A new international research programme will investigate whether glucagon-like peptide-1 (GLP-1) receptor agonists ‒ widely used to treat diabetes and obesity ‒ could be repurposed to prevent the progression of clonal haematopoiesis and its associated diseases.
The GLP-1RA Use to Attenuate Risk and Disease associated with Clonal Hematopoiesis (GUARD-CH) programme, co-led by Philip Awadalla, Professor of Molecular Genetics at Oxford Population Health and the University of Oxford’s Big Data Institute, and Professor Stephanie Xie at Princess Margaret Cancer Centre, Toronto, has received £1.25 million in funding from Cancer Research UK and the Canadian Cancer Society.
Clonal haematopoiesis is a common age-related condition in which blood-forming stem cells carrying acquired mutations expand more rapidly than other stem cells. It affects up to one-third of adults over 60 and is increasingly detected in younger people with metabolic disease.
Although it does not itself constitute cancer, clonal haematopoiesis can substantially increase the risk of myelodysplastic syndromes and acute myeloid leukaemia (blood cancers). It can also promote systemic inflammation, contributing to cardiovascular disease, stroke and other chronic conditions.
Professor Awadalla said ‘Inflammatory and metabolic stresses ‒ including obesity, diabetes, poor diet and air pollution ‒ may create conditions that favour the expansion of mutant blood stem cells.
‘The newly funded programme will test whether GLP-1 receptor agonists such as semaglutide can disrupt this cycle by reducing inflammation and removing the competitive advantage of mutant cells. Our ultimate goal is to establish whether an existing and widely prescribed class of medicines could be used to prevent blood cancers and other diseases in people with clonal haematopoiesis.’
The programme builds on compelling preliminary evidence from the team’s recent study, “Human haematopoietic stem cells remember inflammatory stress,” published in Nature. The study identified a previously unrecognised subset of human blood stem cells that retains a durable molecular memory of inflammatory exposure.
This inflammatory memory state was enriched in ageing, severe infection and clonal haematopoiesis, and its molecular signature could be detected in mature circulating blood cells. In population-level analyses, a stronger inflammatory memory signature was associated with a higher risk of clonal haematopoiesis or death from various causes. These findings provide both a biological mechanism and a measurable molecular signal through which the preventive effects of GLP-1 therapies can now be tested.
Oxford Population Health will lead the new programme’s population-scale and computational components, drawing on expertise from across the department and the Big Data Institute in molecular epidemiology, genomics, multimodal data integration and international cohort studies.
The team will also develop a practical blood test that measures markers of disease to identify individuals most likely to benefit. This will be evaluated through the GUARD-CH prospective study in Canada and the UK, in partnership with Perspectum. The study will follow people with clonal haematopoiesis and metabolic disease for up to four years.
Together, these studies will generate the biological, population and clinical evidence needed to design a future randomised cancer prevention clinical trial.