Heparanase Regulation of Myeloma Metastasis: Mechanism and Therapy

骨髓瘤转移的乙酰肝素酶调节：机制和治疗

• 批准号: 8259527
• 负责人: Ralph D Sanderson
• 金额: $ 33.02万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-03 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259527
• 关键词: Angiogenic Factor; Automobile Driving; Behavior; Binding; Biological Models; Biology; Blood; Blood Circulation; Bone Marrow; Bone neoplasms; Cancer Model; Cells; Cessation of life; Clinical; Data; Dexamethasone; Disease; Distal; Employee Strikes; Enzymes; Gelatinase B; Genes; Goals; Growth; Growth Factor; Heparitin Sulfate; Home environment; Homing; Human; Invaded; Knowledge; Lead; Link; Malignant Neoplasms; Mediator of activation protein; Metastatic Neoplasm to the Bone; Modeling; Multiple Myeloma; Nature; Neoplasm Metastasis; Osteolysis; Osteolytic; Pain; Patients; Pharmaceutical Preparations; Play; Primary Neoplasm; Probability; Proteins; Quality of life; Regulation; Reporting; Resources; Role; SCID-hu Mice; Site; Skeleton; Staging; Testing; Therapeutic; Therapeutic Agents; Tumor Biology; Vascular Endothelial Growth Factors; Work; abstracting; angiogenesis; base; bone; cancer cell; cancer therapy; density; design; experience; heparanase; improved; in vivo; in vivo Model; inhibitor/antagonist; killings; mouse model; neoplastic cell; novel; outcome forecast; prevent; research study; success; tumor; tumor growth

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.

项目总结/摘要 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，并利用这些知识开发新的抗癌疗法。这一近期目标 本研究以多发性骨髓瘤为模型， 癌骨髓瘤是一种毁灭性的癌症，在骨髓中茁壮成长， 骨骼损伤导致患者剧烈疼痛、生活质量差和最终死亡。虽然是 不幸的是，这种癌症的转移性导致患者死亡， 骨髓瘤未知。改善病人治疗的关键在于发展一种机制， 了解骨髓瘤转移和测试新的抑制剂来阻断肿瘤扩散。使用in 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一个关键的驱动程序， 骨髓瘤生长、血管生成、骨质溶解和转移。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， 患者预后不佳。来自我们实验室的惊人的新数据表明，乙酰肝素酶作为一个主 通过上调包括VEGF、MMP-9在内的几种基因的表达来调节骨髓瘤的转移 和uPA/uPAR协同作用以驱动转移。我们假设乙酰肝素酶作为一种关键 通过促进肿瘤细胞初始渗入血液来促进骨髓瘤转移 原发性肿瘤部位，并通过在骨中制备促进肿瘤细胞归巢的转移前小生境， 增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， 与其它抗骨髓瘤化合物组合将提供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建立 骨髓中的转移前小生境目的2将测试一种新的乙酰肝素酶抑制剂， 当作为单一药剂或与 地塞米松。