(MCRC Non-Clinical) Metabolic Drivers of Leukaemia Pathogenesis and Therapy Resistance

About the project

About the Project 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. Eligibility You must hold, or about to obtain, a minimum Upper Second Class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. A related master’s degree would be an advantage International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English language) before contacting potential supervisors to express an interest in their project. Eligibility information can be found on the University's Country Specific information page. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply Apply directly via this link: https://tinyurl.com/577zjazd or on the online application portal, select MCRC PhD Programme as the programme of study. You may only apply for one project within this scheme. Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV) Supporting Statement Academic Certificates and Transcripts Incomplete or late applications will not be considered. Further details are available on our website: CRUK Manchester Centre PhD Training Scheme | Biology, Medicine and Health | University of Manchester Application Timeline Applications open: Monday, 5 October 2026 Application deadline: Monday, 23 November 2026 Interview date: Week commencing 11 January 2027 Start date: September 2027 Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/

Research areas