Intelligent knives, new drugs and cancer detectors
Kat: This is the Cancer Research UK podcast for August 2013. This month we’re discussing the latest advances in cancer research including a “magic wand” for surgery and whether chocolate can detect cancer. Plus, we take a look at a major new lung cancer gene project. And we’ve got this month’s heroes and zeros.
Hello and welcome, I’m Dr Kat Arney, and with me to discuss the latest news is Henry Scowcroft, News and Multimedia Manager at Cancer Research UK.
Henry: Hi Kat. So the first really interesting story this month that we should probably mention is something that hit the headlines a couple of weeks ago, called variously the intelligent knife or “iKnife”...
Kat: Magic wand!
Henry: Yes, magic wand. It got quite a lot of excitement and it is an incredible promising invention. Essentially it’s trying to solve the problem that when cancer surgeons operate, they tend to take an area around the tumour of healthy tissue as well to make sure they’ve got the whole cancer. This development is very exciting. It fits on the end of an existing tool that surgeons use for electrosurgery, and this is something that burns the tissue away rather than cutting with a knife. These devices have been around for decades and they’re used in almost every piece of cancer surgery to some extent or another. This device clips onto the end of it and it can analyse the smoke generated when it burns the tissue, and it can check that smoke for signs of the cancer. So it can tell the surgeon in real time where the edge of the tumour is. It’s very, very exciting technology.
Kat: So what studies have they done at the moment?
Henry: It’s important to stress that this is at a relatively early stage in its development. What they’ve done so far is they’ve used the device to analyse different tissues from around the body and different existing tumour samples taken from patients. So they’ve basically built up a great big test database of different types of tissue. And they’ve now shown that you can go into a patient, while you’re doing surgery, and that the device can tell the difference between different cancer types, different types of tissue, from cancers that have spread from different locations in the body. So they know it works in terms of detecting the tissue.
What they haven’t proven yet – and this is a really important point – is that it actually changes things for patients. So the next step is to do trials where some patients are treated with this device, other patients are treated without it, and they go and compare things like do they recover quicker from the operation, does the cancer come back at a slower rate, and does it actually, ultimately, affect whether patients are cured or not. So we don’t know that yet – that needs to be tested in trials.
Kat: And this is work from a team at Imperial College, and they published this paper so far in Science Translational Medicine, so we look forward to hearing more results from them in the very near future. And now the next story I wanted to talk about was one from Cancer Research UK scientists – this is a team down at the University of Southampton, and they’ve published their work this week in the Journal of the American Chemical Society. Now, this team are looking for drugs that block a molecule called HIF, which switches on the way that cancer cells respond to low oxygen levels. It keeps them growing, it means they can grow a blood supply, they can handle all this kind of stuff.
Henry: Of course, it’s very important, this idea of low oxygen levels is very important in tumour cells, because as tumours get bigger and bigger, they need oxygen and nutrients to survive, and that means getting a decent blood supply. And HIF is a molecule that’s the key switch in this low oxygen response.
Kat: And it’s been very, very difficult to find drugs that work on HIF, to stop it swiitching on this cascade of responses that enable the cells to survive, because it’s made of two bits that come together, and it’s very hard to make drugs that work against that kind of interaction. But there’s some very clever and elegant experiments that the Southampton team have done, so I spoke to Dr Emma Smith, our Senior Science Information Officer, to find out more.
Emma: So the researchers used handy little bacteria grown in the lab to test over 3.2 million molecules – these small molecules were called cyclic peptides. And what they did is they aimed to stop the two halves of HIF coming together, which would then stop it working and doing its job. And what happened is the bacteria were modified so they would only carry on growing when their cyclic peptide was successful at blocking HIF. So this gave the scientists a really quick yes/no answer. So they were able to do this very rapidly, and screen 3.2 million molecules. And that’s how they found the one – the one in 3.2 million. So it’s a really elegant, clever approach with lots of future potential to look at other cancer-causing molecules.
Kat: That was Dr Emma Smith, explaining what the researchers have done. And she talked about the cyclic peptide that they found that works, but unfortunately it’s not really a great drug.
