Study paves way for rational drug targeting of B-cell lymphomas

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A new study from Dana-Farber Cancer Institute may help clinicians and drug researchers choose the most promising genetic targets to attack in a common type of non-Hodgkin lymphoma, say the authors.

The report in the June 10 issue of Cancer Cell provides a new, “big picture” view of an overactive B cell receptor (BCR) signaling pathway that drives about one-third of the blood cancers known as Diffuse Large B-Cell Lymphomas (DLBCL), said Margaret Shipp, MD, chief of the Division of Hematologic Neoplasia and director of the Adult Lymphoma Program at Dana-Farber/Brigham and Women’s Cancer Center and the study's senior author.

“These results identify the components of the pathway that might make the most sense to target” in subsets of the BCR-driven lymphomas, she said.

Several drugs in clinical trials inhibit different molecules involved in BCR signaling, but a rational strategy has been lacking for how and when to use them in BCR-driven DLBCLs, Shipp explained. With insights from the new study, Shipp said, testing can be approached more rationally “rather than randomly testing inhibitors of multiple components of the pathway.” Importantly, the researchers pinpointed the critical survival molecules that prevent the cancer cells from undergoing apoptosis, or programmed cell death, which would normally destroy them.

DLBCL is the most common form of non-Hodgkin lymphoma, a diverse group of blood cancers that account for more than 19,000 deaths a year in the United States. About 60 percent of patients with DLBCL can be cured with current therapy – a combination of a monoclonal antibody and four drugs – while the remaining 40 percent are not, and have an unfavorable prognosis.

The growth and survival of B cells – infection-fighting white blood cells – are controlled by commands from the cell’s environment that stimulate B cell receptors on the cell surface. The signals are then transmitted “downstream” along the BCR pathway to the cell nucleus, where they activate genes that control when and how fast the cell grows. Shipp and colleagues previously found about one-third of DLBCL lymphomas are driven by overactive signaling in the BCR pathway that causes runaway cell growth, like a car with a jammed gas pedal. They labeled these DLBCL cancers “BCR-type.”

Signals move through a molecular pathway like water flowing downstream along branches and tributaries. BCR signals first activate an “upstream” chemical switch called SYK and subsequently trigger “downstream” pathway components, including PI3K/AKT and NF-κB. Drugs that inhibit SYK were shown to tamp down BCR signaling and cause DLBCL cells to die by apoptosis, and produced responses in some patients with BCR-type DLBCL in clinical trials. The promising outcomes prompted further clinical trials of multiple BCR pathway inhibitors,  Shipp said, but scientists “couldn’t put the data together in a way that looked at the entire pathway, to understand what was the most upstream point, what were the branch points, and how that would influence where you direct your efforts in targeted therapy.”

In the new study, Shipp and colleagues found that the molecular survival pathways are different in two types of BCR-dependent DLBCL cancers – those that have low versus high baseline activity of NF-κB, a family of proteins that controls cell growth and survival. This difference could point the way to separate drug targeting strategies for the two types of lymphomas.

The scientists discovered another clever survival trick in the BCR-driven lymphomas. The lymphoma cells need to ensure the health of their outer cell membrane, where the B cell receptors are anchored, so activation in the BCR pathway spurs the cells to make more cholesterol for maintaining the membrane. Shipp called it a “feed-forward” mechanism ensuring that the cells can continue to receive growth signals through the receptors.

In addition, the study found that genetic alterations in the lymphoma cells’ DNA that provide two different mechanisms of increasing BCR signaling and survival.

“The take-home is that these tumors have co-opted a survival pathway used by normal cells, and this group of BCR-driven DLBCL tumors seems to be selectively dependent on this pathway. This provides a rational framework to think about targeted therapies,” Shipp said.

First author is Linfeng Chen, PhD, of Dana-Farber. Other authors are from the Broad Institute, Brigham and Women’s Hospital, and the Mayo Clinic.

The research was supported by National Institutes of Health (P01CA092625) and the Leukemia & Lymphoma Society (SCOR 7391).

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