Study Could Lead to a New Combination Therapy Approach for Leukemia

Microscope image of acute myeloid leukemia cells
Article Summary
  • A study led by Sylvester Director Stephen D. Nimer, M.D., suggests a new route to leukemia treatment.
  • The data show that inhibiting two enzymes, CARM1 and JAK2, resulted in a more potent anti-cancer effect in leukemia cells than inhibiting either enzyme alone.
  • The findings are part of a larger program led by Dr. Nimer investigating CARM1 and related “epigenetic regulators.”

Stephen D. Nimer, M.D., juggles his role as director of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine with work in his laboratory, studying the cellular mechanisms of leukemia.

Despite the stressors of his schedule, Dr. Nimer wouldn’t have it any other way.

“The lab has always been a place of great creativity for me,” he said.

That creative spark has yielded a research study on a potential new approach to treating leukemia. The findings suggests that certain leukemias might respond to a combination of drugs targeting two key enzymes in the cell, CARM1 (coactivator-associated arginine methyltransferase 1) and JAK2 (Janus kinase 2).

Hidehiro Itonaga, Ph.D., a Sylvester researcher and postdoctoral associate in Dr. Nimer’s lab, is first author of the study, published in Nature Communications. But the study also pulled in researchers across Sylvester in a collaborative effort, including technicians, students and postdocs.

“Collaboration and teamwork are important. No one person can do anything by themselves,” said Dr. Nimer.

Two Inhibitors are Better Than One

Dr. Nimer and his colleagues previously showed that quelling CARM1 may effectively counteract acute myeloid leukemia (AML), the most common leukemia in adults. They found that a drug-like inhibitor of CARM1 thwarted leukemia in preclinical models, while leaving normal, non-cancerous cells largely alone.

CARM1 is known to help regulate cell division, growth and survival, which are cellular processes essential for cancer cells.

Dr. Stephen Nimer
Dr. Stephen Nimer

In the new study, Dr. Nimer and his colleagues delved further into the functions of CARM1. They found that its activity was modulated in leukemia cells by another enzyme, JAK2, which is a tyrosine kinase.

Blood cancers are often powered by a hyperactive, mutant form of JAK2. The researchers found that this mutant form modified CARM1 by adding a phosphate group to it, shifting how CARM1 operates and promoting its cancer-like activity in cells.

Next, the researchers asked what would happen if they quelled CARM1 and JAK2 together. They tested the CARM1 inhibitor and ruxolitinib, a drug that inhibits JAK2, in AML cells containing the mutant form of JAK2. Combining both inhibitors yielded a stronger anti-cancer effect than either inhibitor alone.

The study could inform FDA development of new treatments, said Dr. Nimer. JAK2 inhibitors like ruxolitinib are currently approved for blood cancers, but also for autoimmune disorders like rheumatoid arthritis. Several biopharma companies also have preclinical stage programs focused on CARM1. All these efforts could get a boost from the new study, he said.

“This is the kind of work that’s designed to help patients,” said Dr. Nimer. “It’s not only knowledge for knowledge’s sake.”

The publication may also have implications for an inherited form of leukemia. Dr. Nimer and his colleagues found that JAK2-modified CARM1 affected a protein called RUNX1. Some families have members born with mutations in the gene encoding RUNX1, leading to a high risk for leukemia later in life.

“It’s possible that one could develop a therapeutic CARM1 inhibitor and even use it in these individuals to prevent leukemia,” said Dr. Nimer.

A Strong Cancer Epigenetics Program

CARM1 is a type of protein methyltransferase, an enzyme family that regulates proteins by adding a molecule to them called a methyl group.

CARM1 and related enzymes have broad functions throughout the cell and add methyl groups to multiple protein targets, causing enduring changes in cell state.

“We’re continuing to understand what regulates the activity of these enzymes,” which are also part of a broad class of molecules called epigenetic regulators, said Dr. Nimer. He has studied such molecules for over a decade and has helped develop clinical trials at Sylvester testing compounds directed against epigenetic regulators.

“Sylvester has one of the strongest cancer epigenetics programs in the country,” he added.

Supervising research within his nine- to 10-person lab and establishing collaborations with other colleagues helps him relate to the day-to-day challenges faced by the more than 250 other principal investigators at Sylvester.

Conducting laboratory research also helps Dr. Nimer’s recruitment of outstanding investigators to Sylvester.

Tags: Acute Myeloid Leukemia, blood cancers, Dr. Stephen Nimer, Leukemia, Sylvester Comprehensive Cancer Center