This project investigates how colorectal cancer cells survive in the acidic tumour environment and whether blocking AKR1C enzymes can selectively kill them. The researchers will test candidate drugs in cell and animal models to assess their potential as low-toxicity treatments for colorectal cancer.
What issue does this study address?
Bowel tumours can grow faster than their blood supply. Consequently, acidic waste products from cancer metabolism gather in spaces between cells. This produces an acidic environment that is harmful to cells unless adaptation takes place. Acid-resistant cancer cells are more aggressive and harder to eliminate, but their survival mechanisms may reveal new drug targets. This project will investigate a new adaptive mechanism discovered through BRUK-funded research.
What has previous research found?
The team found that tumour acidity activates genes of an enzyme family called AKR1C. Originally, these enzymes were involved in chemotherapy resistance but it is thought they also protect cells from a type of death arising under acidic conditions called ferroptosis. It was found that the combination of acidity and AKR1C inhibitors eliminates cancer cells. This two-hit effect is appealing because it should mainly affect acidic tumour tissue and spare most healthy tissues.
What are the aims and how could this work help people with bowel cancer?
The research team will screen a panel of colorectal cancer cells for AKR1C activity and test various candidate inhibitors, including drugs found to be safe in humans. By inactivating AKR1C enzymes, they will establish their role in ferroptosis and determine which particular “signals” are important in ferroptosis. The most promising drugs will be tested in tumour bearing mice to establish the most refined dosage.
The results will determine whether targeting AKR1C enzymes can sensitise cancer cells to their own acidic products and slow disease progression, as predicted by mathematical models. Certain AKR1C drugs are used in other indications and could be safe for cancer patients.
The research team
This research will be led by Professor Pawel Swietach at University of Oxford.