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: 8065432
• 负责人: Ralph D Sanderson
• 金额: $ 33.1万
• 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/8065432
• 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; Health; 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; 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

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.

描述（由申请人提供）：桑德森实验室的总体目标是确定硫酸乙酰肝素 /肝素酶轴在调节癌症中的作用，并使用这些知识来开发新的抗癌疗法。该项目的直接目标是使用多发性骨髓瘤作为模型癌来定义转移性级联反应的肝素酶调节。骨髓瘤是一种毁灭性的癌症，在骨髓中繁衍生长，并在整个骨骼中传播，导致严重的疼痛，较差的生活质量和最终的患者死亡。尽管不幸的是，尽管这种癌症的转移性杀死了患者，但调节骨髓瘤转移的机制尚不清楚。改善患者治疗的关键在于，对骨髓瘤转移和测试新抑制剂的机械理解以阻断肿瘤传播。使用体内模型，我们已经表明硫酸乙酰肝素降解酶肝酶是骨髓瘤生长，血管生成，骨溶解和转移的关键驱动力。重要的是，我们还发现，酶活性的肝素酶存在于骨髓瘤患者的骨髓中，并且与患者预后差有关。从我们的实验室中引起的新数据表明，肝素酶通过上调了包括VEGF，MMP-9和UPA/UPA在内的多种基因的表达来充当骨髓瘤中转移的主要调节剂，从而协同驱动转移。我们假设肝素酶通过促进原发性肿瘤部位的血液中的初始侵入肿瘤细胞并在骨骼中准备促进肿瘤细胞托管和生长的骨骼前转移壁细分市场来充当骨髓瘤转移的关键介体。鉴于这两个关键功能在转移中，我们进一步假设肝素酶抑制剂与其他抗肌瘤化合物结合使用将为这种致命疾病提供一种新颖而有效的治疗方法。 AIM 1将研究肝素酶在驱动骨髓瘤转移的重要性，乙酰肝素酶的作用及其对乙酰肝素酶对在骨髓中建立静脉前生态的影响的阶段。 AIM 2将在作为单一药物或与地塞米松结合使用时测试一种新型的肝素酶抑制剂在体内的抗转移性作用。公共卫生相关性：肝素酶是一种由癌细胞生产的蛋白质，在帮助它们在整个体内成长和扩散方面起着重要作用。该项目旨在揭示肝素酶的功能并测试新的抗肝酶药物，以确定它是否可以阻止癌症的传播。