Joining forces to fight lung cancer

As we know from Hollywood action movies, the best way to beat the baddies is for the good guys to team up. And sometimes even the most unlikely pairings can be a winning formula.

The same is true of science, where collaborations between and across fields can kick-start big steps forward, such as the partnership between astronomers and genetics researchers that we recently wrote about.

Today, another team of our researchers reveal their latest findings; a study that is rooted in basic research, but has the potential to be developed into a useful clinical tool to guide lung cancer patients’ treatment. In this post, we take a more detailed look at a scientific dynamic duo taking on lung cancer – the biggest cancer killer in the UK.

Meet the good guys

Although their names aren’t quite as well-known as Batman and Robin, Fennell and Bayliss are the stars of this story.

Professor Dean Fennell is a CRUK funded clinician scientist at Leicester University. He specialises in treating people with lung cancer and leads several important clinical trials.

He’s teamed up with Dr Richard Bayliss, a structural biologist, who’s working out the shapes of proteins – the building blocks of cells.

They first started talking about how they could work together on this project after listening to a guest lecture about lung cancer at the university. We asked them to explain how their combined research efforts could have a direct impact on patients and potentially influence the treatment they receive.

The challenge – a doctor’s perspective

Highly magnified lung cancer cells – image courtesy of the LRI EM facility

Lung cancer kills around 35,000 people in the UK alone and over 1.3 million people a year globally. “Because lung cancer is such an incredibly common disease it’s a massive health burden”, said Fennell. “And as doctors our job is to try to find better ways to treat this very challenging type of cancer.

“Since most patients will be diagnosed with lung cancer when it’s already at an advanced stage surgery is usually not an option, and drugs form the backbone of how we treat people.

“For many years standard care has been chemotherapy, but treatments targeted specifically against the lung cancer cells have been limited. But that is changing and this is where our research comes in.”

On average only about a quarter of lung cancer patients who receive chemotherapy will respond.

But for them chemotherapy is beneficial and they survive their disease longer. “What we still don’t know is how to predict who is going to respond and so there’s always a doubt how the patient will fare,” said Fennell “It’s not until we do a scan afterwards that we can see whether the chemotherapy has been effective or not.”

But lung cancer is not just one disease – it’s actually a family of different types of cancer, many of which can potentially be targeted with specific drugs much more effectively.

“If we could identify these subtypes of lung cancer before treatment, there are drugs already in existence we could deploy with a very high probability of the patient having a good response,” he says.

Introducing ALK

One of the drugs Fennell’s team is particularly interested in at the moment is crizotinib – a drug that targets a certain class of lung cancers accounting for around four per cent of all lung cancer cases – these are called EML4-ALK lung cancers (or ALK lung cancers for short).

“What defines ALK lung cancers is a particular fault that’s happened in their DNA – two different genes (EML4 and ALK) fuse together. And this gene fusion forms a souped-up version of the protein which becomes an engine driving the cancer, and it drives it very aggressively,” Fennell explains.

“So these ALK lung cancers tend to grow very fast and spread rapidly. But the important point about this type of lung cancer is that it’s wholly dependent on this engine – and if we can somehow block this souped-up protein with a drug, the cancer can’t survive”.

And that is precisely how crizotinib works.

This drug was shown to shrink lung cancers in patients much more effectively than chemotherapy. And that’s good news; when patients receive this treatment, most do very well indeed. But they eventually develop resistance to the treatment and the cancer starts growing again.

Navigating a crystal maze to solve the shape of proteins

The key to understanding how cancers develop resistance to crizotinib, and ultimately developing more effective treatments for lung cancer, lies in figuring out what’s going on at a molecular level.

And it turns out that ALK is only half the story. And that’s where structural biologists like Dr Richard Bayliss come in.

His work involves understanding the 3-dimensional structure of the molecules inside cancer cells, such as crizotinib’s target: EML4-ALK. This is essential for designing newer ‘targeted’ drugs.

“Crizotinib blocks the ‘ALK’ part of the cancer-causing faulty protein and has been extensively studied by scientists. But virtually nothing was known about the ‘EML4’ part of the protein,” explains Bayliss. “In particular we didn’t know the shape of the EML4 protein.”

His team specialises in finding out the shapes of proteins using a method called X-ray crystallography.

“Essentially we grow crystals of proteins, like crystals of sugar or salt, containing millions and millions of protein molecules packed together. Each of the proteins inside is about a millionth of the size of a grain of sugar,” says Bayliss.

