A significant number of patients with non-Hodgkin's lymphoma have poor clinical outcomes because their cancer cells have become resistant to immunochemotherapy. Scientists at Roswell Park Cancer Institute hope to improve those outcomes by identifying the pathways that lymphoma cells develop to evade immunochemotherapy - and by developing novel therapeutic strategies to shut those pathways down.

Obatoclax, a novel targeted cancer therapy , is capable of inducing two forms of cell death in B cell non-Hodgkin's lymphoma (B-NHL) cells and appears to have the potential to overcome acquired resistance to chemotherapeutic agents, according to a study conducted by Francisco J. Hernandez-Ilizaliturri, MD, Departments of Medicine and Immunology, RPCI. The research will be presented at the 2008 annual meeting of the American Society of Hematology, December 6-9, San Francisco, CA.

B cell non-Hodgkin's lymphoma, a cancer of the cells of the lymph system, makes up about 85% of NHL cases diagnosed in the United States. The Bcl-2 family is a group of proteins known to affect patient outcomes and is involved in development, sustaining and progression of various subtypes of NHL. Dr. Hernandez-Ilizaliturri and colleagues examined the molecular mechanisms of Obatoclax, a targeted therapy, which is designed to inhibit several members of the Bcl-2 protein family.

Studies were conducted in various rituximab-chemotherapy-sensitive or resistant B-cell lymphoma cell lines and in tumor cells isolated from 25 patients with different subtypes of B cell lymphomas and Hodgkin's disease.

Dr Hernandez-Ilizaliturri and his group of investigators demonstrated that Obatoclax is a potent inhibitor of Bcl-2 family proteins, has significant anti-tumor activity against various rituximab-chemotherapy-sensitive or -resistant lymphoma cell lines, as well as in malignant B-cells derived from patients with diffuse large B cell lymphomas (DLBCL). In addition, they found that Obatoclax can enhance the biological activity of rituximab in vitro and sensitize NHL cells to the cytotoxic effects of a wide spectrum of chemotherapy agents. Scientist observed several signal events in NHL cells exposed to Obataclox, suggesting that this novel compound has a dual mechanism of action and is capable of inducing cell death (apoptosis) and/or cell self-degradation (autophagy) in B-NHL cell lines and can potentially be utilized to characterize shared pathways that regulate apoptosis, autophagy and possible necrosis within a given lymphomatous tumor.

"As this class of agents moves forward in the treatment of hematological malignancies, the clinical optimization of Obatoclax and its incorporation into already available rituximab-chemotherapy regimens will likely be the result of translational research aimed at characterizing the molecular apoptotic and non-apoptotic (autophagy) pathways responsible for its anti-tumor activity" said Dr. Hernandez-Ilizaliturri.

Roswell Park Cancer Institute, founded in 1898, is the nation's first cancer research, treatment and education center. The Institute was one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation's leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs.

Roswell Park Cancer Institute