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Wednesday Afternoon Lecture Series (WALS) - Therapy of lymphoma inspired by functional and structural genomics

The NIH Director's Wednesday Afternoon Lecture Series, colloquially known as WALS, is the highest-profile lecture program at the NIH. Lectures occur on most Wednesdays from September through June from 3:00 to 4:00 p.m. in Masur Auditorium, Building 10 on the NIH Bethesda campus.

Each season includes some of the biggest names in biomedical and behavioral research. The goal of the WALS is to keep NIH researchers abreast of the latest and most important research in the United States and beyond. An added treat is the annual J. Edward Rall Cultural Lecture, which features top authors and other cultural icons. All speakers are nominated by the NIH community.

Speaker: Louis M. Staudt, M.D., Ph.D.

Dr. Staudt's laboratory uses genomic technologies to discover molecular subtypes of cancer and develop therapies that target oncogenic regulatory pathways in each subtype. This endeavor is now commonly known as precision medicine and is the direct fruit of the Human Genome Project.

The Staudt laboratory has designed the "Lymphochip," a custom DNA microarray that profiles gene expression in normal lymphocytes as well as in malignant lymphomas and leukemias. His laboratory defined two dominant molecular subtypes of the most common form of non-Hodgkin lymphoma–diffuse large B-cell lymphoma (DLBCL)—and showed that they arise from distinct stages of normal B-cell differentiation, utilize different oncogenic mechanisms, and respond differently to therapy. These subtypes, termed activated B-cell-like (ABC) and germinal center B-cell-like (GCB), are now recognized as distinct diseases. The laboratory has used functional genomics methods (RNAi and CRISPR-Cas9 screens) and structural genomics methods (e.g. cancer gene resequencing) to identify essential regulatory pathways that drive the malignant proliferation and survival of these lymphomas, thereby identifying potential therapeutic targets. For ABC DLBCL, the Staudt laboratory defined a “chronic active” form of B-cell receptor (BCR) signaling that activates the pro-survival NF-kB pathway. Over one fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR, which augment BCR signaling. To attack chronic active BCR signaling therapeutically, the Staudt laboratory initiated clinical trials in relapsed/refractory DLBCL of ibrutinib, a drug used to treat B-cell cancers. Ibrutinib is an irreversible and highly selective inhibitor of the BTK, a key kinase that is required for BCR-dependent NF-kB activation. Monotherapy with ibrutinib induced a high rate of complete and partial responses in ABC DLBCL, while GCB DLBCL tumors rarely responded. When the tumors were genomically analyzed, the scientists found that patients with mutations in the BCR together with mutations in the signaling adapter MYD88 had the highest response rate. This clinical observation led Dr. Staudt's laboratory to delineate molecular mechanisms by which MYD88 augments BCR-dependent NF-kB activation. Based on this knowledge, Dr. Staudt has recently conducted clinical studies in primary central nervous system lymphoma, an aggressive cancer with an ABC gene expression profile and very frequent mutations in the BCR and MYD88. For his lecture, Dr. Staudt will present encouraging responses to ibrutinib alone and in combination with chemotherapy in patients with relapsed and refractory disease.