Novel Glycosaminoglycan Ethers for Prevention of Metastasis

用于预防转移的新型糖胺聚糖醚

• 批准号: 8121926
• 负责人: THOMAS PRESTON KENNEDY
• 金额: $ 21万
• 依托单位: GLYCOMIRA, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121926
• 关键词: Advanced Glycosylation End Products; Adverse effects; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Anticoagulants; Antineoplastic Agents; Biological Assay; Blood Circulation; Blood Platelets; Cause of Death; Chronic; Clinical; Clinical Trials; Coagulants; Disease; Disseminated Malignant Neoplasm; Dose; Enzymes; Ethers; Excision; Family; Glycosaminoglycans; Growth; HMGB1 Protein; Hemorrhage; Heparin; Heparinoids; Human; Hyaluronic Acid; In Vitro; Injection of therapeutic agent; Inorganic Sulfates; Intravenous; L-Selectin; Laboratories; Lead; Leukocyte L1 Antigen Complex; Lewis Lung Carcinoma; Ligands; Low-Molecular-Weight Heparin; Lung; Lymphatic; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Methylation; Modeling; Multiple Myeloma; Mus; Neoplasm Metastasis; Neoplasms; Osteolysis; P-Selectin; Parents; Pathology; Patients; Pharmaceutical Preparations; Phase; Platelet Factor 4; Play; Polysaccharides; Population; Pre-Clinical Model; Prevention; Primary Neoplasm; Process; Rattus; Relative (related person); Role; Safety; Selectins; Small Business Innovation Research Grant; Solid Neoplasm; Structure-Activity Relationship; Subcutaneous Injections; Testing; Therapeutic; Thrombocytopenia; Time; Translating; Translations; Unspecified or Sulfate Ion Sulfates; adhesion receptor; autocrine; bone; cancer care; cancer therapy; heparanase; implantation; improved; in vivo; inhibitor/antagonist; intravenous injection; macrophage stimulating protein; malignant breast neoplasm; monocyte; mouse model; neoplastic cell; novel; pre-clinical; preclinical study; prevent; receptor; subcutaneous; sulfation; tumor; tumor growth

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 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.

描述（由申请人提供）：肝素及其衍生物在动物模型中阻断P-和L-选择素介导的癌症转移性扩散，并有效抑制基质降解酶乙酰肝素酶。此外，用肝素或低分子量肝素进行的几项大型临床试验表明，每日皮下施用肝素或类肝素可显著改善存活率。然而，转化为临床癌症护理一直受到潜在副作用的阻碍，包括长期给予抗凝肝素和类肝素引起的出血。 GlycoMira开发了一个多阴离子代谢稳定的多糖家族，即半合成糖胺聚糖醚（SAGE）。这些新药具有广泛的抗炎活性，包括抑制血小板粘附受体P-选择素和抑制晚期糖基化终产物受体（RECEPTOR for Advanced Glycation End-products，RECEPTOR）与其许多配体的相互作用。最近，我们观察到SAGE，像类肝素一样，可能在预防转移性疾病方面具有重要的临床潜力。在小鼠中单次皮下注射SAGE防止在静脉内注射B16黑素瘤细胞后第28天的植入和肺转移。重要的是，SAGE治疗还显著改善了实验动物在研究过程中的存活率。在该提案中，GlycoMira将测试SAGE可用作抗肿瘤转移的新疗法的假设，该疗法通过抑制选择素介导的血小板和单核细胞与循环肿瘤细胞的附着、抑制乙酰肝素酶以及抑制肿瘤以自分泌方式分泌的血小板的配体的生长和转移促进活性的组合作用。GlycoMira已经鉴定出几种先导化合物，其在临床前研究中显示出高度显著的P-选择素和RAGE抑制活性，但与肝素相比具有较低的抗凝活性。此外，这些SAGE之一具有大的治疗窗，显示静脉内安全性，甚至高达100 mg/kg单次注射或每日10 mg/kg注射。在该I期SBIR项目中，我们将通过以下三个特定目的确定使用皮下SAGE作为人体简单抗癌疗法的可行性：（1）体外检查关键化合物对P-选择素、L-选择素和乙酰肝素酶的抑制作用，（2）通过测量抗凝剂和肝素诱导的血小板减少活性确定安全性，以及（3）在两种临床前转移模型中评价转移抑制作用。 公共卫生相关性：癌症是美国第二大死亡原因，随着人口老龄化，其重要性越来越大。大多数患者死于癌症，因为转移。有大量证据表明，硫酸化多糖如肝素可以通过阻断选择素介导的在肿瘤通过循环扩散中重要的过程以及通过阻断肿瘤细胞的乙酰肝素酶活性来防止转移性癌症扩散。然而，肝素尚未用于预防转移，主要是因为它是一种抗凝剂，可能与出血并发症有关。我们建议开发阴离子，部分亲脂性透明质酸衍生物作为一种合成的，低抗凝血，硫酸多糖的方法来抑制肿瘤的转移扩散。