Inherited polyposis syndromes, including Familial Adenomatous Polyposis, affect around 15,000 people in the UK. These conditions dramatically increase the risk of bowel cancer from around 1 in 18 in the general population to a more than 1 in 3 chance. Patients often develop hundreds of small precancerous growths (polyps) in the bowel from a young age, requiring monitoring and removal by frequent endoscopies and, in many cases, preventative surgery to remove the colon. Despite lifelong cancer risks, there are currently no approved medicines to prevent the disease progressing.
A team in Oxford, led by Professor Simon Leedham (Centre for Human Genetics, Nuffield Department of Medicine) and Professor Christian Siebold (Division of Structural Biology, Nuffield Department of Medicine), have just received funding from Cancer Research UK to develop a new type of preventative treatment for people with inherited polyposis syndromes.
"We want to move prevention much earlier in the course of these diseases," said Professor Simon Leedham. "For patients who currently face decades of repeated surveillance and the possibility of major surgery, an effective preventative medicine could fundamentally change how these inherited cancer syndromes are managed."
Previous research has identified the protein GREM1, which disrupts normal signalling in the intestine and contributes to polyp formation and cancer development. By developing small-molecule drugs that block GREM1, the researchers hope to prevent polyps from developing or slow their growth before they become cancerous.
To identify potential drug candidates, researchers will combine structural biology-based drug screening at the Diamond Light Source synchrotron with artificial intelligence-based drug screening. The most promising compounds will be tested in laboratory models. If successful, in future work, the compounds will progress to further preclinical testing before eventually being evaluated in patients.
Professor Christian Siebold said: "Advances in structural biology and AI now allow us to search for drug candidates with unprecedented precision. Our goal is to discover the first small molecules that can inhibit GREM1 and could be developed into an affordable tablet that could be taken orally over many years by people at high genetic risk of bowel cancer.”
The researchers believe the work could represent an important step towards cancer precision prevention, offering families living with inherited bowel cancer syndromes the possibility of reducing cancer risk without relying solely on repeated surveillance and surgery.