Novel Heparanase Inhibitors for Cancer Therapy

描述(申请人提供)：桑德森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，并利用这一知识开发新的抗癌疗法。该项目的近期目标是设计和开发治疗多发性骨髓瘤的新型肝素酶抑制剂。乙酰肝素酶是一种内切糖苷酶，可以裂解硫酸乙酰肝素链，在许多类型的癌症中表达上调，并促进侵袭性肿瘤的表型。肝素酶存在于许多骨髓瘤患者的骨髓中，这种酶的高水平与血管生成增强和预后不良相关。利用体内模型，我们还表明，肝素酶是骨髓瘤生长、骨溶解和转移的关键驱动因素。总之，这些研究确定了肝素酶是骨髓瘤治疗的可行靶点，并支持了我们的假设，即肝素酶抑制剂将阻止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经过化学修饰的非抗凝剂肝素，它在体外可以有效地抑制肝素酶的活性，在体内可以抑制骨髓瘤的生长。本项目的目标是开发新的低聚糖和乙酰肝素酶抗体抑制剂，使其具有抗骨髓瘤药物的特性。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，他们拥有碳水化合物化学(米兰Ronzoni研究所)、乙酰肝素酶生物学和酶学(Technion，Haifa)、骨髓瘤中硫酸肝素/肝素酶功能(UAB)以及药理学和药物开发(俄亥俄州立大学)方面的专业知识。目的1侧重于乙酰肝素酶活性低聚糖抑制剂的合理设计；目的2侧重于乙酰肝素酶结构和分子模拟研究，以加强低聚糖抑制剂的合理设计；目的3，利用骨髓瘤的体内模型，将测试在目标1中开发的候选药物的特性和有效性，目的是将最有效的化合物转移到临床试验。这些研究提供了治疗骨髓瘤和其他癌症的新疗法，并提供了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，因此这些研究有可能产生重大影响。 与公共健康相关：乙酰肝素酶是一种由癌细胞产生的蛋白质，它在帮助癌细胞生长和在体内扩散方面发挥着重要作用。该项目旨在开发新药，以阻断肝素酶的功能，从而阻止肿瘤的生长和转移。

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. PUBLIC HEALTH RELEVANCE: Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to develop new drugs that will block the function of heparanase and thereby block tumor growth and metastasis.