Putting lung cancer under the magnifying glass

Lung cancer cells (Image from the Cancer Research UK LRI EM Unit)

Lung cancer isn’t one of our most impressive success stories.

While we have much to celebrate for many other cancers – like testicular cancer, which nearly all men now survive – lung cancer remains a stubborn foe.

Yes, decades of crucial tobacco control measures are bringing down rates of smoking-related lung cancers, but it’s still the second most common cancer.  And fewer than one in ten people with the disease survive for more than 5 years.

This is dismal. Things need to change.

The good news is that we’re on the brink of real progress. A couple of weeks ago, we announced that we’re supporting one of the largest ever studies of lung cancer patients, to better understand how the disease evolves as patients go through treatment. This will transform our understanding of the disease and kick-start a new era of lung cancer research.

But this £14 million project – our biggest ever investment into the disease – isn’t all we’re doing. Scientists from our Paterson Institute for Cancer Research recently published a fascinating paper that shows we’re slowly but surely lifting the lid on the faulty genes that fuel patients’ tumours – a crucial step in the search for new treatments.

The research team, led by Dr John Brognard, used a cutting-edge new screening strategy to find out which genetic changes are the culprits in causing lung tumours to grow.

Genes and cancer

First, some basics: cancer is a genetic disease. In other words, it’s caused by faults in our genes. These faults can either be inherited from our parents, or more usually, accumulated throughout our lives. This accumulated damage can be down to things like UV radiation from the sun and tobacco smoke, or just as a natural accident during normal cell division and growth.

But when we look at a fully-grown cancer, we see an extraordinary array of damaged genes, many of which are damaged after the cancer develops, as disease progresses and the chaos inside a tumour builds. The challenge for researchers is to work out which DNA changes are the underlying culprits – the ‘drivers’ – of cancer and which are ‘along for the ride’ and are otherwise harmless.

Researchers’ ability to investigate the faulty genes in cancer cells has developed in leaps and bounds. If the initial Human Genome project around a decade ago produced the world’s first ‘atlas’ of the human DNA sequence, then further projects to establish the function of these genes have served to ‘fill in the landscape‘ with increasingly more detail.

In the past 15 years, we’ve made tremendous progress in establishing the danger zones in this landscape – genes linked to an increased risk, such as BRCA1 – as well as the better neighbourhoods that house cancer-suppressing genes such as p53.

Dr Brognard’s team is striving for a ’street view’ level of understanding – they’re trying to work out ways to identify which mutations are driving cancer in each patient. These can be different from person to person and may even change over time or in response to treatment itself.

‘Actionable’ mutations

In their latest study, Brognard and his team looked at tumour samples from the most common type of lung cancer, called non-small cell lung cancer (NSCLC). There’s a pressing need to know more about this cancer – it affects more than 33,000 people each year in the UK, but researchers only know about half of the ‘driver’ genes involved.

The faulty genes that Brognard’s team were particularly interested in have a particular type of fault called a ‘gain of function’ mutation.

This means that the way in which the genes are altered makes them hyperactive in some way. These gene faults are much easier to design drugs against, since – for a variety of reasons – it is much easier to switch off a hyperactive gene, than to repair a broken one.

Indeed, most of the recent ‘targeted therapies’ that many doctors and researchers are so excited about target these faults. For example, treatments such as erlotinib, gefitinib and cetuximab all target a molecule called EGFR, which, when activated, sends a signal telling the cell to grow. In some lung cancer patients, this molecule has a flaw causing it to send a growth signal more often than it should.

And just last year, we saw the results from the first randomized clinical trial for crizotinib, a drug targeting a faulty gene called EML4-ALK. Similar to EGFR mutations, the faulty EML4-ALK is hyperactive, and promotes lung cancer.

Dr Brognard’s team sought to uncover more such mutations. They started looking at a database of previous research from the Wellcome Trust Sanger Institute, which had catalogued all the DNA faults inside the tumours of six NSCLC patients.

Crucially, cells from these patients’ tumours are still alive and able to be grown in the lab.

In the genetic database, Brognard’ s team looked up alterations that were likely to result in ‘gain of function’ mutations in each patients’ tumour – it turned out that, among the genetic chaos in each sample, each tumour had around 65 such alterations.

Switching from the computer to the lab bench, the team then designed a bespoke collection of molecules called siRNAs, which are able to switch off specific genes.

They then used these siRNAs, one by one, to painstakingly dampen down the activity of each altered gene in each cell sample, watching carefully for any effect on the cells’ growth.

Their findings were clear. Three of the tumours shared crucial tumour-promoting gene alterations that affected the same network of cell signalling, collectively known as the MEK/ERK pathway. These gene faults lead to different elements of the pathway becoming overactive, leaving them permanently in the “on” position and repeatedly telling the cell to grow and divide.

This has immediate implications. A drug that targets this pathway, called trametinib, is already being used in clinical trials, so the fact that half of the cell lines had faults in this pathway is encouraging for the development of this inhibitor to be used in the clinic.

On top of this, the team identified several new types of mutation that could be the target for future drugs.

Taken together, their results demonstrate that using this method, which they call a “targeted genetic dependency screen”, could identify which mutations are driving tumour growth in individual patients. And, as a tumour changes, either in response to treatment or just as it evolves over time, clinicians could use this method to identify which treatments might have the greatest effect.

Where do we go from here?

The work is still in the preliminary stages and was carried out in cells that had originally come from patients but had been growing in a lab for some time. So the method will need verifying in living patients.

On top of this, it’s still only a research concept. At the moment the process takes a few weeks to identify the mutations in a cancer, and a further week to design the tools to dampen down the faulty genes, and more time observe the effect on growing cells taken from a patient.

The whole process will need to be sped up, and made much cheaper, if it is to be used routinely.

As more of this work is done, we will also get a better idea of which mutations are the most common and best treated by targeted drugs. The more of these targetable mutations we find, the more we can develop effective combinations of therapies that can be given to different patients and specific to their individual tumours.

So we refer you back to the first sentence of this article – there’s one crucial word missing – ‘yet’. Lung cancer isn’t yet one of our most impressive success stories. But with continued research like this, sooner or later, it will be.

Alan 

Reference

Fawdar S. et al. (2013). Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer, Proceedings of the National Academy of Sciences, 110 (30) 12426-12431. DOI: 10.1073/pnas.1305207110