Personalising our approach to pancreatic cancer

Pancreatic cancer is one of the biggest research challenges our scientists are working on.

We recently shared the story of our practice-changing ESPAC trials, which played a vital role in establishing the benefits of drugs like gemcitabine for pancreatic cancer patients who’ve had surgery.

But while these studies mark important clinical milestones, it’s hard to ignore the fact that there has been very little progress in treating the disease over the past four decades. And survival from pancreatic cancer remains stubbornly low.

Today, only three per cent of people diagnosed survive for five years or more.

That’s why we’re investing more in research on pancreatic cancer. We want to turn things around for patients with the disease, and kick-start the improvement in survival that’s so desperately needed. And that’s why we’re excited about a new study, published today by our researchers in Glasgow, in the journal Gut.

New findings on an old drug

“We’re starting to realise that pancreatic cancer is not just one disease but many different types” – Dr Jennifer Morton, Cancer Research UK

Dr Jennifer Morton and her team at the Cancer Research UK Beatson Institute in Glasgow found that a drug called rapamycin – most commonly used to stop transplant patients from rejecting their new organ – appears to prevent a certain type of pancreatic cancer from growing in mice, and even caused some tumours to shrink.

Importantly, modified versions of this drug – that avoid the immune-suppressing properties of rapamycin – have already been developed and could be used to treat other tumour types.

What makes this study so exciting is that, if the results are confirmed in people, it’s the first time researchers have been able to target a specific genetic fault in pancreatic tumours, potentially opening up a new route to tackling the disease.

So what did they do?

The team were interested in understanding the genetic make-up of pancreatic tumours, pinpointing the specific faults – or mutations – in the cancer cells’ DNA that cause the disease.

Identifying and understanding these faults is a global effort, and a group of Australian scientists recently read, or ‘sequenced’ DNA extracted from around 140 pancreatic cancer patients and found more than 2000 types of mutation may be involved.

As Dr Morton, says: “We’re starting to realise that pancreatic cancer is not just one disease but many different types. We therefore can’t rely on a ‘one size fits all’ approach to treating it. We need to be more targeted.”

In the face of so much diversity, finding just one gene to target might seem like an impossible task.

But luckily, the researchers had a few leads.

The domino effect

Rampant KRAS can have knock-on effects

The team knew that pancreatic cancers are nearly always caused by a mutation in a gene called KRAS. This initial driving event is followed by several other faulty genes kicking in later as the disease progresses.

KRAS tells a cell to grow and divide and in most pancreatic cancers it’s permanently switched on. Much like falling dominos, rampant KRAS can have knock-on effects, impacting on other genes involved later on in the molecular pathway telling these cells to grow.

One gene that sits downstream of this domino effect is called PTEN. But unlike KRAS, which is switched permanently on, PTEN is permanently turned off in some pancreatic cancers.

This in turn means that another important gene called mTOR is much more active in these types of pancreatic cancers. All three genes – KRAS, PTEN and mTOR – are involved in cell growth.

Enter rapamycin

This is where the clever bit happens: the team knew that mTOR could be switched off by the drug rapamycin. As a result, they reckoned that treating mice with pancreatic cancers caused by mutations in KRAS and PTEN with rapamycin might be able to stop those tumour cells from growing.

And sure enough, that’s what happened.

When mice with this type of pancreatic tumour were given rapamycin, their tumours stopped growing and in some cases, started to shrink in response to the drug.

“This is the first time we’ve been able to pinpoint a genetic fault in pancreatic cancers and match it up with a specific drug,” said Dr Morton.

If at first you don’t succeed…

What makes this study so fascinating is that rapamycin has already been investigated in clinical trials as a pancreatic cancer treatment: it didn’t work.

The reason for this is that rapamycin has a refined set of targets and only impacts on the KRAS, PTEN, mTOR molecular pathway – which only goes wrong in around one in five pancreatic cancers – still only a relatively small proportion overall.

In trials of the drug the small number of cases where rapamycin might have been effective would most likely have been masked by the majority of patients not responding well to the treatment.

“So many of the drugs that we try in clinical trials haven’t worked with pancreatic cancers because we’re still thinking of it as one disease, instead of many different kinds,” said Dr Morton.

“If we can use a targeted, or even more personalised approach, to treating pancreatic cancers we should be able to better select drugs for individual patients. But these findings highlight how we need more research to develop new and improved therapies to hit these targets.”

The future is …personal

So what’s next?

Dr Morton and her team are looking to test whether the drug could be used to treat people with pancreatic cancer. And their initial studies look promising; the same mutations found to be driving the tumours in mice may also be present in human tumour samples – a crucial starting point.

As with many other types of cancer, this latest research on pancreatic cancer demonstrates how we need to get more personal if we are to understand the disease better. And with this latest discovery, we move a step closer to the day we find a way to stop it.

And that’s a day that can’t come soon enough for patients with pancreatic cancer.

Flora Malein is a press officer at Cancer Research UK

Reference

• Morran, et al. (2014). Targeting mTOR dependency in pancreatic cancer Gut, 63 (9), 1481-1489 DOI: 10.1136/gutjnl-2013-306202

Signature image and domino image from Flickr