Henry: You can’t get it into cells, though in the laboratory experiments they got it into the cells artificially, whereas what you need in a good drug is something you can either inject or take as a tablet that will then be absorbed automatically. So this is a starting point to start studying what happens if you switch HIF on and off, but the next step is to find other chemicals that can get into cells easily, that work in exactly the same way.
Kat: And there’s some really nice stuff people can do now with looking at the shapes and structures of molecules, so you can look at the shape of this thing that does work and try and find things that also have that shape. And also as well you could apply this kind of technique, this screen, to many, many other types of interacting proteins which are thought to be ‘undruggable’.
Henry: I think that’s the key point here – there is excitement about targeting HIF but the real excitement is about targeting these so-called protein-protein interactions, and this includes some of the most important proteins in cancer.
Kat: That’s definitely one to watch in the future. And finally, we have a headline in the Daily Mail that we’d like to talk about – this says “Chocolate and fizzy drinks could be used as cancer detectors.”
Henry: Would that be lovely!
Kat: Well it would be lovely, but sadly it’s really gimmicky and inaccurate, and this was very frustrating because it’s actually based on a really great research paper from scientists at our Cancer Research UK Imaging Centre at UCL, and they published this in Nature Medicine. Now what they’ve done is they’ve developed a new type of MRI scanning technique called GlucoCEST, and it detects glucose, which is a type of sugar, which is taken up by cancer cells generally. But they looked at the effects of glucose in mice. Now cancer cells do use sugar differently from healthy cells – this is the basis of things like PET scanning, which uses radioactively-labelled glucose. So the researchers have only done these experiments using mice that were injected with glucose, and they do say in their paper “well if you scaled this up and if it worked in humans, it would be the equivalent of about 14 grammes of glucose, that’s about half a chocolate bar.”
Henry: That’s the thing – when you put into a press release something like “this is about the equivalent of half a chocolate bar”, it often results in the sorts of headlines we saw. And it’s just worth stressing that no chocolate was used in any of these experiments.
Kat: And it wouldn’t be as well! If you used this technique in human patients they would have to fast beforehand, so eat nothing beforehand, and then be given controlled solutions of glucose – you’re not adding anything else that’s in a Mars Bar or a can of Coke that might interfere with it. So it is a good thing because this technique uses just regular glucose, and that avoids things like the radioactivity that you have to use with PET scanning. And it also would fit into the current MRI scanning equipment that many hospitals have. But the thing that really bugs me about this is the headline. Now, I don’t think it’s bad to be a bit pedantic about these things?
Henry: I think it’s very important. Apart from anything else there are all sorts of myths and legends out there about how sugar and cancer are related and eating glucose somehow fuels a tumour, which are all basically not scientific, it’s all basically nonsense to a degree. And headlines like this, when they tap into ideas that are out there like that, they confirm myths that are really not very helpful for cancer patients to be hearing.
Kat: “This is good for you, that’s bad for you, this can cure cancer, chocolate can detect cancer” – and I really feel, having looked at the paper, it was strong enough to stand on its own merits. It didn’t need a gimmicky headline. The fact that you can use just regular glucose, regular sugar, to detect cancer is fantastic news. So it’ll be really good to see how that technique can scale up to human patients. But anyway, that’s Henry Scowcroft, our News and Multimedia manager.
Henry: Thanks Kat.
Kat: Lung cancer is a disease that’s seen relatively little improvement in survival over the years, and it currently claims more than 35,000 lives every year in the UK. Cancer Research UK is committed to improving this dire situation, by finding ways to diagnose lung cancer earlier, and treat it more effectively, as well as more fundamental research aimed at understanding what makes the disease tick on a biological level.
So we’re happy to announce a major new research project that’s the biggest single investment we’ve ever made in lung cancer research – clocking in at £14 million. Led by Professor Charlie Swanton, at our London Research Institute, he and his team will be analysing the genes in lung cancer samples from more than 800 patients, and following them over time as their tumours respond – or don’t respond – to treatment.
