Novel Glycosaminoglycan Ethers for Prevention of Metastasis

说明(申请人提供)：肝素及其衍生物在动物模型中阻断P-和L-选择素介导的肿瘤转移，并有效抑制基质降解酶乙酰肝素酶。此外，几项使用肝素或低分子肝素进行的大型临床试验表明，每天皮下注射肝素或类肝素可显著提高存活率。然而，由于长期使用抗凝剂肝素和肝素类药物可能产生的副作用，包括出血，阻碍了将其转化为临床癌症治疗。GlycoMira已经开发出一种多阴离子、代谢稳定的多糖家族，即半合成糖胺聚糖醚(SAGS)。这些新药具有广泛的抗炎活性，包括抑制血小板黏附受体P-选择素和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，我们观察到鼠尾草和肝素一样，可能在预防转移性疾病方面具有重要的临床潜力。静脉注射B16黑色素瘤细胞后第28天，一次性皮下注射鼠尾草可防止植入和肺转移。重要的是，在研究过程中，SAGE治疗还显著提高了实验动物的存活率。在这项建议中，GlycoMira将验证SAGES可用于抗肿瘤转移的新疗法的假设，其方法是通过抑制选择素介导的血小板和单核细胞与循环中的肿瘤细胞的附着、抑制乙酰肝素酶以及抑制肿瘤以自分泌方式分泌的RAGE的配体的生长和转移促进活性的组合作用。GlycoMira已经确定了几种在临床前研究中显示出非常显著的P-选择素和RAGE抑制活性的先导化合物，但与肝素相比，它们的抗凝活性较低。此外，其中一种鼠尾草具有很大的治疗窗口，即使单次注射或每日注射10 mg/kg，静脉安全性也高达100 mg/kg。在这个第一阶段的SBIR项目中，我们将在三个特定目标下确定将SAGE用作简单的人类抗癌治疗的可行性：(1)检测关键化合物的体外P-选择素、L-选择素和肝素酶抑制作用，(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)在两个临床前转移模型中评估对转移的抑制。 与公共健康相关：癌症是美国第二大死亡原因，随着人口老龄化，癌症的重要性越来越大。大多数患者死于癌症是因为转移。有大量证据表明，肝素等硫酸多糖可以通过阻断在肿瘤循环中至关重要的选择素介导的过程，以及通过阻断肿瘤细胞的乙酰肝素酶活性来防止转移癌的扩散。然而，肝素没有被用于预防转移，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，部分亲脂的透明质酸衍生物作为一种合成的，低抗凝血剂，硫酸多糖的方法来抑制肿瘤的转移扩散。

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.