We are interested in the discovery and development of agents for the prevention of cancer. Primarily, or historically, in our lab this has been dietary derived agents but we’re also now looking at drugs that have been used for other purposes, for other indications, and trying to use those in cancer prevention as well. Most of our work has been on compounds such as resveratrol which is in red wine and red grapes and peanuts and curcumin which is in the spice turmeric. We’ve been looking at those primarily in the prevention of colorectal cancer, so bowel cancer.
We have to be very careful how we talk about our results because it can very easily be taken out of context. Particularly we’ve done a lot of work recently looking at resveratrol, so the compound in wine, and trying to compare the activity of the dose that you can get through the diet and the dose that we’ve used in clinical trials before. So the dose you get through the diet, I tend to describe it as the amount you could get in a couple of large glasses of red wine. Obviously there’s no wine there in what we do but I have to be very careful because then come the headlines ‘Wine prevents cancer’ and it doesn’t but the compound in it can prevent cancer in our laboratory models.
Does this involve working with extracts?
For the resveratrol work we use a synthetic version of resveratrol so it’s not an extract although some other people probably use extracts. For the curcumin work we use an extract of the turmeric, so that’s a bit different.
We have done some work on plant extracts and berry extracts where you can look at compounds called anthocyanins and that has its advantages as well but obviously you’re looking at a mixture, you don’t know what’s causing the effect, so I quite like to make it more basic, make it more simple, and you know what compound you’re looking at and you can try and figure out what mechanisms it’s working through and then optimise the doses to take in the clinical trials rather than having a mixture where you’ve just got too many unknowns at the moment.
Which cancers have you studied in addition to colorectal cancer?
We’ve done a bit in the past on prostate cancer. We have done some trials in prostate cancer patients and we are beginning some work on lung cancer but primarily it’s been colorectal. It’s a really good model; what we always have to keep in mind is that there is a clinical model in which we can test our agents in clinical trials. There’s no point in doing loads of lab work if you can’t then take that into a patient group and colorectal cancer is a really good model because you can identify patients that are at high risk through the bowel cancer screening programme. So patients that have adenomas detected, they have them taken away and then they’re at increased risk of adenoma recurrence or colorectal cancer development. So there’s quite a nice group of patients that we can intervene and give our agents to and see whether they have effects on those patients.
Can you give examples of the studies that you have done?
We do a lot of phase I trials trying to see how much of the compound actually gets into the target tissue, how much gets into the blood, because that’s a big problem with this kind of area of research, particularly with dietary derived agents but also with drugs. There are a lot of papers in the literature where people use concentrations that are a hundredfold higher than what you can ever actually get in a person so we find it’s really important to do those early phase trials, get the pharmacokinetic data and feed that back into our preclinical work so we make our animal models and our cell culture work as representative of the clinic as possible. So we’ve done a couple of studies looking at resveratrol safety and pharmacokinetics and in one of them we used a radio-labelled form of resveratrol, so C14 labelled, gave that to patients that were having surgery for colorectal cancer. We gave it to them at two different doses, so here we were comparing the dietary dose with the dose 200 times higher. We just wanted to see whether it got to the target tissue, how much got there and what was the metabolism like. We found that at both doses, so the low dose and the high dose, you do get resveratrol in the colon. We also did a study in prostate cancer patients and found that in the prostate tissue the profile is very different so you’d have mainly metabolites in the prostate and not really any detectable resveratrol. So that’s going to have an impact on whether resveratrol might actually work in a person for the prevention of prostate cancer.
Then, taking those results, knowing that the tiny dose of resveratrol can get to the colorectum, we did studies using the ApcMin mouse which is a mouse model where the animals spontaneously develop colorectal cancer or polyps in their intestine. We found that the low dose is more effective than the high dose at preventing intestinal adenomas in these mice so that’s suggestive of at least a non-linear dose response or maybe even a bell shaped curve or U-shaped curve with a bigger effect at lower doses.
Do you follow up with the patients?
The patients were purely a phase I trial so there wasn’t any follow-up there but it is our intention for both resveratrol and curcumin to do a trial in that adenoma setting that I mentioned. So we would aim to recruit patients and then give them resveratrol or curcumin or aspirin for a year and then look for evidence of activity in the blood of those patients over time to see whether the doses we’ve chosen are potentially active in those patients. So that’s planned for the next couple of years.
Does aspirin need further investigation as a successful preventative drug?
We are kind of using it as a positive control in this trial because, yes, there’s excellent evidence that aspirin does work. But what we don’t know is we need ways of monitoring whether it’s working in individuals. So the aim of including aspirin here was to try and identify biomarkers in the blood that we can detect. We can analyse proteins in patients hopefully, to say yes it’s working in you, it’s not working in you, you should continue, you shouldn’t and using it as a way also to optimise the dose of aspirin because that’s not quite clear yet. We know that the lower doses and the higher doses can have activity in patients, in people, but it’s not really nailed down what is the best dose for people to take. So we might be able to use these biomarkers to help with that decision as well.
Do you think you’ll make changes to your own diet or take aspirin as you get older?
Based on what I’ve heard over the last six months, definitely. When I hit 45 or so I’ll start taking aspirin. I know a lot of people that do take resveratrol and even curcumin. We often get phone calls and emails from patients that want to take these agents but at the moment the evidence isn’t there so I wouldn’t, no, not at the moment. But aspirin, the evidence is there so I’d definitely consider it when I get a few years older.
