Acute myeloid leukemia (AML) is a blood cancer in which the process of forming mature, differentiated and non-dividing myeloid white blood cells is blocked. This causes immature white blood cells to build up in the bone marrow and disrupt normal blood cell production. One approach to treating the cancer involves targeting of the epigenetic regulator LSD1 to overcome the differentiation blockade. But because LSD1 is also involved in other steps of myeloid cell differentiation, its inhibition was not well tolerated by patients in a clinical trial. A study led by Ludwig Oxford’s Yang Shi and published in a May issue of iScience reported the identification of metabolic processes that could be targeted in tandem to improve this strategy and lower the required dosage of LSD1 inhibitor. Screening a library of drugs, Yang and his colleagues found that targeting fatty acid and purine metabolic pathways in combination with LSD1 inhibition improved significantly on LSD1 inhibition alone in cell culture models of AML differentiation. The team also performed mathematical modeling of the potential effects of varying the concentrations and dosing intervals of such drug combinations on cell maturation and tumor burden. The study establishes a basis for preclinical development of a new AML treatment approach.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).