Targeting CARM1 Inhibits AML and Spares Normal Cells

Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown that inhibiting the enzyme CARM1 (also called PRMT4) dramatically slows acute myeloid leukemia (AML) progression but does not affect normal blood production. This selectivity could make it an ideal drug target for AML – a disease with few treatment options. The study was published online on June 11 in Cancer Cell.

Dr. Stephen Nimer and Gloria Mas Martin in the lab.

“When we tried to generate leukemia using cells that lack the gene CARM1, we couldn’t,” said Stephen D. Nimer, M.D., director of Sylvester Comprehensive Cancer Center and senior investigator on the paper. “Furthermore, when we remove the gene from leukemia cells, the leukemia disappears. This led us to conclude that CARM1 is required for leukemia but not for normal blood function; it suggests that blocking CARM1 should not create toxicity.”

AML develops when stem cells in bone marrow acquire mutations that block the stem cells’ ability to mature into normal blood cells. The disease is quite aggressive and there is a desperate need for targeted therapies. Most patients are over 60, and many have trouble tolerating existing treatments. The five-year survival for elderly patients who do not receive stem cell transplants is at best 20 percent.

“Novel therapeutic approaches are sorely needed for acute leukemia patients,” said first author Sarah Greenblatt, Ph.D., a post-doctoral associate in Nimer’s lab. “They continue to receive non-specific chemotherapy agents and often fail to achieve sustained remissions.”

The study grew out of Nimer’s decades-long efforts to understand the AML1 protein that is often mutated in patients with AML and myelodysplastic syndromes. Recent studies have shown that CARM1, an arginine methyltransferase enzyme, modifies the RUNX1 gene and is highly expressed in several cancers. AML patients with high CARM1 expression have much worse prognoses.

During development, CARM1 is known to keep stem cells in an immature state. Nimer and colleagues wondered if it performs a similar function in AML. Working in cell lines and animal models, the team, which includes investigators from around the globe, showed that CARM1 is essential for AML progression.

“By modeling AML in mice, we were able to show that leukemia cells are dependent on CARM1, while normal cells are not,” said Greenblatt.

The team then tested the CARM1 inhibitor EPZ025654, which is being co-developed by GlaxoSmithKline and Epizyme, in human tumor xenografts and found the molecule significantly reduced AML progression and extended survival.

While further study is needed, these early results show CARM1 is the kind of cancer target researchers and clinicians are looking for: essential for cancer but redundant in normal biological processes.

In addition to AML, CARM1 has been implicated in other leukemias, as well as breast, colorectal, liver, lung and prostate cancers. The authors believe these findings will motivate companies to look closely at this enzyme in other diseases as well.

“There are a number of pharmaceutical companies that are very interested in this target,” said Nimer. “This research should spur them to develop potent and selective inhibitors.”