Bond Group LPT project

Targeting metabolism in aggressive childhood blood cancers

Research Spotlight

September 2025

L to R: Dr. Claire Fitzgerald in the lab with YPAG members Stacey Braddish and Ashleigh Kiernan. 

The Bond Group at Systems Biology Ireland has been awarded new funding from the Little Princess Trust to advance their research into acute myeloid leukaemia (AML), one of the most aggressive forms of blood cancer. Led by Claire Fitzgerald, the project will build on the group’s pioneering work exploring the metabolic vulnerabilities of high-risk leukaemias to develop more effective and less toxic treatments. Importantly, the project was co-created in consultation with the Young Person’s Advisory Group (YPAG), a panel of 12–29 year-olds with lived experience of cancer. Their insight and collaboration have helped shape the project’s focus and design, making it a powerful example of patient involvement and co-creation in cancer research.

Leukaemias are the most common paediatric cancer, with acute myeloid leukaemia (AML) causing the most blood cancer-related deaths in this age group. While therapy options for adult AML have expanded and improved greatly over the last decade, similar treatment advances for children have been missing. Paediatric AML regimens still mostly comprise non-specific cytotoxic agents that frequently cause significant side effects in young people. These treatments also don’t work for all patients, and childhood AML is often resistant to standard chemotherapies, meaning that very intensive and toxic approaches like bone marrow transplant can be needed to clear the disease. Collectively, this indicates that more precise and less toxic treatments are urgently needed to improve outcomes for this disease.

The Bond Group and others have shown that aggressive AMLs often have mutations in a protein complex called ‘Polycomb Repressive Complex 2’ (PRC2), which regulates which genes are turned on and off in the cell. These PRC2 mutations affect at least 15% of all childhood AMLs, where they are associated with poor chemotherapy response and poor prognosis, but the reasons behind this are unclear. Therefore, the current aim is to find out what makes these leukaemias different, and to use this information to find better treatment strategies.

To investigate this, The Bond Group has made multiple cell line models in the lab in which the leukaemia DNA has been changed to mimic the PRC2 mutations found in patient blood cancers.  Using these models, the team has found that PRC2-altered leukaemia cells have very different metabolic pathway activity to their wild-type counterparts, meaning that this could be selectively therapeutically targeted.

The Bond Group has generated some exciting preliminary data using funding from Research Ireland, and have been awarded a grant from the Little Princess Trust ((opens in a new window)https://www.littleprincesses.org.uk/) to enable them to investigate this further.

The team has already performed preliminary drug sensitivity testing with agents that target metabolic processes, with promising early results. To understand this further, and to try to find new candidate therapies that could be used in patients, they will:

• Use the cell line models of PRC2 mutations to comprehensively investigate the metabolic changes in these leukaemias. This will include using next generation methods to test what specific metabolic genes and proteins are affected by PRC2 mutations, to identify which specific metabolic pathways are altered.

They will also investigate how low oxygen concentrations, which is characteristic of the bone marrow, a site of AML relapse,  affect the leukaemia cells’ metabolism and subsequent treatment response.

• The results of these experiments will then be used to identify drugs that can target metabolism in these leukaemias. This may include drugs that inhibit metabolic pathways, or agents that target the molecular processes causing these changes. These approaches will first be tested in the cell line models, using combinations with standard treatment where appropriate, to see if these drugs can effectively kill the leukaemia cells.
• Finally, to fast track any promising therapy strategies for clinical use in future, the team will bring the most promising approaches forward for testing in pre-clinical models. To do so, they will use mouse models that have human PRC2-mutated leukaemia, allowing us to assess the treatments in a live setting, thereby telling them how useful these strategies may be for treating patients in future.

The Bond Group’s research aligns with increasing interest across the research and clinical communities in targeting tumour metabolism and therefore sparing normal cells, with several drugs showing clinical promise in recent years. They aim to build on these advances by harnessing the metabolic Achilles’ heel of high-risk leukaemias to develop more effective and less toxic treatment options for patients with these aggressive blood cancers.

As the Bond Group is co-located in the Irish National Children’s Cancer Service (NCCS), they place patient and public involvement (PPI) at the heart of their research. This team led the creation of the Young Person’s Advisory Group (YPAG) ((opens in a new window)https://www.ypag.ie/) at the NCCS, the first of its kind in Ireland, and has been heavily involved in all ongoing YPAG activities since the first meeting in 2022. 

The YPAG comprises young people (12-29 years) who have had a lived experience of cancer. YPAG members have shared their personal experiences of how the long-term effects of chemotherapy continue to affect their lives, providing a vivid example for scientists in our group of the potential importance and impact of their research. A key message is that these young people want to see kinder treatments with fewer side-effects. 

This aim underpins this Little Princess Trust funded proposal, which is the first The Bond Group has written with YPAG help. This involvement will continue during this project through the involvement of YPAG members Stacey Braddish and Ashleigh Kiernan.

This will also link with parallel efforts to involve the YPAG in research that includes the use of patient samples, as is planned in this project. The YPAG have expressed strong wishes to be involved in this area, so that young people with cancer might be more informed about what their samples and data are used for, and what impact and importance this might have. The aim is to provide information to young people and their families regarding the importance of their contributions to scientific and clinical discoveries, to empower them to make informed decisions about their participation in research, and to provide young people with cancer with a concrete sense of the research they help to advance.