A New Therapeutic Target for Diffuse
Large B Cell Lymphoma?

The bcl-6 protein is a transcriptional repressor whose normal function contributes to germinal center formation. Mutations in the bcl-6 gene have been frequently reported in DLBCL. The role of these mutations in lymphomagenesis is unknown, and the effect of these mutations on prognosis is controversial.

Clarification on this issue is provided at today’s Scientific Plenary Session. Dr. Jose Polo from the Albert Einstein College of Medicine, in collaboration with investigators from The University of Toronto and the Mount Sinai School of Medicine, present data which implicate the bcl-6 protein as a critical factor for lymphoma growth in bcl-6 expressing cell lines and in tumor xenograft models. Their work focused on the N terminal domain of the protein, a region termed BTB. They found several bcl-6 co-repressors acted by binding to specific sequences in the BTB domain. They then engineered small molecule inhibitors of this domain, called BTB peptide inhibitors (BPI). BPI administered to cells in culture was able to penetrate cells, localize to the nucleus, and specifically inhibit the interaction between bcl-6 protein and its co-repressors. BPI administered to mice reproduced the phenotype of bcl-6 negative mice, unable to form normal germinal centers in response to T cell antigens. To investigate the role of bcl-6 in DLBCL, cell lines were treated with BPI. Growth arrest and apoptosis were demonstrated in the bcl-6 positive cells, while they were not observed in the bcl-6 negative cells. Impressively, BPI administered to human DLBCL xenotransplants completely suppressed growth of the tumors without any demonstrable toxicity to normal organs. These experiments strongly implicate the bcl-6 gene product as a key protein and as a therapeutic target in some DLBCL subtypes.

For those of you wishing to hear more about the latest in diffuse large B cell lymphoma, plan to attend the Diffuse Aggressive Lymphoma Education Session today at 9:45 a.m. Dr. Richard Fisher, Chairman of the Southwest Oncology Group Lymphoma Committee, will provide an update on the state of treatment for advanced stage DLBCL. In his session, he reviews the data supporting the addition of rituximab to CHOP chemotherapy for older and younger patients. R-CHOP is the new standard against which newer strategies must be measured. Despite the improvements realized with the addition of rituximab, a substantial proportion of patients continue to die from this disease, and further improvements are needed. Strategies examining dose intensification and up-front autologous stem cell transplantation are also discussed. Dr. Thomas Miller discusses the treatment of limited stage DLBCL in this session. This was an area which seemed fairly cut-and-dried a few years ago, but updated data from SWOG, from ECOG, and new data from the GELA have raised new questions regarding the optimal treatment of these patients. Risk stratification is a concept readily applied to other diseases (AML for example) and needs to be incorporated into our thinking about limited stage DLBCL. Dr. Miller outlines an approach for risk stratification that can be used in current practice as well as form the basis for future trial design. The final speaker, Dr. Owen O’Connor, discusses treatment strategies for mantle cell lymphoma. Mantle cell is a particularly problematic lymphoma subtype for which no standard initial therapy exists. Proteasome inhibition is showing promise for relapsed mantle cell lymphoma in ongoing phase II studies, and Dr. O’Connor discusses the rationale for the use of bortezomib in this disease as well as other emerging strategies.