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Study Paves Way for Rational Drug Targeting of B-cell Lymphomas

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Key Points

  • Researchers found that the molecular survival pathways are different in two types of B-cell receptor–dependent diffuse large B-cell lymphomas—those that have low vs high baseline activity of nuclear factor–kappaB.
  • Activation in the B-cell receptor pathway spurs the lymphoma cancer cells to make more cholesterol for maintaining the outer cell membrane, which ensures that the cells can continue to receive growth signals through the receptors.
  • The findings may help researchers develop targeted therapies for this group of B-cell receptor–driven lymphomas.

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. The report, published in the June 10 issue of Cancer Cellprovides a new, “big picture” view of an overactive B-cell receptor signaling pathway that drives about one-third of diffuse large B-cell lymphomas, 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 senior author of the study.

“These results identify the components of the pathway that might make the most sense to target” in subsets of the B-cell receptor–driven lymphomas, Dr. Shipp said.

B-cell Receptor–driven Lymphoma

Several drugs in clinical trials inhibit different molecules involved in B-cell receptor signaling, but a rational strategy has been lacking for how and when to use them in B-cell receptor–driven diffuse large B-cell lymphomas, Dr. Shipp explained. With insights from the new study, she 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.

Dr. Shipp and colleagues previously found that about one-third of diffuse large B-cell lymphomas are driven by overactive signaling in the B-cell receptor pathway that causes runaway cell growth.

Potential for Targeted Therapy

In the new study, the researchers found that the molecular survival pathways are different in two types of B-cell receptor–dependent diffuse large B-cell lymphomas—those that have low vs high baseline activity of nuclear factor–kappaB, 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 survival trick in the B-cell receptor–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 B-cell receptor pathway spurs the cells to make more cholesterol for maintaining the membrane. Dr. 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 B-cell receptor signaling and survival.

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

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

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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