Targeting CXCR4 with Cell-Penetrating Pepducins Enhances Survival in Disseminated Lymphoma

Abstract 4244

The G-protein coupled receptor, CXCR4, which normally regulates interactions between stroma and hematopoietic stem cells in the bone marrow, is highly expressed on a variety of malignant hematological cells, such as lymphoma and lymphocytic leukemia cells. A new treatment concept has arisen that CXCR4 may be an effective therapeutic target as an adjunct to standard clinical treatments of hematologic malignancies. In this study we developed novel cell-penetrating lipopeptide antagonists of CXCR4, called pepducins, to interdict signaling to intracellular G-proteins in response to the CXCR4 ligand, SDF-1. We demonstrated that pepducins targeting the first (i1) or third (i3) intracellular loop of CXCR4 completely abrogated SDF-1-mediated chemotaxis of lymphocytic leukemia and lymphoma cell lines, as well as primary cells isolated from patients with chronic lymphocytic leukemia. Pepducins enhanced apoptotic cell death in lymphoma and primary leukemia cells when used in combination with the CD20-targeted antibody, rituximab. Furthermore, pepducin treatment significantly increased survival both as monotherapy and in combination with rituximab in mice with disseminated lymphoma. Together, these data demonstrate that CXCR4/SDF-1 signaling is effectively inhibited by cell-penetrating pepducins, suggesting that these lipopeptide antagonists may represent a potentially new treatment strategy for lymphoid malignancies.