June 8, 2021—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 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. In the hope of developing less toxic treatments, researchers are looking for new drug targets that can help restore normal myeloid cell differentiation.
One such target is the epigenetic regulator LSD1. Inhibition of LSD1 has been shown to overcome the differentiation blockade seen in AML. However, because LSD1 is also involved at other points in the maturation pathway of myeloid cells, treatment with an LSD1 inhibitor was not well tolerated by patients in a clinical trial. Researchers are therefore looking for combination drug strategies that might permit the use of lower and less toxic doses of the LSD1 inhibitor.
Contributing to these efforts, Barry Zee in the laboratory of Ludwig Oxford’s Yang Shi and colleagues at Ludwig Harvard and other U.S. institutions report in iScience the identification of metabolic processes that could be targeted to that end. Screening a library of drugs, the researchers found that targeting fatty acid and purine metabolic pathways in combination with LSD1 inhibition improved significantly upon the differentiation achieved with LSD1 inhibition alone in cell culture models. The team also performed mathematical modeling of the potential effects of varying concentrations and dosing intervals of proposed drug combinations on cell maturation and tumor burden in vivo.
The study establishes a basis for additional preclinical development of a potentially new AML treatment approach.