Overcoming Treatment Resistant Tumours

Now, one of the key problems in the treatment of cancer is that tumours, having initially responded very nicely to a course of chemotherapy, can often subsequently become resistant to that same treatment which makes the cancer much harder to manage. To explain how this happens and how we might be able to overcome the problem, Dr. Simon Cook works at the Babraham Institute in Cambridge joins us.

Chris - First of all, tell us a little bit about why a cancer does that? Why do people start off responding very nicely to a drug and then their cancer comes back, and now, it won't respond?

Simon - Cancer is driven by the activation of specificsignalling pathways in the cell and some of the new drugs which are being used to treat cancer now inhibit these specific pathways. The analogy I like to use is if you arrive at King's Cross St. Pancras and you want to go by underground to Leicester Square, if Russell Square is closed then you can't get through. The analogy there is that the new drugs are like blocking Russell Square so you can't go through the Piccadilly Line down to Leicester Square. The point is that tumours are tenacious in their ability to get around these blocks and so, they'll just hop on a different train and go to Euston and then come down the Northern Lane to get to Leicester Square. So, there is heterogeneity in tumour cells and tumour cells which respond very well initially to drugs which inhibit the Piccadilly line for want of a better phrase, will switch over and select out to use a different pathway to maintain cell proliferation, cell division and cell survival.

Chris - So, when someone has a tumour, if we were to look at the cells in that tumour, we wouldn't see one type of cell only. We would see a mixture of the cells with many different genetic changes, making them all behave in a very different way. So, when we throw drugs at it, the ones that are sensitive to that drug will be killed or inhibited, but this will select out a population of cells that just by chance happen to have genetic changes that have - as you've put it quite nicely there - got the ability to jump on another train and take them around whatever that blockade the drug is imposed is.

Simon - That's absolutely correct and in many senses, this is sort of Darwinian evolution taking place at the cellular level that you need two basic ingredients for evolution. You need genetic heterogeneity and you need a selection pressure. The genetic heterogeneity is in the tumours. We know from increasingly advanced methods for analysing tumour genetic mutations that there are really thousands and thousands of genetic mutations in each individual tumour, and the selection pressure is some of the new drugs that we're adding, and you're absolutely right, the vast majority of the cells die, but a very small subset essentially seed for regrowing, and taking that different path.

Chris - So when someone is put on therapy and they've got a cancer to start with, it's going to have a mixture of these different genetic changes, making it sensitive to some things and not others. Does this mean then that just going in with one drug is a flawed strategy because comparing it with say, treating a virus infection, we know that if you used just one drug in people who have HIV then you very quickly get viruses coming out which can just bypass that drug in the same way? The way that virologists get around this is to put patients on several drugs at once to make it much harder. So is that what cancer biologists are, or need to be doing?

Simon - Yes, very much. So, there are some cancers which are almost single-gene diseases. Perhaps the best example is chronic myeloid leukaemia where that is very much driven by a single gene and there are now very good drugs which inhibit that and make that to a great extent a manageable disease. But for many other cancers, because of these multiple mutations, yes, I think increasingly the way to go is going to be using combinations of different drugs which target these different signalling pathways inside the cell.

Chris - So, tell us a bit about your work in the sense that you're saying you're now trying to dive inside the cell, and unpick some of these - for want of a better phrase - tube maps to see how cells are doing what they're doing to find out ways of stopping them doing this train jumping trick.

Simon - That's exactly right. So, we're growing human tumour cells in the laboratory and we're treating them with some of the very new specific drugs, and we're generating resistant human tumour cell lines in the laboratory then actually analysing how they've remodelled their tube map, how they remodel their signalling pathways, which pathway they're now using, is that pathway a pathway which we can inhibit with another drug so that if we can understand how tumour cells respond and react, and acquire resistance to drug A, and if we can identify the mechanism by which they're doing it, then that may actually validate using drug B as well.

Chris - What about the fact that many cancer biologists will say that a common misconception is to call cancer one disease? There are many, many different types of cancers in different types of tissues which can all have different origins, and therefore, one drug does not treat all.

Simon - That's absolutely true. I think this is perhaps an area where the general public are less aware that in fact, for example, lung cancer is not just one form of cancer. There's non-small cell lung cancer and there's small lung cancer. There are now, for some forms of non-small cell lung cancer, very good drugs which can often give quite good responses, but those drugs are no good against small cell lung cancer. The same applies with breast cancer, the same applies with colorectal cancer. These different types of colon cancer are driven by different driving oncogenes; different driving cancer genes and therefore, drugs which work for one form won't necessarily work for another.

Chris - So, this whole idea of personalised medicine and tailoring therapies to individual diseases is probably the way it's got to go, but it's going to get very costly.

西蒙-毫无疑问,是的。我认为一些人规范ulate that in the future, a patient coming in to the clinic to start with will have that tumour typed to work out which mutations are there and this will tailor them to a particular drug or combination of drugs. And presumably, that will happen for every person because it will potentially be different for every person. And by necessity therefore, it's taken a lot of time and effort, and money to generate these drugs and so, I guess understandably, drug companies are going to want to see a return on that investment.

Chris - Some people say, just to finish this off, there's never been a better time to get ill, really. Would you agree?

Simon - I think it's a very exciting time in cancer therapy because we're seeing a return of 20 years, 25 years of research to actually understand what's causing cancer. We now understand in many cases and we now have very good therapies coming through because of that understanding. So yes, I could see why they might say that.