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.

项目摘要/摘要 桑德森实验室的总体目标是确定乙par硫酸盐 /肝素轴轴的作用 调节癌症并利用这些知识来开发新的抗癌疗法。直接目标 该项目是为了使用多发性骨髓瘤作为模型来定义转移性级联反应的肝素酶调节 癌症。骨髓瘤是一种毁灭性的癌症，在骨髓中生长并在整个过程中传播 骨骼导致严重的疼痛，生活质量差和最终死亡。虽然这是 不幸的是，这种杀死患者的癌症的转移性，调节转移的机制 骨髓瘤未知。改善患者治疗的关键在于开发机理 了解骨髓瘤转移并测试新的抑制剂以阻断肿瘤传播。使用 Vivo模型，我们已经证明了乙par硫酸盐降解酶Heparanase是 骨髓瘤生长，血管生成，骨溶解和转移。重要的是，我们还发现 酶活性的乙酰肝素酶存在于骨髓瘤患者的骨髓中，并且与之相关 患者预后不良。从我们的实验室中删除新数据表明肝素酶充当大师 通过上调几种基因的表达，包括VEGF，MMP-9 和UPA/UPAR共同努力驾驶转移。我们假设乙酰肝素酶是关键 通过促进肿瘤细胞在血液中的初始插入到血液处的骨髓瘤转移介质 原发性肿瘤部位并通过在骨骼中准备促进肿瘤细胞寄养和 生长。鉴于转移中的这两个关键功能，我们进一步假设肝素酶抑制剂 结合其他抗肌瘤化合物，将为一种新颖而有效的治疗方法提供 这种致命的疾病。 AIM 1将研究肝素酶在驱动骨髓瘤转移中的重要性， 转移的阶段，肝素酶发挥作用及其对肝素酶建立的影响 骨髓中的物转移壁细分市场。 AIM 2将测试一种新型的肝素抑制剂 当作为单个药物或与 地塞米松。