New Combination Therapy Proves Highly Effective against non-Hodgkin's Lymphoma Cells
November 5, 2010
Research from the laboratory of Ari M. Melnick, MD, Division of Hematology and Medical Oncology, has resulted in a promising new combinatorial therapy for diffuse large B cell lymphoma, an aggressive and rapidly progressive cancer that affects approximately 21,000 new people each year. This research, published in The Journal of Clinical Investigation, may hold significant implications for patient survival rates.
Diffuse large B cell lymphoma (DLBCL), a non-Hodgkin's lymphoma, accounts for approximately 40 percent of adult lymphoma cases. Left untreated, the disease is fatal, but approximately 60 percent of cases are curable with cytotoxic chemotherapy combined with monoclonal antibody immunotherapy. Dr. Melnick's research focuses on developing new treatments that are both more effective and less toxic to the patient. His latest study, performed in vitro and in human xenografts in mice, focused on the lymphoma oncogene BCL6.
BCL6 is a gene involved in modulating the response of a class of white blood cells known as B cells, one of the numerous cells deployed by the human immune system to fight infections. A mutation of BCL6 is implicated in at least 70 percent of DLBCL cases. A 2009 study from Dr. Melnick's group first showed that a protein called RI-BPI is highly effective at disabling the mutated gene and eradicating lymphoma cells, but its mechanism of action remained unclear until the current study. In the current paper, Dr. Melnick and his colleagues show that the BCL6 oncogene works by triggering a cascade of molecular events - activating certain cellular proteins and turning off others - that together form a tight wall of defense around a lymphoma cell. RI-BPI reverses some of those molecular events, effectively destabilizing the oncogene by disarming its molecular arsenal. Furthermore, the investigators showed that the effectiveness of RI-BPI is multiplied when combined with other agents that target other proteins along the BCL6 molecular pathway.
Not only is the new, combinatorial therapy a far more powerful weapon against DLBCL cells, it is also far gentler on healthy tissue than chemotherapy and has fewer side effects than treatment with monoclonal antibodies. Because their survival does not depend on the proteins targeted by the new therapy, healthy cells are largely unaffected by it. Dr. Melnick's findings also suggest that, though its mutated form is an oncogene, the normal form of BCL6 may actually play the opposite role - protecting B cells from becoming cancerous. This discovery may also help fuel future investigations.
The study was supported by the Leukemia and Lymphoma Society and the Chemotherapy Foundation. The investigators hope to begin clinical trials in the near future.
Click here to read the research paper.