Gerard Evan lung pancreatic cancer

Roderik Kortlever, Trevor Littlewood and Gerard Evan Gerard Evan lung pancreatic cancer

There comes a point when we all ask: ‘what am I doing with my life?’ It’s a question often tied to career choices as we plot the road to follow.

Cancer researchers are no different. When embarking on their career, they have to choose a topic they often dedicate their life to researching.

And with over 200 types of cancer, there’s a lot to choose from.

Plus, much like in music and fashion, there are often trends in cancer research that come and go. This can make it tough to predict what will be in the spotlight next.

But some scientists know right from the beginning what area of cancer they’re going to work on, and what they hope to achieve.

And some choose this path knowing they’re taking on a huge challenge.

Professor Gerard Evan, who works in the Department of Biochemistry at the University of Cambridge, is one of these people.

He’s spent the majority of his career researching two genes: Ras and Myc. They are faulty or hyperactive in the vast majority of cancers, and so have attracted huge interest as potential targets for drugs.

But they carry a label that might put most young scientists off. They are said to be ‘undruggable’. Evan wasn’t one of those young researchers.

Not content with the challenge of tackling these genes, Evan also studies their role in lung and pancreatic cancers, two of the hardest-to-treat cancers.

We spoke to him about how he came to choose this path, what he’s working on right now, and what his hopes are for the future of cancer research.

The defining moment

“I’ve always studied cancer,” Evan explains. “From when I was a grad student in the early ‘80s right up to now, it’s always been my passion.”

Back then, when Evan was starting his career, scientists knew the Ras and Myc genes existed inside cells, and that when hyperactive or faulty these so-called oncogenes could cause cancer. But they didn’t know much else.

If you want to dam the river, you’re better to do it further down, rather than blocking each upstream tributary. Ras and Myc are like the point at which all the tributaries in a cancer cell meet

– Professor Gerard Evan

Then, in 1983, Professor Robert Weinberg and his team at MIT in the US made a discovery that would shape the rest of Evan’s career.

Weinberg’s team showed that if mouse cells had just a faulty version of Ras or Myc on their own, nothing happened. The cells didn’t turn into cancer cells. But, if the cells contained a faulty version of both genes, they would turn cancerous and cause a tumour to form.

“This fundamentally changed how we thought about oncogenes,” says Evan. “It showed us that they have to work together in cooperative ways in order for a cancer to form.”

It was this notion that sparked Evan’s interest in Ras and Myc, which he’s been researching ever since.

“Cancer cells develop because of genetic mistakes that cause the cell to grow and divide out of control. But most of these genetic mistakes eventually feed into and converge on Ras and Myc. The way I see it, it’s a bit like a river. Rivers have many upstream tributaries, but eventually they all flow together and meet at one point, before flowing out to the sea.

“If you want to dam the river, you’re better to do it further down, rather than blocking each upstream tributary. Ras and Myc are like the point at which all the tributaries in a cancer cell meet. They’re a common denominator across many, perhaps all, cancer cells.”

And it’s this commonality that Evan hopes to exploit.

“If we can find a way to target and block Ras and Myc, then we might not even have to worry about all the other genetic mistakes. We’d be targeting a vulnerability that is shared across cancers rather than the ones unique to each cancer and each patient.

No easy task

It’s a relatively simple idea to explain: develop drugs that switch off Ras and Myc and you’ll kill most cancer cells.

But decades of research have taught us that this is far more difficult in practice.

Despite knowing more about these genes than ever before, scientists still haven’t found a way to successfully develop drugs to switch them off. That’s why those in the cancer research field often call Ras and Myc ‘undruggable’.

This doesn’t deter Evan.

“Yes, I do like a challenge,” he says.

But it’s more than that.

“It’s the idea that if we can block Ras and Myc, these engines that are common across most cancer cells, the payoff would be huge. It could mean more generalised treatments that can be deployed against many different cancer types.

“That’s something I find really exciting and motivating.”

Evan also points out that the idea of something being ‘undruggable’ is a moving target – it isn’t set in stone.

“Things are constantly changing in the field of cancer research,” he says, recalling a time when the idea of developing specific drugs that are now standard treatment for certain cancers was laughed at.

“Today, not only do we have these drugs, but they’re widely used as cancer therapies. I’m convinced we’ll see the same thing with Ras and Myc in the future.

“But as scientists we need organisations like Cancer Research UK to help us get there. It’s an organisation that encourages people to think outside the box, and that’s what we need if we’re going to turn Ras and Myc from being ‘undruggable’ to ‘druggable’.”

