Gangliosides

Abstract

Gangliosides are acidic glycosphingolipids that are expressed on the cell surface where they may play a role in the metastatic process and have proven to be uniquely potent targets for antibody-mediated immune attack using cancer vaccines or monoclonal antibodies. Five gangliosides are important targets for cancer therapy: GM2, GD2, and GD3 expressed primarily on tumors of neuroectodermal origin such as neuroblastomas, sarcomas, and melanomas; fucosyl GM1 expressed on small-cell lung cancers; and sialyl Lewisa (Lea), also known as CA19.9, expressed on cancers of the colon, pancreas, and breast. Vaccines and especially monoclonal antibodies targeting GD2, GD3, and sLea are able to prevent tumor establishment or slow tumor growth in preclinical models, but regression of visible or palpable tumors has proven more difficult. Recently, this has proven possible with radioimmune or antibody drug conjugates targeting sLea. These types of monoclonal antibody conjugates may represent the future of ganglioside-targeted therapy. Randomized clinical trials with vaccines targeting GM2, GD2, and GD3 gangliosides have been negative to date. However, randomized clinical trials with monoclonal antibodies targeting GD2 (UnituxinTM) in neuroblastoma patients have been positive, and UnituxinTM is now FDA approved for treatment of high-risk neuroblastoma patients. Radioimmune or antibody drug conjugates targeting gangliosides have not yet been tested in the clinic.