To find out more about this ambitious programme, called TRACERx, our reporter Greg Jones spoke to Professor Swanton.
Charlie: So we’re going to be looking at how lung cancers, principally non-small cell lung cancers (NSCLC) change over time, and how their spatial and temporal variation gives us some insight into potential new therapeutic strategies for patients. So, what we’ve realised from our work over the past year or two is that tumours are not just single entities, but they’re composed of multiple different subclones that may be intermingled or spatially separated, and what we’re also realising is that tumour are evolving over time. So there’s a spatial and temporal aspect to tumour biology that many of the sequencing approaches that have been taken so far have largely not taken into account – principally because of the cost involved and also I think the awareness now that tumours are markedly more heterogeneous than perhaps we had imagined initially.
The idea with TRACERx – which stand for Tracking Cancer Evolution through Therapy (Rx) - is that we ask patients with primary NSCLC to consent to this study which would enable us to acquire any tumour material that is surplus to pathology requirements following surgery. So these are patients with primary, operable lung cancer. And we will subject each tumour to multiple sequencing approaches to identify what are the shared mutations in every region, and what are the diverse heterogeneous mutations in every region.
And then if the patient is unfortunate enough to suffer recurrence of the disease, or metastatic disease, we’ll ask if the patient would kindly consent to a further biopsy, so that we can compare the biopsy at sites of metastatic disease to the original primary, to ask the principal question “how has the disease changed over time?”, to better understand the biology of metastatic disease, to better understand resistance to therapy, and ultimately to come up with better clinical approaches to treat this disease and stop this from happening.
Greg: So in terms of how long the studies going to be, where patients are going to be recruited, the details of the research?
Charlie: So it’s a nine year study in total starting from October this year, it’s going to take place in six clinical centres in the UK, six Cancer Research UK-funded clinical trial centres, as well as close collaborations with Caroline Dive at the Cancer Research UK Paterson Institute and the London Research Institute, Cancer Research UK-funded scientists there as well. We’re in collaboration with the UCL Cancer Institute and also the expertise coming from our immunology colleagues, both at UCL and in Birmingham with Gary Middleton’s team, and with Jacqui Shaw, who is our circulating tumour DNA expert in Leicester. So we have a number of scientific and clinical collaborators – 65 people in all – that will make this study possible.
Greg: And you talked about how the data requirements are going to be enormous. Can you explain why this is going to be such an enormous undertaking in terms of the amount of data you’re going to generate?
Charlie: So we’re sequencing tumours from 850 patients, but we’re not just sequencing one tumour, we’re sequencing up to six, seven or even eight coding exomes from each tumour during the disease course. Now a coding exome has about 50 million basepairs, and we’re sequencing at a depth that is relatively unprecedented in these studies, of 500X coverage. So if you take that into account, along with the number of tumours we’re sequencing and the number of regions we’re sequencing in each tumour, and comparing primary to metastatic disease, we’re talking about a requirement for probably six petabytes worth of data storage, and the equivalent of sequencing 42 and a half thousand whole genomes at 1X coverage, in order to really get to grips with the diversity within a single tumour.
Greg: You’ve described this as your “Everest”, if you like. Why is it your Everest, and how do you think we’re going to overcome it?
Charlie: I think when we look at it at the moment, it just looks simply unachievable. I think we’re programming where we’re going to be in two or three years time with our sequencing technologies and building up our informatics support to make such a study possible. So if you look at it at face value at the moment, this mountain looks too big to climb. But I think with CRUK’s national breadth in terms of its clinical trials centres, its national breadth in terms of its basic science provision across the core-funded institutes and the programmatic-funded centres that we’re collaborating with, together I think we’re going to be a lot stronger and able to tackle this major research question a lot more effectively by bringing together expertise from very diverse areas of basic science and translational medicine, to better understand NSCLC biology.
That was Professor Charlie Swanton talking to Greg Jones. The results of TRACERx could make a big difference to the lives of lung cancer patients in the future, as fewer than one in ten currently survive for more than five years. One of the lucky ones was Joe Suckling from Derby, who shares his story of his diagnosis and treatment.
