Inhibiting powerful protein with new agents may supply broad benefit for lymphoma patients

Published on May 14, 2013 at 5:23 AM · No Comments

A soon-to-be-tested class of drug inhibitors were predicted to help a limited number of patients with B-cell lymphomas with mutations affecting the EZH2 protein. However, a research team, led by investigators at Weill Cornell Medical College, now report that these agents may, in fact, help a much broader cross section of lymphoma patients.

The study, reported in Cancer Cell, found that the EZH2 protein the drug agents inhibited is a powerful regulatory molecule in B-cells, and a key driver of cancer in these immune cells.

The study's lead investigator, Weill Cornell Medical College's Dr. Ari Melnick, suggests that combining an EZH2 inhibitor with another related targeted therapy may offer a much improved treatment for follicular lymphoma, a cancer that currently has no cure, as well as a non-toxic alternative to chemotherapy for at least a third of diffuse large B-cell lymphomas. Because these two lymphomas account for 70 percent of adult lymphomas, Dr. Melnick believes the new therapy could potentially help a broad cross section of lymphoma patients.

"Our research indicates that these inhibitors will be remarkably effective. I am very optimistic," says Dr. Melnick, the Gebroe Professor of Hematology/Oncology, professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell. "Researchers had thought EZH2 inhibitors would only help patients with a mutation in their EZH2 gene, which represents a small subset of lymphoma patients. What we found is that a majority of lymphomas turn out to be dependent on normal EZH2, not just mutated EZH2."

Tumor Cells Depend on the EZH2 Master Regulator

The new study was aimed at understanding what normal as well as mutated EZH2 does within B-cells -- basic information that remained unknown despite more than a decade of research into the protein.

The role of B-cells (white blood cells known as B-lymphocytes) is to produce antibodies against invading microbes. What the researchers discovered is that EZH2 is required in order for the immune system to generate germinal center B-cells, which are the cells that make the most powerful type of antibodies.

Germinal center B-cells divide extremely quickly and try to create within them the high affinity antibodies that will be beneficial to fight off invading infections. This process happens constantly because of our exposure to microorganisms.

"Most B-cell lymphomas arise from germinal center B-cells -- germinal centers are the engine for formation of lymphomas," says Dr. Melnick. "The reason for this is because germinal center B-cells divide very, very quickly while at the same time mutating their antibody genes. Unfortunately, many other genes get mutated when this happens, which can eventually result in lymphoma formation."

It turns out that the behavior of germinal center B-cell is orchestrated by EZH2, Dr. Melnick discovered. "EZH2 is a master regulator protein that turns off the brakes that prevent cell division, so it allows cells to divide without stopping," he says.

EZH2 also has a second function, which Dr. Melnick calls "surprising and perhaps even more important.

"It prevents germinal cells from transitioning to antibody-secreting cells," he says. "Indeed, in the normal immune system EZH2 prevents B-cells from exiting germinal centers so that these cells can continue to undergo sustained rapid cell division, which continues until the immune system says to stop. Then EZH2 goes away, and B-cells can develop into antibody-secreting cells, which send antibodies into the circulation to fight off infection."

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