The latest plot twist in the treatment of prostate cancer

Understanding how tumour cells can become resistant to treatment is one of the biggest challenges facing scientists and doctors today.

At times, the twists and turns a cancer takes can feel more like the plot of a Hollywood thriller than something rooted in biology. And prostate cancer is just one example of a disease with several complicated plotlines.

In 1941, at the University of Chicago, Dr. Charles Huggins pioneered a therapy that would transform how we treat prostate cancer that has spread.

The approach works by limiting the levels of the body’s male sex hormones – known as androgens – which the tumour cells rely on to grow.

It’s still used today, and hasn’t really changed since 1941. But tumour cells often find ways to overcome this ‘androgen deprivation therapy’ and start growing again.

Researchers around the world are trying to understand how cells develop resistance and a new study, published in the journal Science Translational Medicine, turns accepted wisdom on its head in an attempt to tackle it.

In a small, early stage study, US scientists have shown that prostate cancer cells could be killed by high doses of a particular male hormone called testosterone, something that contradicts the very nature of prostate cancer.

But first let’s start with what we know.

The theory of prostate cancer

Prostate cancer is the most common cancer among UK men, with more than 110 patients diagnosed with the disease each day.

It can be cured if diagnosed early, but once it starts to spread the story can become more complicated.

Following the discovery that prostate cancer is influenced by androgens, Dr. Huggins found that using oestrogen to “chemically castrate” men with advanced prostate cancer helped patients by slowing down the growth of their tumours. He was even awarded a Nobel Prize in 1996 for this ground breaking work.

His study was the first to show that you could use drugs to stop androgen production but it wasn’t until the 1960s that scientists concluded that chemical castration was as effective as surgical castration and began using oral oestrogen to treat men with advanced prostate cancer. However, they soon noticed that lowering testosterone levels with oestrogen came with some pretty serious side effects and wasn’t enough to cure the men of their prostate cancer.

So over the next 20 years scientists worked at developing drugs that would either stop androgens from being made or stop androgens from reaching the tumours.

But the sad truth is that more often than not, men who have their androgen levels subdued will become resistant to ‘castration’ treatment at some point.

In order to overcome the drug resistance doctors give a “second-line” therapy that works by blocking signals sent by protein molecules that sit on the surface of cells and respond to androgens. Unfortunately, tumour cells can develop resistance to these treatments too.

And it’s here that the latest study steps in.

Plot Twist

The team, led by Professor Samuel Denmeade from Johns Hopkins University in the US, enrolled 16 patients with castration-resistant prostate cancer onto their study. They found that in some patients, drug-resistance could be reversed by first boosting levels of testosterone to far beyond what’s normally seen in the body, before dropping testosterone levels again. For some men it was like hitting a reset button and they responded to castration drug therapy again.

The men received treatments that switched their testosterone levels from high to low over a four week period – something the researchers dub ‘bipolar androgen therapy’. And this treatment cycle was repeated three times.

Of the 16 patients enrolled in the study, 14 men completed these three cycles and were monitored further. The team analysed levels of the blood marker PSA, which can be used as an indicator of how the disease is progressing (although there are some well documented challenges that come with using this marker).

The new treatment approach produced a notable decrease in PSA levels in half of the patients (seven out of 14), suggesting that the tumour cells may be responding to the treatment. Ten of the men also had secondary tumours that could be picked up by CT scan, and half of these patients saw those tumours shrink following the bipolar therapy.

Interestingly, 10 out of 10 patients who were suitable for follow up after they completed bipolar therapy saw their PSA levels fall again when the hormone therapy that they used to be resistant to was reintroduced. And the researchers believe that this re-sensitisation to treatment could be a promising avenue for further research.

But this new approach goes against pretty much everything we generally know about prostate cancer.

Prostate cancer cells thrive on testosterone. So on paper it doesn’t really make sense to load up the body with more of what fuels tumour growth. That would be like throwing a grenade at a house that’s on fire. Surely it can only make things worse?

But this new study complements recent research showing that tumour cells that are used to low levels f testosterone can be killed by a surprise high dose of the hormone. Researchers believe this may be down to the unexpected increase in the hormone stopping the cancer cells’ ability to copy their DNA. And it may also trigger catastrophic breaks in cells’ DNA, causing them to die.

But further, larger scale studies will be required to confirm this.

“This is major new hope,” says Professor Charlotte Bevan, a UK based prostate cancer expert from Imperial College London. The men can start re-taking their hormone therapy, that they were previously resistant too, which, according to Professor Bevan is “the best case scenario”.

“However, no one is saying this isn’t a risky strategy,” she adds.

Risky Business

This new approach is risky because at the start the remaining cancer cells are weakened but by giving high doses of testosterone, BAT may feed the really strong cancer cells which could be detrimental.

The authors themselves are quick to caution in their paper: “BAT is in no way ready for widespread adoption and should only be administered in the context of a clinical trial until its safety and efficacy can be confirmed,” they write.

It’s only through carefully piecing together each element of this complex story that scientists will have the final word on advanced prostate cancer.

And this study shows that for some people, an unexpected twist could be just what their story needs. We’ll be keeping an eye out for the sequel.

– Misha

Reference

• Schweizer, M., et al. (2015). Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study Science Translational Medicine, 7 (269), 269-269 DOI: 10.1126/scitranslmed.3010563

Image

• Image via flickr, used under a CC-BY 2.0 license