14 May 2019

Vulnerabilities discovered in a subset of acute myeloid leukaemia (AML) could lead to new and effective treatments, US researchers have reported.

The team of scientists found that in both mouse and human models of AML with IDH mutations, arsenic trioxide combined with all-trans retinoic acid – already being used to treat acute promyelocytic leukaemia (APL) – was “powerfully and exquisitely effective”.

The team was led Dr Pier Paolo Pandolfi, director of the Cancer Center and Cancer Research Institute at Beth Israel Deaconess Medical Center, Boston, USA.

“There is an acute need to develop rational combinations to treat disease and overcome resistance that arises in response to therapy,” said Dr Pandolfi. “By providing a critical understanding of the mechanisms underlying the disease, we identified a therapeutic strategy for treatment of this type of AML.”

About 20% of AML cases involve a mutation in the metabolic enzyme called IDH. In their study, published in the journal Cell Research, Dr Pandolfi and his team worked out the mechanism for how AML cells which carry IDH mutations become resistant to therapies.

They then identified critical vulnerabilities and demonstrated that this combination of drugs worked as well against this form of AML, in primary cells in vitro, and in patient-derived xenograft mouse models.

“With my lab's previous discovery that all-trans retinoic acid and arsenic trioxide is curative in the treatment of acute promyelocytic leukaemia, witnessing the translation of this same therapy to possible therapeutic approaches for other forms of AML is extremely rewarding,” said Dr Pandolfi.

Source: Mugoni, V., Panella, R., Cheloni, G., Chen, M., Pozdnyakova, O., Stroopinsky, D., Guarnerio, J., Monteleone, E., Lee, J.D., Mendez, L., Menon, A.V., Aster, J.C., Lane, A.A., Stone, R.M., Galinsky, I., Zamora, J.C., Lo-Coco, F., Bhasin, M.K., Avigan. D., Longo, L., Clohessy, J.G., Pandolfi, P.P. (2019) “Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy”, Cell Research, available from doi: 10.1038/s41422-019-0162-7


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