A new targeted drug has not only triggered remissions in patients with a common form of leukemia, but also caused cancer cells to reveal one of the drug’s resistance plans, researchers at the Dana-Farber Cancer Institute and other research centers report in a new pair. of studies in the journal Nature.
One of the papers presents the results of a clinical trial in which about 40% of patients with subtypes of acute leukemia had a complete response — disappearance of all signs of cancer — to treatment with the drug rebumenib. The other paper reveals a molecular reversal by which leukemia cells come to bypass the drug and assert their growth.
The papers point to the promise of the targeted approach to treating acute leukemia exemplified by revumenib and the potential to extend its benefits with drugs that disrupt the resistance mechanism, the researchers say.
“The two genetic subtypes of acute leukemia implicated in this research account for approximately 40% of all cases of acute myeloid leukemia (AML) in children and adults,” says Scott Armstrong, MD, PhD, president of Dana-Farber/Boston Children’s. Center for Cancer and Blood Disorders and co-senior author of the paper on revumenib resistance. “They are driven by a reordering of it MLL1 gene or a mutation in NPM1 gene. Both types depend on a protein called menin to maintain their growth.’
The first of the new Nature studies report a phase I/II clinical trial of the drug revumenib, which targets menin, in 68 patients with acute leukemia unresponsive to other treatments. The trial, called the AUGMENT-101 study, found that of 60 evaluable patients, 53% responded to the drug and 30% had a complete response.
“For patients with acute leukemia who have had multiple prior treatments, this is a very encouraging result,” says Armstrong. “However, after the second cycle of treatment, some patients developed resistance to rebumenib.”
In their subsequent study, Armstrong and his colleagues looked for a source of this resistance.
Menin is a critical part of the cell’s “epigenetic” machinery for turning gene activity on and off. It binds to chromatin — the braid of DNA and protein packaging inside the nucleus — and calls upon large complexes of proteins to come together. The complexes tighten or loosen the DNA coils, changing the level of gene activity at that point. One of the key proteins in these complexes is MLL1, its product MLL1 gene.
“Revumenib contains a small molecule that blocks the interaction of menin and MLL1,” says Armstrong. “AUGMENT trial shows it can induce remission in a high proportion of patients.”
When Armstrong and colleagues analyzed bone marrow samples from some of the patients who became resistant to revumenib, they found that many had developed mutations in MEN 1, the gene that makes the protein menin. The mutation results in a distorted version of menin that doesn’t bind well to revumenib but attaches as tightly as ever to MLL1. As menin and MLL1 renew their interaction, leukemia cells start growing again.
The finding provides “formal proof in patients that menin itself is a valid target for therapy in both genetic subtypes of AML,” Armstrong says.
In a sense, revumenib acts as a kind of truth-telling serum to leukemia cells: by putting the cells under pressure, it prompts them to reveal one of their survival strategies. “The fact that the cell has gone to so much trouble to mutate MEN 1 To survive is a strong indication that we’re hitting a target that the cell actually relies on,” Armstrong says.
Revumenib’s ability to stress leukemia cells to the point where they develop a mutation to stay alive is proof of the drug’s effectiveness, he continues. “This is the first time that a drug that targets a complex of chromatin-binding proteins has been shown to exert this degree of pressure on cancer in a human patient.”
Monitoring the development of mutations in MEN 1 and other genes in patients with acute leukemia, doctors may be able to identify patients at high risk of relapse, Armstrong reports. Such patients may then benefit from further treatment. His discovery MEN 1 Mutation as a mechanism of resistance suggests that new drugs that specifically target menin or other chromatin-associated proteins could prevent or delay resistance to revumenib or treat patients who have become resistant to the drug.
“Seeing the work of Dr. Armstrong to translate elegantly to the clinic where patients — including some at Dana-Farber, who had dramatic responses to dire situations — was very gratifying personally and professionally,” says Richard Stone, MD, partner at Dana-Farber. -author of both Nature studies. “We are now ready to magnify the impact of these results by conducting clinical trials combining revumenib with standard chemotherapy as well as new agents, also based on the preclinical work done in large part by Drs. Armstrong.”