Heparanase Regulation of Myeloma Metastasis: Mechanism and Therapy

项目摘要/摘要 桑德森实验室的总体目标是确定硫酸乙酰肝素轴/肝素酶轴在 控制癌症，并利用这一知识开发新的抗癌疗法。眼前的目标是 这个项目是以多发性骨髓瘤为模型来确定肝素酶对转移性级联反应的调节。 癌症。骨髓瘤是一种毁灭性的癌症，它在骨髓中生长旺盛，并在 骨骼导致剧烈疼痛，生活质量下降，最终导致患者死亡。虽然它是 不幸的是，这种导致患者死亡的癌症的转移本质，调节肿瘤转移的机制 骨髓瘤是未知的。改善病人治疗的关键在于发展一种机械化 了解骨髓瘤的转移并测试新的抑制物以阻断肿瘤的扩散。使用中 活体模型中，我们已经证明，硫酸乙酰肝素降解酶乙酰肝素酶是一个关键的驱动因素 骨髓瘤的生长、血管生成、骨溶解和转移。重要的是，我们还发现 骨髓瘤患者骨髓中存在具有酶活性的乙酰肝素酶，其与 患者预后差。来自我们实验室的惊人的新数据表明，乙酰肝素酶起着主要的作用 通过上调血管内皮生长因子、基质金属蛋白酶-9等基因的表达调控骨髓瘤的转移 和uPA/uPAR协同作用，推动肿瘤转移。我们假设乙酰肝素酶是一把钥匙 骨髓瘤转移的中介物通过促进肿瘤细胞最初的血管内进入血液 通过在骨中准备转移前的壁龛来促进肿瘤细胞的归巢和 成长。鉴于这两个在转移中的关键功能，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联合使用将提供一种新的、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促进骨髓瘤转移中的重要性。 肝素酶发挥作用的转移期(S)及肝素酶对转移期的影响 骨髓中的转移前壁龛。Aim 2将测试一种新型肝素酶抑制剂的抗肿瘤活性 单药给药或联合用药的体内转移效应 地塞米松。

Project Summary/Abstract 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.