Novel Therapeutic Leads from Non-anticoagulant Heparin Derivatives That Block Galectin-3-mediated Cancer Metastasis

Cancer cell metastatic spread to secondary tumour sites is the main reason for cancer-associated mortality. Our recent studies have shown that a small protein called galectin-3 whose concentration is highly increased in the blood circulation of cancer patients plays a very important role in promoting cancer cell spreading. Galectin-3 binds to cancer cells and increases the likelihood that any cancer cells released into the circulation will seed at distant organs and develop into secondary tumours. Therapeutic agents that can inhibit this action of galectin-3 therefore have considerable potential to prevent cancer spread and improve chances of survival. We have evidence showing that chemical modification of certain naturally-accurring glycan compounds can inhibit this effects of galectin-3 on cancer cell spread in the laboratory. The unmodified forms of those compounds are widely used in clinic as blood thinning agents to prevent clotting but our modificcations block these anti-clotting effects thus considerably increasing the likely safety of these compounds if used long term. This study aims to identify small fractions of these specific glycan compounds that have particular efficancy against galectin-3-mediated cancer cell spread. This will lay the foundation for identification of 1 or 2 lead compounds for subsequent clinical trials in cancer patients. The galectin-3 inhibitors developed from such a strategy could be useful for the treatment of most cancer types during several cancer stages.

Blood-borne metastasis is the main reason for cancer mortality. We have identified a new therapeutic target based on the metastasis-promoting interaction between the circulating galactoside-binding protein, galectin-3, and cancer cells. Galectin-3 binds the oncofetal Gala1,3GalNAc- (TF) carbohydrate antigen that is commonly over-expressed on cancer cell surface molecules, including the large transmembrane mucin MUC1. Galectin-3 promotes metastasis by enhancing disseminating cancer cell adhesion to vascular endothelium and by inducing homotypic aggregation of cancer cells to form microemboli. Galectin-3 induces clustering of cell surface MUC1 with consequent exposure of underlying adhesion molecules but also causes substantial MUC1-independent stimulation of adhesion and enhances invasion. Agents that can inhibit these interactions therefore have potential as novel metastasis inhibitors to improve patient survival. We have preliminary data showing that certain non-anticoagulant chemically-modified heparin derivatives can potently inhibit the galectin-3-ligand interaction and block galectin-3-mediated cancer-endothelial adhesion. The proposed studies will identify optimised fractions of these specific heparin derivatives that have particular efficacy, using a focussed screening program testing in vitro and in vivo activity against galectin-3-mediated cancer cell invasion and metastasis, and thus identify lead compounds for taking forward to clinical trials.