BACR & ECMC: Therapeutic interventions for cancer prevention

Tumour metabolism in chemoprevention

Dr Farhat Din – The University of Edinburgh, Edinburgh, UK

The conference has been fantastic; it’s been two packed days and every session has been relevant and really thought-provoking. There have been great questions from the audience and really high quality speakers. So it’s been an exciting time.

Can you tell us about your talk at BACR 2016?

I was giving an overview of some of the work that we’ve been doing in Edinburgh and this is using aspirin to try and interrogate some of these energy and metabolism signalling pathways because we have a drug that we know works at a population level. And really taking it back to the bench to try and dissect out mechanism to lead to insights around energy and metabolism signalling. Certainly what we’ve shown is that aspirin inhibits mTOR signalling which is a key metabolic regulator and, indeed, inhibits protein translation so the development of new proteins. We’re trying to work out selectively which proteins might be inhibited. Excitingly what we’ve also seen in human mini-gut models, or organoids, is that aspirin can rescue an abnormal phenotype and reduce stem cell marker expression. So these were quite preliminary unpublished findings that we have so far and very exciting to share them with the audience and get feedback on those.

Can you tell us about the mechanisms of the mTOR signalling pathway?

mTOR signalling has been shown in itself to be upregulated in colorectal cancer in around 35-40% and lots of negative regulators of mTOR such as p10 and LKB1 are in fact tumour suppressor genes in well-known colorectal hereditary susceptibility syndromes. Also layered into that are all of the environmental stimuli that come in to this central mTOR hub in terms of diet, so what we eat affects the mTOR signalling pathway, physical activity affects AMPK and mTOR and layered into this are other signalling pathways such as Akt ERK, again which are dysregulated in the adenoma to carcinoma sequence in colorectal cancer. So what we’re envisaging is that you have environmental insults from diet, lifestyle, obesity, lack of physical activity, coupled with potentially genetically susceptible colorectal epithelium which then results in abnormal metabolism within colonic crypts. What we’re trying to do is to use aspirin and other chemopreventive agents such as metformin to see whether this increase towards intestinal cancer stem cell stem-ness can be downregulated or dialled down using some of the chemopreventive agents to try and understand more about cancer biology but then also working towards thinking how we can use these agents in a precision prevention way in terms of stratifying populations that we can then go on to use some of these agents in.

What are your thoughts on drug repurposing and chemoprevention on a healthcare level?

Part of my involvement with the UK Therapeutic Cancer Prevention Network, which is an ECMC network, is that we are extremely interested in drugs and drug repurposing, specifically because there are, in fact, a wealth of drugs that we know can reduce the risk of cancers, of many different cancers, and what we need to do in this current era of masses of money being spent on developing new drugs but it’s actually to exploit the wealth of information that we already have from case control studies, epidemiological studies, saying that agent X or Y reduces cancer risk. So what we need to do is to, in my view, move from developing new drugs for advanced diseases to really shifting our thought process towards thinking about how we can prevent cancer, how we can prevent colorectal cancer in my field, rather than thinking about developing new agents just to target advanced disease. I’m not saying advanced disease is not important but we need to now integrate a lot of the genetic environmental information that we have to try and stratify populations so that we can undertake risk profiling. Actually, if you tell somebody about their personalised risk and say, ‘In fact because you have these risk factors your risk is elevated by this amount,’ that people can then actually understand, well, if I did these lifestyle interventions I could reduce risk or, indeed, here are some agents that may reduce my risk. And that’s a discussion which we need to start looking towards in the next few decades.

We know that one drug doesn’t fit all and we’ve had some fantastic talks today at looking at metabolism and environmental factors in obesity that drives aberrant metabolism. We know that people’s responsiveness is going to be different and we really need to drill down on who is going to be responsive to what agent and to understand biomarkers of response or, indeed, resistance.