After a recent discovery, British scientists believe existing drugs could be repurposed to treat rare leukaemia and herald a “new era” for how an aggressive form of blood cancer is treated.
Described as a “largely incurable disease”, acute myeloid leukaemia (AML) is a cancer that causes the bone marrow to produce a large number of abnormal blood cells, reports The Independent.
Now, a study co-led by The Institute of Cancer Research, London, and the University of Oxford, has found that blocking an enzyme in the body’s cells which senses changes in oxygen levels could stop the disease from progressing.
In the presence of oxygen, these enzymes, known as hypoxia-inducible factor prolyl hydroxylases (PHDs), become active – to target and destroy proteins called hypoxia-inducible factors (HIF).
When oxygen levels are low, PHD enzymes are less active, leading to higher HIF levels.
The research team explored whether boosting HIF levels could prevent the progression of AML.
They genetically modified mice and de-activated PHD enzymes, which increased HIF levels and stopped disease progression without impacting the production of normal blood cells.
A similar enzyme-blocking process is used in drugs that treat anaemia, they said, and showed the same effect on leukaemia in both mouse cells and patient samples.
The team has also created a new compound called IOX5, which inhibits PHDs without affecting other enzymes.
Kamil Kranc, a professor of haemato-oncology at The Institute of Cancer Research, London, said: “Therapy for acute myeloid leukaemia has barely changed in several decades. 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 an impact on the normal blood cell production within the bone marrow.”
AML is most common in patients over 75.
It is hoped the findings of the research – published in the journal Nature Cancer – will now be tested in clinical trials.
“Our next challenge is to progress the existing drugs and our new, more selective compound, to clinical trials,” said Kranc.
“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.”
Professor Kristian Helin, chief executive of The Institute of Cancer Research, London, said: “Cancer exists in a complex ecosystem within the body, and this work provides important insights into that ecosystem, and how cancer uses signals within the environment – such as those relating to oxygen levels – to grow and develop.
“This study is also an excellent example of cancer researchers and chemists working closely to develop and test new cancer therapeutics.”
Study details
The selective prolyl hydroxylase inhibitor IOX5 stabilises HIF-1α and compromises development and progression of acute myeloid leukaemia
Hannah Lawson, James P. Holt-Martyn, Kamil Kranc et al.
Published in Nature Cancer on 18 April 2024
Abstract
Acute myeloid leukaemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukaemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal haematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukaemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilisation, is a promising nontoxic strategy for AML, including in combination with venetoclax.
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