08 July 2022

US researchers have revealed promising new drugs designed to destroy leukaemia cells. Although the drugs are years away from being tested in cancer patients, a study published in the journal Leukaemia highlights their potential.

Researchers from Rice University in Houston, Texas, previously screened 45,000 small-molecule compounds to find a few that targeted mitochondria – the parts of the cell which produce energy. In this new study, they worked with a team from the University of Texas MD Anderson Cancer Center to study eight of the most promising compounds, firstly in acute myeloid leukaemia (AML) cells.

They identified between five and 30 closely related analogues for each, and conducted tens of thousands of tests to systematically determine how toxic each analogue was to AML cells, both when administered individually or in combination with existing chemotherapy drugs such as doxorubicin.

Previous work by Rice biochemist Dr Natasha Kirienko and Anderson physician-scientist Dr Marina Konopleva had shown how the eight compounds targeted mitochondria and induce mitophagy – a ‘housekeeping’ process where old mitochondria are dismantled and recycled.

During times of extreme stress, cancer cells can temporarily forgo mitophagy to get an emergency energy boost. They hypothesised that mitophagy-inducing drugs might weaken leukaemia cells and make them more susceptible to chemotherapy. The team found that six of the eight small-molecule compounds were deadly to AML cells.

They found five were also effective at killing acute lymphoblastic leukaemia (ALL) cells and chronic myelogenous leukaemia (CML) cells. Control studies found all the mitophagy-inducing drugs caused far less harm to healthy cells.

The researchers also tested one of the most effective compounds, PS127E, in a ‘mouse clinical trial’ – where AML cells from humans are injected into mice. They showed that the drug extended survival in this mice.

 “Although this is very promising, we’re still some distance from having a new treatment we can use in the clinic,” Dr Kirienko said.

“We still have a lot to discover. For example, we need to better understand how the drugs work in cells. We need to refine the dose we think would be best, and perhaps most importantly, we need to test on a wide variety of AML cancers. AML has a lot of variations, and we need to know which patients are most likely to benefit from this treatment and which are not. Only after we’ve done that work, which may take a few years, would we be able to start testing in humans.”

Source: Panina SB, Pei J, Baran N, Tjahjono E, Patel S, Alatrash G, Konoplev S, Stolbov LA, Poroikov VV, Konopleva M, Kirienko NV. (2022) “Novel mitochondria-targeting compounds selectively kill human leukemia cells.” Leukaemia, doi: 10.1038/s41375-022-01614-0

Link: https://www.nature.com/articles/s41375-022-01614-0

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