‘This doesn’t mean these cancers are incurable’

Not content with taking on the challenge of Ras and Myc, Evan has chosen to take on another challenge – studying these genes in two cancers that are notoriously hard to treat with stubbornly low survival: lung and pancreatic cancer.

“For me and my close collaborator Dr Trevor Littlewood, who is co-leader of our laboratory, it’s all related. We know Ras and Myc are involved in both the more treatable cancers and those, like lung and pancreatic cancer, that are harder to treat. This means that there is a common process underlying both the treatable and less treatable diseases,” he says.

There are many cancers that used to be untreatable but which now succumb to new therapies. These past successes inspire us to tackle the tougher diseases

– Professor Gerard Evan

When speaking about hard-to-treat cancers, Evan takes a very practical approach.

“Every cancer has a mechanism that causes it to grow and divide uncontrollably. For some, we understand that mechanism really well and have really good ways to treat them, which means a lot of people survive.

“But for other cancers, including lung and pancreatic, we don’t fully understand their mechanisms. And this means that, for now, these cancers are hard to treat and few people survive them.

“For me, this doesn’t mean these cancers are incurable. It just means we haven’t yet found the right approach to treating them yet. There are many cancers that used to be untreatable but which now succumb to new therapies. These past successes inspire us to tackle the tougher diseases.

“And it’s why we need more research; so we can better understand the mechanisms of cancers where survival is low and improve the situation.”

In new research, published today in the journal Cell, Evan’s team has discovered more about how Ras and Myc work together in lung cancer.

They found that tumours growing in mice whose cells produced a faulty version of Myc as well as Ras looked remarkably different to tumours formed from cells with just faulty Ras.

Adding in a faulty version of Myc almost instantly made the lung tumours become far more aggressive and invasive. It drove the rapid and dramatic movement of immune cells both in and out of each lung tumour.

Lung cancer immune cells

A lung cancer showing cancer cells carry activated Myc (red) that become flooded with immune cells (green). Credit: Professor Gerard Evan

They also showed that these rapid cell movements are essential for lung tumours to be able to rapidly and aggressively grow and spread.

But interestingly, as soon as they took Myc away using a lab-based bit of genetic engineering work, the tumours immediately returned to their original, non-aggressive states.

“It was amazing to see,” says Evan. “When we switched off Myc in lung tumours in the lab, it was like the shutters came down. The tumours stopped growing aggressively and shrivelled back to their former benign state before Myc was activated.”

Evan and his team believe this new understanding of how Ras and Myc work together in lung cancer will bring them closer to developing ways to mirror these effects in people.

“It’s early stage research,” he cautions, “but we’re so excited about what we found.”

This work is particularly exciting because the findings may cross over with other cancers too, including pancreatic cancer, which Evan works on as part of the Stand Up To Cancer Pancreatic Cancer Dream Team.

Evan calls the Dream Team the most wonderful collaboration he’s ever been involved with.

“I get to work with heroes of mine on a regular basis as part of the Dream Team. It’s an honour and a privilege to be part of it.”

Aside from allowing him to meet his heroes, the collaboration allows Evan to work with cancer doctors in a new way.

“These are people who regularly have patients who die and who are desperately trying to find new ways to treat them,” he says. “They’re the ones who take what people like us find out about the mechanisms of cancer cells and then apply it to patients.

“Working so closely with doctors in this way is illuminating, sometimes frustrating but always encouraging – it forces me to think about things in a different way.”

The future looks bright

There’s no doubt Evan is extremely passionate about cancer research, and is optimistic about what the future holds.

“In the last 10-15 years, there’s been an explosion in our understanding of cancer. Previously, it was a ‘black box’ disease where we knew very little about what we were dealing with. Today, we know so much and it’s given us new treatments that can cure some people, and we’re still learning and developing more each day.

“My intuition tells me we’re on the verge of some really exciting discoveries and developments.”

And despite its extremely challenging nature, Evan is optimistic about the future of his work on lung and pancreatic cancers and Ras and Myc.

“I believe that in the future, we’ll smile when we remember how Ras and Myc used to be said to be ‘undruggable’ and that we’ll get to a point where survival for cancers like lung and pancreatic has improved dramatically.

“But we’re not there yet. We still have a lot to do, which is why I still do what I do.

“And I couldn’t do it without Cancer Research UK. They’ve funded my work in many different ways over the years and continue to do so.

“It’s absolutely true to say I wouldn’t be where I am in my career without them.”