Professor Dean Fennell

Professor Dean Fennell

One of our leading experts in lung cancer, Professor Dean Fennell, shares his thoughts on this devastating disease.

Lung cancer is an enormous health burden both in the UK and globally. It’s incredibly common and kills roughly 35,000 people every year in the UK alone – and more than 1.3 million people worldwide.

But despite its prevalence, and the strain it places on healthcare, progress in treating lung cancer has been slow.

Historically, the disease has always been viewed as one that’s difficult to treat, and this has led to a general lack of interest in trying to move treatments forwards. The reluctance to carry out research into lung cancer was further increased by the perception that we’d hit a plateau with treatment about 10 years ago, and many people in the field felt that we’d reached the limit of what we could achieve in this disease.

The road to targeted therapies

In fact, what we’ve actually seen over the last ten years is the development of exciting new approaches to personalised (or ‘stratified’) treatments for people with lung cancer.

The current situation is the majority of patients still have chemotherapy – but we know that most of these patients, many of whom don’t respond, have underlying genetic faults driving their cancer which make them good candidates for new, targeted drugs already in use against other types of cancer.

So the huge challenge facing us now is identifying exactly what these underlying genetic faults are, so we can match the treatment to the patient. We also need to solve the logistical matters of developing laboratories that can provide the diagnostic tests on a wide enough scale – something that’s being trialled through Cancer Research UK’s Stratified Medicine Programme – and designing and running clinical trials to test the effectiveness of new targeted therapies.

As an example of the success we’ve seen already with this approach, you need look no further than treatments designed to target a protein called EGFR – for example erlotinib, gefitinib, and cetuximab – that have revolutionised lung cancer therapy. Doctors treating patients whose cancers are suitable for these drugs have seen a complete transformation in the way we manage their disease.

And last year we saw the results from the first randomised clinical trial of a new lung cancer drug called crizotinib, which targets a faulty protein called EML4-ALK. Compared to standard chemotherapy, crizotinib is much more effective and has far fewer side effects for people whose cancers carry this particular fault.

Finally, the recent sequencing of the genetic landscape of lung cancer has opened up even more potential avenues for tackling the disease. It is helping us design even newer targeted drugs, or investigate the potential of drugs used to treat other types of cancers or diseases based upon the underlying genetics.

And it might even lead us to re-visit drugs that have previously been tested in lung cancer patients as a whole group and not shown good results – but which might actually be hugely beneficial in a select subgroup of patients.

But there’s still a long journey ahead

Although we’re now making good progress in delivering more effective targeted therapies, there are further hurdles we need to jump. Primarily, we need to find ways to tackle drug resistance.

Even with the best treatments we’ve got, the biggest problem is that patients who respond well at first ultimately develop resistance to these drugs. If we want to cure people with lung cancer, we’re going to have to find a way to overcome drug resistance and keep the cancer in remission.

We now have very robust ways to study the biology underlying drug resistance in the laboratory. These methods mimic almost exactly what happens in patients, giving us the scientific tools we need to really get to grips with it.

But one problem that has come to light is that, for any given drug, there is no single solution. A cancer can become drug resistant via several different routes, and at the moment we have no way of telling which pathway a patient’s cancer will go down.

To further add to this challenge, different cancer cells within an individual’s tumour can go down different pathways to achieve resistance. This means you may have different groups of cells in different parts of the lungs that have acquired different genetic faults, all of which allow them to keep growing despite continuing treatment.

As a consequence, if you treat cells that have taken one pathway to resistance, you may only be killing a small part of the cancer, and the rest of the disease will carry on growing. So we’re looking for ways we can tackle all of the resistant cells at once, despite the various pathways driving their resistance.

Coupled with this is the very physical problem of actually pinning down the genetic mistakes that both cause and drive resistance in lung cancer. The technology to map the faults in DNA is readily available and straightforward to use, so in theory it is simple to match targeted therapies to the right patient. But in practise this is not so straightforward. Obviously, lung cancer develops in the lungs, but it’s actually extremely difficult for surgeons to access and take samples (biopsies) of these tumours.

This becomes even more of a conundrum when people become resistant to drugs. Do we take them back into surgery to collect more samples? At this point people are generally more unwell and less fit to cope with the impact of surgery.

Furthermore, as I mentioned earlier, different parts of the tumour can develop independently, so taking a sample from one tumour site may not reflect the genetic changes that have happened elsewhere. And if we aren’t able to identify the different genetic faults that are driving the cancer, throwing various drugs at it is like playing darts with a blindfold on.

Fresh ideas

One of approach that’s generating a lot of excitement, and that we’re trying here in Leicester, is developing ways to monitor cancers using blood tests instead of needing to remove a piece of the tumour itself.

As the tumour grows some of its cells die and, as they do so, they release their DNA into the patient’s blood. So what we’re able to do now is get the tumour’s DNA profile from a small blood sample.

We’ve just seen some very promising early lab results from a joint project involving a randomised clinical trial with a US pharmaceutical company, and it’s clear that it could provide an easy way of pinpointing the genetic mistakes causing the development of lung cancer in the first place.

But, importantly, it could also allow us to monitor the disease over time, detecting break-away parts of the tumour as they become drug resistant and working out how they’ve achieved it.

This is the vital information we need to get patients the best targeted treatments, both from when they are first diagnosed to when they become resistant to therapy. And this is the next quantum leap for us in terms of improving survival rates for lung cancer.

Spotting it earlier

Lastly, these new approaches could even have a wider impact by using them to detect lung cancer at an earlier stage.

At the moment we usually only see lung cancer patients when their cancer is fairly advanced, as this is when people start experiencing symptoms. Sadly, by this point surgery or radiotherapy are usually no longer viable options.

But the approaches we are developing to monitor the disease could be adapted to screen for lung cancer too. If we have a genetic profile specific to lung cancer cells that can detect the cancer early on, we have a potentially cheap and simple way to screen people.

To give a good example of how this may be used, imagine we have a patient who has smoked for 40 years. If we do a blood test and detect a mistake in a gene called KRAS (a common genetic fault in lung cancers), it would provide very solid grounds to investigate further with medical scans to check for early tumours.

If we were able to detect lung cancers earlier than we do now, we could make really significant inroads into the stubborn survival rates, and cure more patients.

So, looking to the future, it’s clear that after many decades of frustration, there’s a bright future ahead for lung cancer research – in treatment and care, and in spotting patients early – and the possibility of substantial progress in the coming years.


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