Novel Glycosaminoglycan Ethers for Prevention of Metastasis

用于预防转移的新型糖胺聚糖醚

基本信息

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
项目类别：
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

项目摘要

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，并且它们有效地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，每日皮下注射肝素或类肝素可显着提高生存率。然而，长期服用抗凝肝素和类肝素可能产生的潜在副作用（包括出血）阻碍了其向临床癌症护理的转化。 GlycoMira 开发了一系列聚阴离子、代谢稳定的多糖，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-选择素以及抑制晚期糖基化终产物受体 (RAGE) 与其许多配体的相互作用。最近，我们观察到 SAGE 与类肝素一样，在预防转移性疾病方面可能具有重要的临床潜力。在静脉注射 B16 黑色素瘤细胞后第 28 天，对小鼠进行单次皮下注射 SAGE 可防止植入和肺转移。重要的是，在研究过程中，SAGE 治疗还大大提高了实验动物的存活率。在这项提案中，GlycoMira 将测试这样的假设：SAGE 可作为一种针对肿瘤转移的新型疗法，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生长的综合作用。以及肿瘤以自分泌方式分泌的 RAGE 配体的促进转移活性。 GlycoMira 已鉴定出几种先导化合物，这些化合物在临床前研究中显示出高度显着的 P-选择素和 RAGE 抑制活性，但与肝素相比，其抗凝血活性较低。此外，其中一种 SAGE 具有较大的治疗窗，即使单次注射 100 mg/kg 或每日 10 mg/kg 注射也显示出静脉注射安全性。在这个 I 期 SBIR 项目中，我们将通过以下三个具体目标确定使用皮下 SAGE 作为人类简单抗癌疗法的可行性：(1) 在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来确定安全性，以及 (3) 评估两种临床前转移模型对转移的抑制作用。公共卫生相关性：癌症是美国第二大死因，并且随着人口老龄化而变得越来越重要。大多数患者因癌症转移而死亡。有大量证据表明，硫酸多糖（例如肝素）可以通过阻断选择素介导的对肿瘤通过循环扩散至关重要的过程以及阻断肿瘤细胞的乙酰肝素酶活性来预防转移性癌症扩散。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合成的、低抗凝剂、硫酸化多糖方法来抑制肿瘤的转移扩散。