Joe: It started off with a niggling cough and the cough gradually got worse and worse. This was late 2008. By January, it was really bad so I went to the doctors. Originally, I was told by the doctor that it was just a cough and I’d have to wait for it to go. A week later it was still there so I kept going back. They sent me for an X-ray, said I’d got a chest infection and gave me some antibiotics. That almost cured the cough but then 2 days later it was back with a vengeance. So I went back to the doctors again, another set of antibiotics and that didn’t touch it at all.
So after that I was sent for another X-ray. They decided perhaps there was something on the X-ray. From there, they stuck a tube down my throat and had a look at what was going on. They found a blockage and sent me for a CT scan and a PET scan. I went off to get the results for these tests still thinking I’d got a very bad chest infection. The doctor said to me: “we’ve found a blockage, we’ve got the results back – it’s a tumour. We’ll call it what it is – it’s cancer – and we’re going to have to take your right lung out to get rid of it”. And that’s exactly how he said it to me. But the thing was, by the time I’d got my head around the fact “he’s just told me I’ve got cancer”, he’d also told me what we’re going to do about it. So there was no time to fret, no time to worry about what we’re going to do about it because I knew straight away.
So they took me into theatre to take the right lung out and, when they looked back down the throat again, the tumour was too close to the cross-connection in the lungs for them to be able to take the tumour out. So they sent me back up again and then sent me off for radiotherapy. And I underwent CHART radiotherapy, which is something that was developed by Cancer Research UK. It’s 12 days of intense radiotherapy, three times a day: 08:00 in the morning, 14:00 in the afternoon, 20:00 at night. And they told us that when we finished a couple of weeks later we’d feel very tired and washed out. I came back from the first session and that was me – bang – out like a light. And it was like that for the whole 12 days. I’d arrived at the hospital that day at the start of the treatment hardly able to walk, I couldn’t keep food down and I was in a real mess.
A week after the treatment finished, I was having a shower and I coughed and a big tube-like lump came out. I thought, that’s a bit worrying. And then a bit later I coughed again and another bit came out but it wasn’t quite so big. And I coughed like that all day and I was just bringing stuff up – these tubes. And they were getting thinner and thinner and what I realised was that the tumour had shrunk and this was all the muck that was stuck behind it and was being cleared. And I suddenly realised that this tumour was going away. Two months later at the CT scan they couldn’t even see it.
I was just so incredibly lucky but it shouldn’t be luck. And that’s why this new research is so important, to understand what the tumour is doing, why the tumour is growing the way it is and to be able to target the tumour without the big sledgehammer of surgery or radiotherapy. And then hopefully more lung cancer patients will survive.
Kat: That’s Joe Suckling there.
And finally, it’s time for our heroes and zeros. Our heroes this month are the half a million people whose lives have been saved from cancer over the past 30 years thanks to advances in research, as well as the scientists, doctors and nurses who helped along the way. And the number of cancer deaths prevented is expected to double to one million by the end of this decade. Eight in ten people now survive skin cancer, and nearly all men – that’s 96 per cent – will survive testicular cancer for more than ten years. We’ve seen big improvements in survival for many cancers – such as breast and bowel cancers – but we know there is so much more to do. We’re now focusing in particular on cancers where survival has changed little, such as lung, pancreatic, and oesophageal cancers, as well as brain tumours.
And our zero of the month is the Government, who have kicked the issue of standardised packaging for tobacco into the long grass by shelving plans to introduce plain packs for the time being. The announcement has been controversial, and raised questions over the role of Prime Minister David Cameron’s advisor Lynton Crosby, and his alleged connections with the tobacco industry. Along with our supporters, we’ll continue to campaign for standardised tobacco packaging, which will provide one less reason for kids to start smoking – a habit that kills half of all long-term users.
That’s all for this month, we’ll see you again next month for a look at all the latest cancer news. We’d also like to answer your questions in our podcast, so please email them to email@example.com, post on our facebook page, or tweet us – that’s @CR_UK. And if you’re listening to this on Soundcloud, please leave us a comment with your feedback. Thanks very much and bye for now.