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 two preclinical 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.
Thesaurus Terms: 27e10 Antigen;Abscission;Advanced Glycation End Products;Advanced Glycosylation End Products;Adverse Effects;Age;Amphoterin;Animal Model;Animal Models And Related Studies;Animals;Anti-Cancer Agents;Anti-Inflammatories;Anti-Inflammatory Agents;Anti-Inflammatory;Antibodies;Anticoagulant Agents;Anticoagulant Drugs;Anticoagulants;Antiheparin Factor;Antiinflammatories;Antiinflammatory Agents;Antineoplastic Agents;Antineoplastic Drugs;Antineoplastics;Assay;Autocrine Systems;Bioassay;Biologic Assays;Biological Assay;Bizzozero's Corpuscle/Cell;Bleeding;Blood Circulation;Blood Platelet Factor Iv;Blood Platelets;Blood Monocyte;Blood Platelet Factor 4;Bloodstream;Breast Cancer;Cd62l Antigens;Cd62p Antigens;Calcium-Binding Myeloid Protein P8,14;Calgranulin;Calprotectin;Cancer Drug;Cancer Treatment;Cancers;Cause Of Death;Chemokine (C-X-C Motif) Ligand 4;Chromosomal Protein, Nonhistone, Hmg1;Chronic;Circulation;Clinical;Clinical Trials;Coagulants;Common Rat Strains;Deetjeen's Body;Disease;Disorder;Disseminated Malignant Neoplasm;Dose;Drugs;Enzymes;Ethers;Excision;Extirpation;Fm1 Gene Product;Factor 4;Family;Gmp-140;Generalized Growth;Glycans;Glycosaminoglycans;Growth;Hgf-Like Protein;Hmg-1;Hmg-1 Protein;Hmg1;Hmg3;Hmgb1 Protein;Hpse Protein;Hayem's Elementary Corpuscle;Hemorrhage;Heparanase-1;Heparin;Heparin Neutralizing Protein;Heparin-Binding Protein P30;Heparinic Acid;Heparinoids;High Mobility Group Box Protein 1;High Mobility Group Protein 1;High-Mobility Group (Nonhistone Chromosomal) Protein 1;High-Mobility Group Box 1;Human;Hyaluronic Acid;In Vitro;Injection Of Therapeutic Agent;Injections;Inorganic Sulfates;Intravenous;L-Selectin;L1 Antigen;Lam-1;Lam-1 Leukocyte Adhesion Molecule;Lecam-1;Lecam-3;Lmwh;Laboratories;Lead;Leu-8 Antigen;Leukocyte L1 Antigen Complex;Leukocyte L1 Protein;Lewis Lung Carcinoma;Ligands;Low-Molecular-Weight Heparin;Lung;Lung Respiratory System;Lymphatic;Lymphocyte Adhesion Molecule 1;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Marrow Monocyte;Marrow Platelet;Measures;Mediating;Medication;Mel-14 Antigen;Melanoma Cell;Metastasis;Metastasize;Metastatic Cancer;Metastatic Malignant Neoplasm;Metastatic Neoplasm;Metastatic Tumor;Methylation;Mice;Mice Mammals;Migratory Inhibitory Factor-Related Protein Mrp;Modeling;Modern Man;Mucopolysaccharides;Multiple Myeloma;Murine;Mus;Myelomonocytic Antigen L1;Neoplasm Metastasis;Neoplasms;Neoplastic Disease Chemotherapeutic Agents;Nonhistone Chromosomal Protein Hgm1;Osteolysis;P-Selectin;Prgf-2 Protein;Parents;Pathology;Patients;Pb Element;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Plasma-Cell Myeloma;Platelet Factor 4;Platelet Alpha-Granule Membrane Protein;Platelets;Platelets Reticuloendothelial System;Play;Polysaccharides;Population;Pre-Clinical Model;Preclinical Models;Prevention;Primary Neoplasm;Primary Tumor;Process;Protein Methylation;Ron Proto-Oncogene Product;Rat;Rats Mammals;Rattus;Receptor Protein;Recombinant Platelet Factor 4;Relative;Relative (Related Person);Removal;Role;Sbir;Sbirs (R43/44);Sbp-1;Safety;Scatter Factor 2;Secondary Neoplasm;Secondary Tumor;Selectins;Small Business Innovation Research;Small Business Innovation Research Grant;Small Inducible Cytokine B4;Small Inducible Cytokine Subfamily B, Member 4;Solid Neoplasm;Solid Tumor;Structure-Activity Relationship;Subcutaneous Injections;Sulfates;Sulfoglucuronyl Carbohydrate Binding Protein;Surgical Removal;Tq1 Antigen;Testing;Therapeutic;Thrombocytes;Thrombocytopenia;Thrombopenia;Time;Tissue Growth;Translating;Translations;Treatment Side Effects;Tumor Cell;Tumor Cell Migration;Tumor-Specific Treatment Agents;Unspecified Or Sulfate Ion Sulfates;Adhesion Receptor;Advanced Glycation Endproduct;Anticancer Agent;Anticancer Drug;Anticancer Therapy;Autocrine;Blood Loss;Blood Thinner;Bone;Cancer Care;Cancer Metastasis;Cancer Therapy;Chemical Structure Function;Clinical Investigation;Disease/Disorder;Drug/Agent;Gamma-Thromboglobulin;Heavy Metal Pb;Heavy Metal Lead;Heparan Sulphate Endoglycosidase;Heparanase;Hepatocyte Growth Factor-Like Protein;Implantation;Improved;In Vivo;Inhibitor;Inhibitor/Antagonist;Intravenous Injection;Macrophage Stimulating Protein;Malignancy;Malignant Breast Neoplasm;Malignant Breast Tumor;Model Organism;Monocyte;Mouse Model;Myeloma;Myelomatosis;Neoplasia;Neoplasm/Cancer;Neoplastic Cell;Neoplastic Growth;Novel;Ontogeny;Platelet Factor Iv;Pre-Clinical;Pre-Clinical Study;Pre-Clinical Trial;Preclinical;Preclinical Study;Preclinical Trial;Prevent;Preventing;Pulmonary;Receptor;Resection;Side Effect;Social Role;Structure Function Relationship;Subcutaneous;Sulfate;Sulfation;Therapy Adverse Effect;Thrombocyte/Platelet;Thrombopoiesis Inhibitor;Treatment Adverse Effect;Tumor;Tumor Cell Metastasis;Tumor Growth
