Novel Glycosaminoglycan Ethers for Prevention of Metastasis

描述（由申请人提供）：在动物模型中，肝素及其衍生物阻断P-和l -选择素介导的癌症转移扩散，它们有效地抑制基质降解酶肝素酶。此外，几项使用肝素或低分子量肝素进行的大型临床试验表明，每日皮下给药肝素或类肝素可显著提高生存率。然而，长期服用抗凝肝素和类肝素可能产生的副作用（包括出血）阻碍了将其转化为临床癌症治疗。GlycoMira开发了一个多阴离子，代谢稳定的多糖家族，半合成糖胺聚糖醚（SAGEs）。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（RAGE）与其许多配体的相互作用。最近，我们观察到SAGEs，像肝素一样，可能在预防转移性疾病方面具有重要的临床潜力。单次皮下注射SAGE可阻止静脉注射B16黑色素瘤细胞后28天的植入和肺转移。重要的是，SAGE治疗也显著提高了实验动物在研究过程中的存活率。在这一提议中，GlycoMira将测试SAGEs可以作为一种新的治疗肿瘤转移的假设，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，抑制肝素酶，抑制肿瘤以自分泌方式分泌的RAGE配体的生长和转移促进活性。GlycoMira已经确定了几种先导化合物，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，抗凝血活性较低。此外，其中一种SAGEs具有较大的治疗窗口，静脉注射安全性甚至高达100 mg/kg单次注射或10 mg/kg每日注射。在这个I期SBIR项目中，我们将通过以下三个特定目的来确定皮下sage作为人类简单抗癌疗法的可行性：(1)在体外检测关键化合物的p选择素、l选择素和肝素酶抑制作用；(2)通过测量抗凝血和肝素诱导的血小板减少活性来确定安全性；(3)在两种临床前转移模型中评估其对转移的抑制作用。

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.