Alan Ashworth: Enough of the back slapping, let's find a cure for cancer

The molecular biologist has revolutionised treatment of breast cancer. His next challenge? The lungs. Steve Connor meets Alan Ashworth

Professor Alan Ashworth is on a mission. He made his name by helping to discover one of the key breast cancer genes and now he wants to destigmatise lung cancer, a disease tainted by its association with smoking and an unhealthy lifestyle.

Professor Ashworth has marshalled his considerable powers of persuasion to establish a unique collaboration between the leading medical centres in London. He wants to do something about the pitifully low survival rates of lung cancer patients – fewer than 10 per cent are still alive five years after diagnosis.

The aim of the London Lung Cancer Alliance is to set up a variety of research initiatives to understand and treat an invariably fatal disease that strikes some 42,000 people a year in the UK – the second most commonly diagnosed cancer after breast cancer.

Unlike breast cancer, however, research into lung cancer has been hampered by its "Cinderella" status – left behind in the hi-tech race to develop radical new therapies based on genetic analysis. It also doesn't help that lung cancer patients often feel that they are being blamed for their plight.

"We should get rid of this stigmatisation, which is increasingly biased in terms of class and culture. We need to do more research, which means getting more people into clinical trials. This [initiative] represents a renewed effort," said Professor Ashworth.

"Lung cancer is a very common disease, but in effect it is many different diseases. The idea is to change outcomes of the disease by trying to get as many patients into clinical trials as possible and harmonise and optimise treatments as much as we can. Outcomes for lung cancer are worse in the UK than in the rest of Europe or North America. There are various reasons for that. Late presentation is one, but the amount of attention we give to it is another. There is also a stigma attached to the disease, which is wrong."

Professor Ashworth, 52, is the chief executive of the Institute of Cancer Research in London, a world-class research centre attached to, but independent of, the nearby Royal Marsden Hospital in Chelsea. He is a fellow of the Royal Society and winner of a clutch of major scientific accolades, including the 2010 Meyenburg Award in Germany, a possible precursor to a Nobel Prize, for his work on breast cancer drugs known as PARP inhibitors.

In 1995, he was a member of the team that co-discovered the BRCA2 gene, which causes one of the inherited forms of breast cancer. It was his later work on BRCA2 mutants that led to the discovery of how to attack breast cancer cells with PARP inhibitors. These drugs block an important enzyme called poly (ADP-ribose) polymerase (PARP) from repairing the damaged DNA of tumour cells.

The idea, called synthetic lethality, is to prevent cancer cells from repairing their damaged DNA so they continue to accumulate mutations and die rather than continue replicating.It was a neat trick to play on breast cancer cells. Healthy cells can survive PARP inhibitors, but cells with the breast cancer mutations don't.

Professor Ashworth is one of a new breed of cancer researchers who view the disease as a molecular challenge. He wants to understand what causes a cell to become cancerous by analysing in minute detail the mutations that arise within the cancer cell's genome – the three billion genetic "letters" of the DNA alphabet.

He also has a personal interest in lung cancer, having recently seen his father die of the disease. "It was one of those weird coincidences. I started to get involved in setting up this London lung cancer alliance and then he was diagnosed with lung cancer," Professor Ashworth said.

"I worked on cancer for years and years, but you see it very differently when you are on the other side and you see how dreadful the treatments are. He died within six months of diagnosis, a totally predictable course of events, and yet there was nothing available in terms of treatment," he said.

"It's incumbent on the research community to stop slapping each other on the backs about the latest genome sequence and get real about using this information in improving cancer treatment."

The revolution in cancer genomics brought about by the progressively higher speed and lower cost of DNA sequencing has meant that scientists can contemplate the prospect of viewing all the relevant genetic mutations within a patient that give rise to a developing cancer.

Some of the mutations will be inherited, such as those in the breast cancer genes. Most arise during the course of someone's life, aided and abetted by various environmental insults – such as smoking.

"Cancer genomes have multiple changes that cause them to be the cancer, but they get a lot of collateral damage as well because they basically don't care what state their genome is in. That's one of the hallmarks of cancer cells," Professor Ashworth said.

"You can tell how many cigarettes somebody has smoked by an analysis of their DNA because carcinogens in cigarette smoke cause damage to their DNA that the cell can't cope with. The same with UV light – you can tell pretty much how much time someone has spent in the sun," he said.

The London Lung Cancer Alliance, which will eventually be rolled out to include other cities, attempts to capitalise on the DNA revolution by offering patients the opportunity to undergo genome analysis to assess what kind of experimental treatment may be suitable for their particular set of mutations. In other words, personalised medicine based on your genetics rather than your symptoms.

"In the old days, a pathologist would look down a microscope and say 'that's the cancer and it's going to do X'. What we realise now is that if you take different bits of the cancer, you get different answers," Professor Ashworth explained.

"Within an individual cancer, there are likely to be lots of competing clumps of genetically similar tumour cells, which we call clones. They compete and evolve along Darwinian lines and they change as a patient is being treated. We need to take more dynamic measurements of this process," he said.

In the past, cancers were lumped together according to the organ or tissue they affected – "lung" or "breast", for instance. Genome analysis has revealed that each individual cancer is, in fact, composed of many different subtypes based on a unique genetic fingerprint.

This has led to a new way of setting up clinical trials to assess the effectiveness of a particular therapy, Professor Ashworth said. Instead of needing large-scale "phase 3" trials involving thousands of patients monitored for many years, it should be possible work out if a new drug works purely on the basis of smaller "phase 2" trials of just a few hundred or even dozens of patients.

"The problem [with phase 3 trials] is that it's one size fits all. You are treating for the average," he said.

"If you are treating 10 women with breast cancer in order to give a benefit to one of them, it's quite a shocking figure. The rationale for targeted therapy is that it only works on a subset that you predetermine, so why try it out on everybody?"

Professor Ashworth is spearheading this approach with a new tumour-profiling unit at his institute. This will rapidly sequence the DNA of patients, comparing their healthy cells, for instance, with the mutations that occur within their tumour cells over a period of treatment. "The challenge is to scale it up so that every patient has their genome sequenced; their normal DNA and their tumour DNA," he said.

It is hoped that the 3,000 people across London who are diagnosed with lung cancer each year will be enrolled in the research programme, with the aim of making the kind of scientific breakthroughs seen in the treatment of breast cancer.

"It's almost a cliché, but it's about making cancer a chronic disease. We're not there yet, but we shouldn't lose sight of a cure."

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