Bowel Research UK is a charity registered in England and Wales: 1186061 Title: Re-evaluating colorectal cancer diagnostic markers and therapies in the context of tumoral acidosis: towards molecularly stratified treatments that consider in-vivo chemical selection pressures Research Lead: Professor Pawel Swietach Location: The Department of Physiology, Anatomy and Genetics at the University of Oxford Our Funders Bowel Research UK is grateful to the MIVA Foundation for their generous award of £26,200 in support of this research project into the treatment of aggressive bowel cancer. We present the following Year 1 Interim report on the project’s progress. Background to the project Aims Our overarching aim is to understand: how colorectal cancer cells respond to acidity which they produce through their own metabolism. how adaptations to surviving in an acidic environment could make colorectal cancer cells vulnerable to drugs which target them. Methods We used a large sample of live, reproducing colorectal cancer cells. We used these to distinguish cells that are acid-resistant and acid-sensitive and implemented testing to understand and block these mechanisms. Outcomes We have identified key ways in which cancer cells respond to excess acid, including new enzyme activities. We have described how high acidity can limit cells’ hypoxia (oxygen deprivation) responses. We find that acidity may play a bigger part in cancer development than previously anticipated. Research Project Year 1 Interim Report to the MIVA Foundation August 2025 Let’s end bowel cancer and bowel disease. Bowel Research UK is a charity registered in England and Wales: 1186061 A Summary from the Research Team The growth of aggressive bowel tumours is powered by their metabolism. This metabolism results in the production of waste products that tend to accumulate in the tumour mass. Some of these products are acidic, which means that the immediate environment surrounding the cancer cells becomes an unusually harsh one. However, the fact that cancer cells continue to proliferate under such conditions suggests that they have developed ways to adapt to this. We believe that this process is important to study because it may reveal vulnerabilities for new drugs to target, ultimately killing cancer cells. Our Bowel Research UK project is attempting to understand this process. We want to understand how acidity interacts with another major chemical feature of tumours called hypoxia (oxygen deprivation). We have now identified the distinct responses to acidosis that merit further investigation. Our Bowel Research UK-funded research demonstrated how the presence of acid can reduce the cell’s responses to hypoxia. This has now been published in The Journal of Cell Biology 1 and indicates that cancer cells’ responses to acidity may be very important. DPhil student Matthew Dean is working alongside Prof. Swietach to study tumour acidosis and how better understanding could lead the way for new and improved cancer treatments. We found that when cancer cells become resistant to acid, they produce an enzyme that is poorly understood but may offer survival advantages. We have implemented methods to measure this enzyme and study what its blockers do to cancer cells. For the rest of the project, we will focus on seeking the role of this enzyme in the disease process 1 “Acidosis attenuates the hypoxic stabilization of HIF-1 α by activating lysosomal degradation”. White B, Wang Z, Dean M, Michl J, Nieora N, Flannery S, Vendrell I, Fischer R, Hulikova A, Swietach P. Bowel Research UK is a charity registered in England and Wales: 1186061 How could this research benefit patients? Bowel cancer cells produce an acidic chemical environment that they create through their own metabolic activity. This environment is normally harsh for cells so; in order to grow and spread, the most aggressive cancer cells develop adaptations to survive it. We are looking at ways of disarming this survival advantage while ensuring minimal toxicity to the human body. Thanks to this research, we are discovering new mechanisms to block this survival response. Some of the mechanisms could make use of repurposed existing drugs, which can offer benefits faster than it would take to develop new compounds. We also believe that blocking the cells’ adaptations to high acidity can improve other therapies, notably immunotherapies, which work less successfully when tumours are acidic. Since the mechanisms we are looking at apply in general to growing solid tumours, this research could apply to patients with tumours in other parts of the body as well as the bowel. The next stages We aim to understand better the broader significance of AKR enzyme activity for cancer growth. This is likely to be more extensive that initially anticipated and is therefore worthy of further work. We postulate that the AKR enzyme is a key survival strategy and without it, cancer cells cannot grow. We may discover new drugs that inhibit the enzyme, which would be patentable. We are applying to the Medical Research Council in support of further work on this subject. As part of Professor Swietach’s research team, DPhil student Zhenyi Wang is pioneering a method to understand variation between cancer cells and what this means for aggressive cancer cell behaviour. “We are grateful to the MIVA Foundation for making this research possible.” - Professor Pawel Swietach Bowel Research UK is a charity registered in England and Wales: 1186061 “We think that a good way of derailing malignant growth is by disabling the mechanisms that facilitate growth under harsh conditions. Our recent findings provide new insights into how this could be achieved. We are particularly excited about the prospects of specifically targeting adapted cancer cells while sparing healthy tissue. This could make cancer treatment more effective with fewer side effects.” - Professor Pawel Swietach