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Revumenib, an experimental treatment tested in a US clinical trial, triggered remissions in patients with aggressive leukemia, but also caused cancer cells to reveal one of their resistance patterns.
Acute myeloid leukemia is the most common blood cancer in adults. Although it remains rare (between 2 and 3 cases out of 100,000 people per year), it is nonetheless worrying: in this aggressive form of leukaemia, the three-year survival rate is only 25%. But a new experimental drug, Revumenib, could advance the research. Several studies published in the journal Nature conducted by researchers at the Dana-Farber Cancer Institute and other research centers update their findings.
Complete remission for 30% of participants
According to the researchers, Revumenid is thought to work by inhibiting a protein called menin, which appears to play an important role in some forms of leukemia. These cancers are characterized by carrying a mutation of the NPM1 gene or a rearrangement of another gene, called KMT2A. The researchers focused on these two genetic subtypes. The 68 patients recruited for the study called AUGMENT-101 had relapsed or refractory acute leukemia that had not responded to previous treatments. 60 of these patients had NPM1/KMT2A-related cancer and received oral treatment every 12 hours for 28 days. Of these eligible patients:
- 53% showed some response to revumenib;
- 30% (18 patients) showed complete remission.
“For patients with acute leukemia who have undergone several previous treatments, this is a very encouraging result,” said Scott Armstrong, MD, PhD, president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and co-lead author of the paper.
But updated evidence of leukemia cell resistance
However, the study also revealed another piece of information: a molecular counter-movement by which the leukemia cells bypass the drug and reaffirm their growth.
“After the second treatment cycle, some patients developed resistance to revumenib” announce the researchers.
In their follow-up study, Armstrong and his associates looked for a source for this resistance. The menin mentioned above is an essential element of the “epigenetic” mechanism of the leukemia cell to activate and deactivate the activity of genes. It binds to chromatin – a braid of DNA – and summons large protein complexes to join it. One of the key proteins in these complexes is MLL1, or,”Revumenib contains a small molecule that inhibits the interaction of menin and MLL1″ concludes Armstrong.
An apprenticeship for the rest of the tests
The researchers thus explain that revumenib acts as a sort of “revealing” serum on leukemic cells: by putting the cells under pressure, it encourages them to disclose one of their survival strategies. Information that is not as negative as it seems:
“The fact that the cell has gone through so much to mutate in order to survive is a strong indication that we are hitting a target that the cell is really leaning on,” Armstrong said. The ability of revumenib to stress leukemia cells to the point where they develop a mutation to stay alive speaks to the effectiveness of the drug. This is the first time that a drug targeting a chromatin-binding protein complex has exerted such pressure on cancer in a human patient.”
In light of these findings, research should now consider new drugs that specifically target menin or other chromatin-associated proteins to prevent or delay resistance to revumenib, or treat patients who have become resistant to the drug. “We are now ready to amplify the impact of these results by conducting clinical trials combining revumenib with standard chemotherapy as well as with new agents” say the associated authors.