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Professor Yang Shi’s group demonstrates that combining drugs targeting epigenetic and metabolic pathways can overcome the arrest of white blood cell differentiation in this blood cancer.

Acute myeloid leukaemia (AML) is a type of blood cancer in which the process of forming mature, differentiated and non-dividing myeloid white blood cells is blocked. This blockage causes immature white blood cells to build up in the bone marrow and disrupt normal blood cell production.

Currently, most cases of AML are treated with chemotherapy or blood stem cell transplant, but these have significant side effects that make them unsuitable for frailer patients. One approach for developing less toxic treatments for AML is to search for new drug targets that are involved in the control of white blood cell differentiation and maturation so that this process can be restored.

One such drug target is the epigenetic regulator LSD1 and inhibition of LSD1 has been shown to overcome the differentiation blockade. However, because LSD1 is also involved at other points in the development of mature myeloid white blood cells, treatment with an LSD1 inhibitor was not well tolerated by patients in a clinical trial. Instead, a combination strategy is being explored, with researchers searching for drugs that target other differentiation-regulating pathways that can be used in combination with lower, less toxic doses of the LSD1 inhibitor.

Reported in the journal iScience, Dr Barry Zee from Ludwig Oxford’s Professor Yang Shi’s group together with collaborators identified metabolic targets that enhanced white blood cell differentiation caused by LSD1 inhibition. Specifically, by screening a library of drugs, they found that targeting fatty acid and purine metabolic pathways in combination with LSD1 inhibition resulted in a greater level of differentiation in cell culture models than with LSD1 inhibition alone. The team also performed mathematical modelling using the data collected from their in vitro experiments to predict the impact of varying concentrations and dosing intervals of the drug combinations on cell maturation and tumour burden in vivo.

While further experiments are required to gain more in vivo evidence, the data from the triple drug treatment in this study provides the groundwork for future clinical testing of this new AML treatment approach.

 

Image credit: © The Authors CC BY-NC-ND 4.0

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