A new class of drugs may help in the treatment of acute myeloid leukaemia (AML), according to a joint UK-US project.
Researchers at Ludwig Institute for Cancer Research in Oxford, UK, have pinpointed GSK3 inhibitors as a potential combination therapy with inhibitors of LSD1 – an ‘epigenetic’ enzyme discovered in 2004, which is known to be produced at high levels in AML cells.
The laboratory study suggests the combination might remove the ‘differentiation block’ present in AML, which stops the leukaemic myeloid progenitors from maturing and ensures the leukaemia stem cells keep renewing themselves.
Targeting this differentiation block has been a successful approach in acute promyelocytic leukaemia, which can be cured in 95% of cases with a combination of all-trans retinoic acid and arsenic trioxide.
LSD1 inhibitors are already known to remove the differentiation block in AML – but the researchers say they have also proved excessively toxic. So the team searched for another drug which could improve the effectiveness of LSD1 inhibitors.
In studies on AML cell lines, AML cells donated by patients, and mouse models of AML, the researchers showed that an inhibitor of GSK3 enzyme works synergistically with an LSD1 inhibitor, with the potential to limit toxicity. The researchers say that clinical trials of the GSK3 inhibitor, under way for other cancers, suggest it is well tolerated.
The experiments suggest the combination will target leukemic cells and avoid healthy ones, they report in the journal Nature.
Researcher Professor Yang Shi, of the University of Oxford, said: “Our findings provide compelling evidence to support the testing of this combination therapy in AML patients, especially since both of the inhibitors involved are not only available but have been developed for human use and are currently being evaluated in the clinical trials.
“The drug combination we have identified works by activating genes that drive cell differentiation while suppressing genes that promote cell proliferation and cancer growth.”
Fellow researcher Amir Hosseini, of the University of Oxford, said: “We are also encouraged by the observation that the gene expression signature induced in leukemic cells by this combination therapy correlates with that observed in the cancer cells of AML patients who live relatively longer.”
Source:
Hosseini A, Dhall A, Ikonen N, Sikora N, Nguyen S, Shen Y, Amaral MLJ, Jiao A, Wallner F, Sergeev P, Lim Y, Yang Y, Vick B, Kawabata KC, Melnick A, Vyas P, Ren B, Jeremias I, Psaila B, Heckman CA, Blanco MA, Shi Y. (2025) “Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.” Nature, 16 April 2025, doi: 10.1038/s41586-025-08915-1.
Link: https://www.nature.com/articles/s41586-025-08915-1
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