Metabolic drivers of leukaemia pathogenesis and therapy resistance

Project Outline

Chronic myelomonocytic leukaemia (CMML) is an aggressive myeloid blood cancer defined by expansion of malignant monocytes. Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the only standard-of-care disease-modifying therapies, but 50–70% of patients fail to respond. This highlights the need to better understand the biological mechanisms driving CMML progression and those governing HMA response and resistance, to identify novel therapeutic strategies and improve treatment outcomes. 

Leveraging multi-omic profiles (transcriptomic, epigenomic, plasma metabolomic, and proteomic) from treatment-naïve patients and age-matched healthy controls, our group has uncovered profound metabolic dysregulation in CMML. Of specific interest, altered fructose metabolic pathway is observed across different malignant cell populations including monocytes, neutrophils and stem cells. 

This proposal will investigate how altered metabolic pathways contribute to CMML pathogenesis and influence sensitivity or resistance to HMAs. The first aim will define how altered fructose metabolism impact monocyte biology and disease progression. We will then evaluate whether targeting these metabolic pathways offer therapeutic efficacy in primary leukaemia models. The second aim will investigate metabolic mechanisms underlying HMA response. By integrating metabolomic data from responders and non-responders in the AMMO study – a recently completed UK phase 2 trial of the oral decitabine derivative ASTX727 – with transcriptome and epigenome datasets, we will identify novel biomarkers of response and uncover opportunities for rational combination therapies.  

The successful candidate will use cutting-edge techniques, including stable isotope carbon tracing, patient-derived xenografts, and other -omics approaches to define the mechanistic links between altered metabolism, disease progression, and treatment response.  The ultimate goal is to identify novel therapeutic vulnerabilities and biomarkers for prospective patient stratification in future interventional trials. Overall, this project offers an exciting opportunity to work in a highly collaborative research environment with world-class facilities while contributing to research with genuine potential to improve outcomes for patients with CMML.

Applications for this project are now open. Please complete your application on The University of Manchester website.