer might differ from the next is progressing at such a rate that new breakthroughs are being reported every day. And we’re not only hearing about ways to treat advanced prostate cancer, but also ways to prevent it occurring in the first place.
There is very definitely light at the end of this tunnel, which is getting brighter as world-class researchers like these get together to share the newest developments and plan ways to work together in future.