The scientists then use X-rays to work out the shape of the protein in minute detail.

Using this technology, Dr Mark Richards (a researcher in the Bayliss lab) uncovered the structure of the closely-related EML1 protein. And because the EML1 and EML4 proteins are very similar, they were able to use this information to give a clear picture of the shape of EML4.

“When we looked at the shape of EML4 closely, it was striking that we could predict the protein’s shape would be severely disrupted by being fused with ALK, and that the protein would be quite unstable. This is fairly rare among these kinds of fusions that drive cancers,” says Bayliss.

This unexpected discovery points towards a potential target for new drugs to treat ALK lung cancers, and might help overcome resistance to crizotinib. The unstable nature of the EML4-ALK fusion means blocking a ‘chaperone’ protein, called Hsp90, is a potential new avenue.

Stabilising shapes

The four-part structure of EML1 – coloured blue, green, orange and pink, these four parts come together to make the protein.

Proteins are the workhorses of our cells, carrying out all kinds of jobs from supporting a cell’s structure to creating energy, sending messages and repairing damaged DNA.

Proteins need to have a certain shape to function correctly. Chaperone proteins like Hsp90 help to fold proteins into the right shape and keep them stable – a role that becomes critical if the proteins have any kind of mistakes in them.

But cancer cells often make faulty proteins, so stopping the chaperones from working prevents the faulty proteins being folded and working properly and means the cells are likely to die.

Drugs that exploit this dependence on Hsp90 are known as Hsp90 inhibitors. And our researchers have been instrumental in developing some of the most promising Hsp90 inhibitors, which have already shown encouraging results in clinical trials.

But normally, neither the EML4 nor ALK proteins need Hsp90 to fold into shape correctly. But the faulty EML4-ALK fusion protein found in cancer cells is unstable, so becomes dependent on Hsp90 to help it assemble.

This is a new property that’s only found in the cancer – but not healthy – cells. “And this makes it a weakness that can be exploited by using Hsp90 inhibitors,” explains Bayliss.

The second exciting thing that Dr Bayliss and his team noticed was that EML4-ALK fusions come in several different variants, so not all patients have exactly the same faulty protein.

The ALK part is almost always the same, but the EML4 half of the faulty protein varies a lot. The two most common forms of the faulty protein (called variants 1 and 2) have unstable shapes that are likely to be dependent on Hsp90 to work properly.

“And this makes them good candidates for Hsp90-blocking drugs,” says Bayliss. “But there’s another version, called variant 3, that’s found in around a third of ALK lung cancer patients and doesn’t need help from Hsp90 to fold. This makes it unlikely that Hsp90 inhibitors will work for these people.”

Although the molecular structures from the Bayliss lab predicted that Hsp90 inhibitors should work for at least some ALK lung cancers, this idea needed to be tested in the lab, and then in patients. And this is where Professor Fennell and his clinical team come in.

Turning theory into reality

To prove this idea worked, Fennell’s team made some special cells in the laboratory with the different variants of EML4-ALK. “We were then able to test drugs that block Hsp90 to see whether the drug would work in each of the variants.

“And we found precisely what was predicted by Richard and his team – lung cancer cells that have variants 1 or 2 respond to the Hsp90-blocking drugs, but those with variant 3 don’t,” he said.

“So we can conclude from this that we now have a way of potentially predicating how well drugs that target Hsp90 are going to work for an individual based upon the exact way the EML4 and ALK genes have fused together.”

But they need evidence from clinical data and a partnership with a Boston-based pharmaceutical company is providing this crucial information. Professor Fennell is leading an international trial – called CHIARA – testing an Hsp90 inhibitor in patients with EML4-ALK fusions. This will tell Fennell and Bayliss if their theory is correct.

Thanks to the combined efforts of the duo – revealing the structure of EML4 and how this relates to drug responsiveness – they might have found a way to anticipate how well patients are likely to do if treated with Hsp90 inhibitors.

“We think this information will help us to tailor treatment for patients with EML4-ALK better,” predicts Fennell.

The final part to this story is that Hsp90 inhibitors also seem to be able to overcome drug resistance.

Fennell sums it up: “So not only do we have an opportunity to treat patients with a more effective combination of drugs in the first instance, we may also be able to provide a new option for people with lung cancer that has become resistant to crizotinib, who – up until now – have no treatments left available to them.”

Emma

Reference

• Richards M.W, et al. (2014). Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical  -propeller domain, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1322892111