Novel Glycosaminoglycan Ethers for Prevention of Metastasis
DESCRIPTION (provided by applicant): Heparin and its derivatives block P- and L-selectin mediated metastatic spread of cancer in animal models, and they potently inhibit the matrix degrading enzyme heparanase. Moreover, several large clinical trials performed with heparin or low molecular weight heparin have shown that survival is significantly improved by daily subcutaneous administration of heparin or heparinoids. Nevertheless, translation into clinical cancer care has been stymied by potential side effects, including hemorrhage, from chronic administration of anticoagulant heparin and heparinoids. GlycoMira has developed a family of polyanionic, metabolically stabilized polysaccharides, the semi- synthetic glycosaminoglycan ethers (SAGEs). These new drugs have broad anti-inflammatory activities, including inhibition of the platelet adhesion receptor P-selectin and inhibition of the interaction of the Receptor for Advanced Glycation End-products (RAGE) with its many ligands. Recently, we observed that SAGEs, like heparinoids, may have important clinical potential in preventing metastatic disease. A single subcutaneous injection of a SAGE in mice prevents implantation and lung metastasis at Day 28 after intravenous injection of B16 melanoma cells. Importantly, the SAGE treatment also substantially improves survival of experimental animals over the time course of the study. In this proposal, GlycoMira will test the hypothesis that SAGEs can be used as a novel therapy against tumor metastasis by the combined actions of inhibiting selectin-mediated attachment of platelets and monocytes to circulating tumor cells, by inhibiting heparanase, and by inhibiting the growth- and metastasis-promoting activities of ligands for RAGE secreted in autocrine fashion by tumors.GlycoMira has identified several lead compounds that show highly significant P-selectin- and RAGE-inhibiting activities in pre-clinical studies, yet have low anti-coagulant activities compared to heparin. Moreover, one of these SAGEs has a large therapeutic window, showing intravenous safety even as high as 100 mg/kg single injection or daily 10 mg/kg injections. In this Phase I SBIR project, we will establish the feasibility of using subcutaneous SAGEs as simple anti-cancer therapies in humans in three Specific Aims by (1) examining key compounds in vitro for P-selectin, L-selectin, and heparanase inhibition, (2) determining safety by measuring anticoagulant and heparin-induced thrombocytopenia activities, and (3) evaluating inhibition of metastasis in twopreclinical metastasis models. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of death in the U.S. and is growing in importance as the population ages. Most patients die from cancer because of metastasis. There is abundant evidence that sulfated polysaccharides such as heparin can prevent metastatic cancer spread by blocking selectin-mediated processes important in tumor spread through the circulation, and by blocking heparanase activity of tumor cells. However, heparin has not been employed to prevent metastasis, largely because it is an anticoagulant and might be associated with bleeding complications. We propose to develop anionic, partially lipophilic hyaluronic acid derivatives as a synthetic, low anticoagulant, sulfated polysaccharide approach to inhibiting metastatic spread from neoplasms.
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