Aspirin in the 21st century
Effects of aspirin on colorectal cancer
Dr Farhat Din – University of Edinburgh, Edinburgh, UK
What evidence supports aspirin for the prevention of CRC?
Certainly over the years epidemiological data, animal model data and data from clinical studies has shown that aspirin reduces the incidence of colorectal cancer by about 40%. So we do know that this drug works at a population level.
What led you to research the use of aspirin in CRC?
I’ve been very interested, thinking about colorectal cancer and thinking about the causation behind colorectal cancer. We now have a lot of information that suggests colorectal cancer is largely an environmental disease with a 65% contribution from the environment in terms of diet and lifestyle with the remainder being heritable. We also know that aspirin works at a population level in reducing colorectal cancer instance. So what I was interested in doing is to try and work out whether we have some of these risk factors such as obesity, lack of physical activity and diabetes and metabolic syndrome which are all associated with colorectal cancer, whether there are specific signalling pathways within cells that have increased activity with a change in energy balance. What I’m trying to do is to investigate whether aspirin realigns some of this deranged metabolic machinery within cancer cells and in patients.
Can you tell us more about your specific research in this area?
We’ve been looking specifically at a pathway called the AMPK and mTOR signalling pathway and we were the first to show that aspirin activates the AMPK kinase in colorectal cancer cells in an animal model and, indeed, in patients who were treated with aspirin. We also see that aspirin inhibits the mTOR kinase and its downstream readouts. So why is mTOR important? We know that aberrant or increased mTOR activity has been seen in several cancers, including colorectal cancer, with an increase in protein production which is one of the hallmarks of cancer. So what we’re trying to see is that through inhibiting mTOR whether we are then getting a decrease in protein translation, which we have seen, and to try and investigate whether there are specific proteins that are being inhibited that are relevant to colorectal cancer initiation and then progression to more advanced disease.
What have been some of the data you have obtained to date?
The data that we have shows that aspirin activates the AMPK kinase and inhibits mTOR and induces autophagy within colorectal cancer cells. New data that I’ve presented here today shows that aspirin inhibits protein translation and some of these effects are likely to be mTOR dependent but there are also mTOR independent effects of aspirin on the translation of proteins.
Would there be any benefit of combining aspirin with an mTOR inhibitor?
One of the reasons why some of the mTOR inhibitors, some of the specific mTOR inhibitors, have been a little bit disappointing in clinical trials is the issue of feedback signalling and negative feedback signalling. I think the advantage of using aspirin in trying to interrogate these signalling pathways is that it is likely to inhibit several key nodes within a pathway to try and abrogate effects of negative feedback signalling. We know that with specific mTOR inhibitors in solid cancers such as colorectal cancer, they haven’t shown as much of a decrease in the overall survival and cancer specific survival. So I think here aspirin may well have an advantage by targeting multiple nodes within this aberrant pathway. There are certainly trials which are ongoing to try and combine mTOR inhibitors with MAP kinase inhibitors and the same thing in terms of trying to target several nodes within an aberrant cancer pathway where aspirin may have the advantage and certainly some of our data from the lab suggests this, is that it is, in fact, targeting multiple points of the pathway. We’re using aspirin as a screen to try and interrogate which are the critical nodes that need to be either inhibited or activated to prevent cancer.
Any other aspects of your research that you would like to highlight?
One of the very exciting things that we’re doing currently is to try and look at some of the effects of aspirin in organoids, so these are crypt structures from human colonic epithelium, and trying to use this as a model system where we can interrogate some of the effects on the signalling. So the development of human colonic organoids from normal patients and indeed from patients who are genetically predisposed, such as patients with FAP, really gives us a good opportunity for trying to investigate these pathways and to try and recapitulate human mucosa quite separately from cell line work.
Do you have a take home message?
The clinical message is that aspirin works and the foundation in bringing together lots of researchers to try and answer how it works is critical because we do need to know. We do need to be able to stratify populations so that we can work out in which patients aspirin will prevent colorectal cancer.
