Menin, a protein located in the nucleus of various human cell types, often functions as a tumor suppressor by inhibiting excessive cell growth and division. If a mutation in the menin gene causes the protein to be defective or absent, uncontrolled cell growth begins — cell growth that could lay the foundations for cancer.
Dana-Farber research has also found that menin in its normal form has the potential to drive cancer. Research by Scott Armstrong, MD, PhD, senior vice president for drug discovery and chief research strategy officer at Dana-Farber, along with collaborators elsewhere, found that menin cooperates with mutant or rearranged proteins to drive acute myeloid leukemia (AML), one of the most difficult forms of leukemia to treat.
These insights led Dana-Farber researchers and collaborators to develop menin inhibitors that block these interactions. Today, two menin inhibitors are approved by the U.S. Food and Drug Administration for the treatment of patients with relapsed AML with certain genetic mutations that are found in up to 40% of cases.
How is menin involved in acute leukemia?
Under normal circumstances, menin is involved in blood development. It facilitates a complex of proteins involved in an epigenetic process that marks and unravels DNA to activate genes that control cell division. Research by Matthew Meyerson, MD, PhD, director of Dana-Farber’s Center for Cancer Genomics, found menin works by cooperating with the MLL family of proteins.
Later work by collaborators at Stanford revealed that menin plays a role in a specific form of AML. They found that menin facilitates the growth of KMT2A mutant leukemia cells. Mutations in KMT2A create an abnormal form of the MLL1 protein that turns normal white blood cells into leukemia cells. Menin facilitates the growth of these KMT2A mutant leukemia cells and is required for their growth.
How was a menin inhibitor discovered?
Armstrong has been studying MLL-driven leukemias for over 20 years. His lab uncovered more about how mutant MLL and menin work together, which genetic programs are activated by the complex they form, and how these programs cause leukemia cells to form. Armstrong’s lab also set out to find a small molecule drug to hinder menin’s actions.
In 2019, the Armstrong lab, working collaboratively with Syndax Pharmaceuticals, described a class of menin inhibitors that could eradicate leukemia in preclinical studies. This work prompted the clinical testing of a first-in-class menin inhibitor called revumenib. Subsequent clinical trials at Dana-Farber and throughout the United States demonstrated revumenib, a pill taken by mouth, had minimal side effects and the power to help patients with advanced AML reach remission.
Simultaneously, Armstrong’s lab also identified that blocking menin could be effective in patients whose AML harbored NPM1 mutations, interrupting the formation of a complex between mutant NPM1, MLL, and menin that activates a genetic program that drives leukemia.
“The two genetic subtypes of acute leukemia involved in this research account for approximately 40% of all cases of acute myeloid leukemia (AML) in children and adults,” says Armstrong. “They’re driven by a rearrangement of the KMT2A gene or a mutation in the NPM1 gene. Both types depend on a protein called menin to sustain their growth.”
What menin inhibitors are approved for AML?
So far, two menin inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for adults and children aged 1 year and older with relapsed or refractory AML:
- Revumenib is approved for patients with the KMT2A mutation and for patients with an NPM1 mutation.
- Ziftomenib is approved for patients with an NPM1 mutation.
What research is ongoing related to menin inhibitors?
Researchers in Armstrong’s lab continue to investigate menin inhibitors, tackling the issue of drug resistance. They have already uncovered insights that could lead to future solutions, including developing new drug molecules that deprive menin of any potential to bind MLL or combining menin inhibitors with other drugs including chemotherapy, which is still standard therapy for AML, and potentially in the future with other targeted therapies.
“Menin inhibitors have been validated and approved as a new therapy, but as we’ve learned in the past, combinations of therapies are likely to be more effective,” says Armstrong. “Exciting trials of combinations are underway now in newly diagnosed and relapsed settings.”