British scientists have developed a new kind of drug that could treat acute myeloid leukaemia (AML) by targeting enzymes that sense oxygen levels.
In laboratory studies involving mice and cell lines, the researchers showed that blocking certain oxygen-sensing enzymes could significantly halt the development of the disease, without affecting normal production of blood cells.
These enzymes can be blocked with existing drugs that treat anaemia – but the team have developed a new drug with improved selectivity and the potential for reduced side effects
The research team was made up of scientists at the Institute of Cancer Research, London, the University of Oxford and Queen Mary, University of London. They reported their findings in Nature Cancer.
The project has involved study of hypoxia inducible factor prolyl hydroxylases (PHDs). These enzymes are stimulated by oxygen and target hypoxia inducible factor (HIF) proteins for their destruction. Inactivated HIF proteins contribute to aggressive AML – so the project has been examining the prospects for boosting HIF levels.
The new potential drug candidate is called IOX5 and selectively inhibits PHDs, the researchers say. The laboratory studies showed it “significantly” blocked progression of AML, especially when combined with the AML drug venetoclax, they report.
Researcher Professor Kamil Kranc, of the Institute of Cancer Research, said: “There is a huge need to discover better treatments for this aggressive disease. We’ve shown for the first time that targeting the pathways that our cells use to respond to oxygen levels could provide a new way to treat leukaemia, without impacting the normal production of blood cells within the bone marrow.
“Our next challenge is to progress the existing drugs and our new, more selective compound, to clinical trials. We’re hopeful this research will pave the way towards a new era of AML treatments, and we’d like to explore whether these therapies could also be beneficial for solid tumours.”
Source:
Lawson H, Holt-Martyn JP, Dembitz V, Kabayama Y, Wang LM, Bellani A, Atwal S, Saffoon N, Durko J, van de Lagemaat LN, De Pace AL, Tumber A, Corner T, Salah E, Arndt C, Brewitz L, Bowen M, Dubusse L, George D, Allen L, Guitart AV, Fung TK, So CWE, Schwaller J, Gallipoli P, O'Carroll D, Schofield CJ, Kranc KR. (2024) “The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.” Nature Cancer, 18 April 2024, doi: 10.1038/s43018-024-00761-w
Link: https://www.nature.com/articles/s43018-024-00761-w
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