Scientists have unveiled one of the most detailed studies of acute myeloid leukaemia (AML) ever undertaken, helping explain the limitations of a powerful new drug.
Researchers at three major centres embarked on the project to establish why a powerful new drug, enasidenib, was having disappointing results.
The findings were reported in the latest Nature Medicine.
Enasidenib can help up to 15% of patients who have an IDH2 gene mutation, which prevents bone marrow cells from differentiating into blood cells. The drug restores normal cell production and leads to temporary remission from disease in about 40% of cases.
However, clinical trials have found the drug only works for an average of nine months.
The latest project was undertaken at the Gustave Roussy Cancer Campus and Inserm in Paris, France, the MRC Molecular Haematology Unit and the MRC Weatherall Institute of Molecular Medicine at the University of Oxford, UK, and at Memorial Sloan Kettering Cancer Center, New York, USA.
The scientists analysed samples from 37 patients, studying changes over the course of treatment.
The study found that the drug restored the normal function of cancer cells, restoring their functions - but the cloned cells still contained the IDH2 mutation.
The researchers found the cloned cells went on to develop new mutations, making them resistant to the drug.
Researcher Dr Stéphane de Botton, from Paris, said: "Enasidenib [is] a very good example of a modern cancer therapy that specifically targets principally cancer cells, sparing normal cells, and in this regard is very safe and has limited side effects. Now that we have shown that it needs to be combined with other drugs to stop the cancer returning, we think that it's important that the combination therapy should be given to AML patients early on in their disease.
“International trials are now taking place comparing combinations of enasidenib and other drugs with the normal standard of care.”
Dr Lynn Quek, from the Oxford team, said: “We used techniques to study genetic mutations on a cell-by-cell basis, and re-constructed the family tree of a patient's AML.
“We then tracked changes in the family of AML cells as they responded to enasidenib and as patients lost response to the drug. This is the first time that anyone has done such a detailed study at a single cell level.
“As enasidenib is a new anti-leukaemic drug, it was vital to understand the effects of the drug on leukaemic cells.”
Source: Quek, L., David, M.D., Kennedy, A., Metzner, M., Amatangelo, M., Shih, A., Stoilova, B., Quivoron, C., Heiblig, M., Willekens, C. and Saada, V., 2018. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nature Medicine, p.1.
Link: https://www.nature.com/articles/s41591-018-0115-6
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