Heparanase Regulation of Myeloma Metastasis: Mechanism and 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。该项目的直接目标是使用多发性骨髓瘤作为模型癌症来定义乙酰肝素酶对转移级联的调节。骨髓瘤是一种破坏性的癌症，在骨髓中生长并扩散到整个骨骼，导致患者严重疼痛，生活质量差，最终死亡。虽然这种癌症的转移性导致患者死亡，但不幸的是，骨髓瘤转移的调节机制尚不清楚。改善患者治疗的关键在于发展对骨髓瘤转移机制的理解，并测试新的抑制剂来阻断肿瘤扩散。使用体内模型，我们已经表明硫酸乙酰肝素降解酶乙酰肝素酶是骨髓瘤生长、血管生成、骨质溶解和转移的关键驱动因素。重要的是，我们还发现酶活性乙酰肝素酶存在于骨髓瘤患者的骨髓中，并且与患者预后不良相关。来自我们实验室的惊人的新数据表明，乙酰肝素酶通过上调包括VEGF、MMP-9和uPA/uPAR在内的几种基因的表达，作为骨髓瘤转移的主要调节因子，这些基因协同作用以驱动转移。我们假设，乙酰肝素酶作为骨髓瘤转移的关键介质，通过促进肿瘤细胞在原发肿瘤部位的初始内渗到血液中，并通过在骨中准备转移前的小生境，促进肿瘤细胞归巢和生长。鉴于这两个关键功能的转移，我们进一步假设，乙酰肝素酶抑制剂与其他抗骨髓瘤化合物的组合将提供一种新的和有效的治疗方法，这种致命的疾病。目的1将研究乙酰肝素酶在驱动骨髓瘤转移中的重要性，乙酰肝素酶发挥其作用的转移阶段以及乙酰肝素酶对在骨髓中建立转移前小生境的影响。目的2将测试一种新的乙酰肝素酶抑制剂在作为单一药剂或与地塞米松组合施用时的体内抗转移作用。乙酰肝素酶是一种由癌细胞产生的蛋白质，在帮助癌细胞生长和扩散到全身方面起着重要作用。该项目旨在揭示乙酰肝素酶的功能，并测试一种新的抗乙酰肝素酶药物，以确定它是否可以阻止癌症的扩散。

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 define heparanase regulation of the metastatic cascade using multiple myeloma as a model cancer. Myeloma is a devastating cancer that thrives in the bone marrow and disseminates throughout the skeleton leading to severe pain, poor quality of life and eventual death of the patient. Although it is the metastatic nature of this cancer that kills patients, unfortunately, the mechanisms regulating metastasis in myeloma are unknown. The key to improving patient treatment lies in developing a mechanistic understanding of myeloma metastasis and testing new inhibitors to block tumor dissemination. Using in vivo models, we have shown that the heparan sulfate degrading enzyme heparanase is a key driver of myeloma growth, angiogenesis, osteolysis and metastasis. Importantly, we also discovered that enzymatically active heparanase is present within the bone marrow of myeloma patients and it correlates with poor patient prognosis. Striking new data from our lab indicates that heparanase acts as a master regulator of metastasis in myeloma by upregulating expression of several genes including VEGF, MMP-9 and uPA/uPAR that work in concert to drive metastasis. We hypothesize that heparanase acts as a key mediator of myeloma metastasis by promoting initial intravasation of tumor cells into the blood at the primary tumor site and by preparing pre-metastatic niches in bone that facilitate tumor cell homing and growth. Given these two critical functions in metastasis, we further hypothesize that heparanase inhibitors in combination with other anti-myeloma compounds will provide a novel and potent therapeutic approach to this deadly disease. Aim 1 will examine the importance of heparanase in driving myeloma metastasis, the stage(s) of metastasis where heparanase exerts its effects and the influence of heparanase on establishing pre-metastatic niches in the bone marrow. Aim 2 will test a novel heparanase inhibitor in for its anti- metastatic effects in vivo when administered either as a single agent or in combination with dexamethasone. 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 reveal how heparanase functions and to test a new anti- heparanase drug to determine if it can block the spread of cancer.