Novel Heparanase Inhibitors for Cancer Therapy

描述（由申请人提供）：Sanderson实验室的总体目标是确定硫酸乙酰肝素/乙酰肝素酶轴在调节癌症中的作用，并利用这些知识开发新的抗癌疗法。本项目的近期目标是设计和开发新型乙酰肝素酶抑制剂来治疗多发性骨髓瘤。乙酰肝素酶是一种切割硫酸乙酰肝素链的糖苷内切酶，在许多类型的癌症中上调并促进侵袭性肿瘤表型。许多骨髓瘤患者的骨髓中存在乙酰肝素酶，其中高水平的该酶与血管生成增强和预后不良相关。使用体内模型，我们还表明乙酰肝素酶是骨髓瘤生长、骨质溶解和转移的关键驱动因素。总之，这些研究将乙酰肝素酶确定为骨髓瘤治疗的可行靶点，并支持我们的假设，即乙酰肝素酶抑制剂将阻断骨髓瘤肿瘤的生长和进展。在初步的原理验证研究中，我们已经合成了一种化学修饰的非抗凝肝素，其在体外作为乙酰肝素酶活性和骨髓瘤肿瘤生长的有效抑制剂。本项目的目标是产生新的寡糖和乙酰肝素酶抗体抑制剂，这些抑制剂具有有利于其作为抗骨髓瘤药物开发的特性。为了实现这一目标，我们组建了一个由资深科学家组成的跨学科团队，他们具有碳水化合物化学（米兰Ronzoni研究所）、乙酰肝素酶生物学和酶学（海法Technion）、硫酸乙酰肝素/乙酰肝素酶在骨髓瘤（UAB）中的功能以及药理学和药物开发（俄亥俄州州立大学）的专业知识。目标1侧重于乙酰肝素酶活性的寡糖抑制剂的合理设计;目标2侧重于乙酰肝素酶结构和分子建模研究，这将增强寡糖抑制剂的合理设计;目标3，使用骨髓瘤的体内模型，将测试目标1中开发的候选药物的特性和功效，目标是将最有效的化合物推向临床试验。这些研究通过为骨髓瘤和其他癌症提供新的治疗方法，并通过提供有关乙酰肝素酶的新结构信息，将有助于揭示这种重要酶的作用机制，具有很大的影响力。

DESCRIPTION (provided by applicant): The overall goal of the Sanderson Lab is to determine the role of the heparan sulfate / heparanase axis in regulating cancer and to use this knowledge to develop new anti-cancer therapies. The immediate goal of this project is to design and develop novel heparanase inhibitors to treat multiple myeloma. Heparanase, an endoglycosidase that cleaves heparan sulfate chains, is upregulated in many types of cancers and promotes an aggressive tumor phenotype. Heparanase is present in the bone marrow of many myeloma patients where high levels of the enzyme correlate with enhanced angiogenesis and poor prognosis. Using in vivo models, we have also shown that heparanase is a key driver of myeloma growth, osteolysis and metastasis. Together, these studies identify heparanase as a viable target for myeloma therapy and support our hypothesis that inhibitors of heparanase will block myeloma tumor growth and progression. In preliminary proof-of-principle studies, we have synthesized a chemically modified, non-anticoagulant heparin that acts as a potent inhibitor of heparanase activity in vitro and myeloma tumor growth in vivo. The goal of this project is to generate novel oligosaccharide and antibody inhibitors of heparanase that have characteristics favorable for their development as anti-myeloma drugs. To accomplish this we have assembled an interdisciplinary team of senior scientists having expertise in carbohydrate chemistry (Ronzoni Institute, Milan), heparanase biology and enzymology (Technion, Haifa), heparan sulfate/heparanase function in myeloma (UAB) and pharmacology and drug development (Ohio State). Aim 1 focuses on rational design of oligosaccharide inhibitors of heparanase enzyme activity; Aim 2 focuses on heparanase structural and molecular modeling studies that will enhance rational design of oligosaccharide inhibitors; Aim 3, using in vivo models of myeloma, will test the characteristics and efficacy of drug candidates developed in aim 1 with the goal of moving the most efficacious compounds toward clinical trials. These studies have potential for high impact by delivering new therapeutics for myeloma and perhaps other cancers and by providing new structural information on heparanase that will help unravel the mechanism of action of this important enzyme.