Prostate cancer: researchers begin to unpick drug resistance

The recent arrival of two new drugs for advanced prostate cancer – abiraterone and enzalutamide – has offered a lifeline to men with the disease.

They both work by switching off a molecule found in prostate cancer cells which is vital for them to grow – the androgen receptor. And trials have shown that they can transform the lives of patients with the disease, who previously had no other options available. One of the drugs, abiraterone, was developed in Cancer Research UK funded laboratories.

But the drugs don’t work for everyone – some men don’t respond to them at all.

And even among men who do respond, these drugs aren’t cures. They can hold the disease at bay for months – even years – but the cancer almost always develops so-called ‘secondary’ resistance, and starts growing again. So understanding more about how they work, and how resistance develops, is a vital subject for cancer researchers.

This week, US researchers studying exactly this issue have made a significant discovery, published in New England Journal of Medicine.

As well as unravelling some of the tricks prostate cancers use to evade these androgen receptor drugs, their findings could also lead to a blood test to tell which men are most likely to benefit from them in the first place.

Variations on a theme

The discovery centres on the presence in the bloodstream of so-called ‘splice variants’ of the androgen receptor molecule. These are alternative versions of the receptor that seem to appear in prostate cancer cells as the disease develops.

“We don’t really understand yet how these arise or exactly how they act,” explains Imperial College London’s Professor Charlotte Bevan whose lab, funded largely by Prostate Cancer UK, studies the androgen receptor. “But there’s quite a lot of evidence from laboratory studies that their presence or absence in prostate cancer cells is linked to disease resistance.”

The US team, led by Dr Emmanuel Antonarakis at Johns Hopkins University Hospital in Baltimore, set out to discover whether one of these variants – ‘androgen-receptor splice variant 7’, or AR-V7, could be detected in the blood of men who were about to start treatment with either abiraterone or enzalutamide.

AR-V7 had previously been implicated in drug resistance in lab studies. “So we hypothesized that the detection of AR-V7 in men with advanced prostate cancer would be associated with resistance to abiraterone or enzalutamide,” Antonarakis’s team wrote in the New England Journal.

They found that it did indeed predict drug resistance: none of the men who had AR-V7 in tumour cells extracted from blood samples showed any sensitivity to either drug.

A graphic representing the androgen receptor molecule

“This is a really interesting finding,” Bevan told us. “To those of us in the field, this isn’t all that surprising – it’s what a lot of laboratory results have predicted. But it’s great to see the idea validated in patients, rather than cells in the lab.”

The discovery also yields clues as to the how the resistance can be overcome. AR-V7 is missing the portion of the ‘normal’ androgen receptor that receives instructions to tell the prostate cancer cells to grow – and it’s these instructions that both new drugs are designed to shut off.

Because this receiver is missing, AR-V7 is permanently switched on, and able to transmit signals from a second region of the molecule known as the ‘N-terminus’. And this allows it to fuel the growth of prostate cancer cells.

“This implies that drugs that target the androgen receptor’s ‘N-terminus’ could offer an extra option for men whose disease has developed resistance to our current drugs,” says Bevan. Such drugs are already being worked on, she told us.

Testing times

But the immediate implication of the research is in laying the groundwork for a test to tell who is likely to benefit from these drugs – something that has economic as well as health consequences.

“These are very expensive drugs,” says Cardiff University’s Professor Malcolm Mason, one of the UK’s leading prostate cancer doctors. “Anything that could show how best to use them could have a profound effect on their cost/benefit analysis – something that’s ever more essential in the current climate,” he added.

Although both drugs are approved for use on the NHS in men who’ve already had chemotherapy and have no other options, the National Institute of Health and Care Excellence (NICE) recently said ‘no’ to abiraterone for use before chemo, in part because of the drug’s high price.

These new finding comes with caveats though. It was a small study – just 62 men were involved, half of whom had abiraterone and half enzalutamide. “This definitely needs validation in a larger study,” says Mason, a point also emphasised by Bevan, and the authors themselves.

On top of this, says Bevan, “AR-V7 is unlikely to be the single mechanism of resistance. The androgen receptor is a slippery fish, and has many ways to slip through the net each time we target it.

“But this research is very encouraging – it shows that there’s at least one common mechanism for resistance to both new androgen receptor drugs, and confirms that targeting this molecule in new ways is going to bring more benefits, in terms of treatments that can make a big difference to men with advanced prostate cancer,” she said.

“We just need to work out how best to use these drugs, alongside any new ones we will undoubtedly develop.”

Reference

• Antonarakis, E., Lu, C., Wang, H., Luber, B., Nakazawa, M., Roeser, J., Chen, Y., Mohammad, T., Chen, Y., Fedor, H., Lotan, T., Zheng, Q., De Marzo, A., Isaacs, J., Isaacs, W., Nadal, R., Paller, C., Denmeade, S., Carducci, M., Eisenberger, M., & Luo, J. (2014). AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1315815
• Image credit: “PDB 1xow EBI” by Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute – http://www.ebi.ac.uk/pdbe-srv/view/images/entry/1xow600.png, displayed on http://www.ebi.ac.uk/pdbe-srv/view/entry/1xow/summary. Licensed under Public domain via Wikimedia Commons.