Targeting CARM1 inhibits AML and spares normal cells

It slows acute myeloid leukemia (AML) progression.

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

A new study by the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine has suggested that inhibiting the enzyme CARM1 (likewise called PRMT4) significantly moderates acute myeloid leukemia (AML) progression yet does not influence normal blood creation.

According to scientists, this selectivity could make it an ideal drug target for AML. AML creates when stem cells in bone marrow obtain transformations that block the stem cells’ capacity to develop into ordinary blood cells. The disease is very aggressive and there is a desperate requirement for focused diagnosis. Most patients are more than 60, and numerous experience difficulty enduring existing medications. The five-year survival for elderly patients who don’t get stem cell transplants is best case scenario 20 percent.

Stephen D. Nimer, M.D., director of Sylvester Comprehensive Cancer Center said, “When we tried to generate leukemia using cells that lack the gene CARM1, we couldn’t. 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.”

CARM1 keeps stems cells in an immature state. Scientists wondered if it performs a similar function in AML. Working in cell lines and animal models, the group, which incorporates specialists from around the world, demonstrated that CARM1 is basic for AML movement.

Experimenting on mice, scientists found that leukemia cells are dependent on CARM1, while normal cells are not. at that point tried the CARM1 inhibitor EPZ025654, which is being co-created by GlaxoSmithKline and Epizyme, in human tumor xenografts and found the molecule fundamentally diminished AML movement and expanded survival.

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.

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

The study was published online on June 11 in Cancer Cell.