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肝素/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。这个项目的直接目标是确定肝素酶调节转移级联使用多发性骨髓瘤作为模型癌症。骨髓瘤是一种毁灭性的癌症，它在骨髓中生长，并扩散到整个骨骼，导致严重的疼痛，生活质量差，最终导致患者死亡。尽管骨髓瘤的转移性导致患者死亡，但不幸的是，骨髓瘤的转移调节机制尚不清楚。改善患者治疗的关键在于发展对骨髓瘤转移的机制理解和测试新的抑制剂来阻止肿瘤扩散。通过体内模型，我们已经证明硫酸肝素降解酶是骨髓瘤生长、血管生成、骨溶解和转移的关键驱动因素。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，它与患者预后不良有关。我们实验室惊人的新数据表明，肝素酶作为骨髓瘤转移的主要调节剂，通过上调几种基因的表达，包括VEGF、MMP-9和uPA/uPAR，这些基因共同推动转移。我们假设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进入血液，并在骨中准备转移前龛，促进肿瘤细胞的归巢和生长。鉴于这两个在转移中的关键功能，我们进一步假设肝素酶抑制剂与其他抗骨髓瘤化合物联合使用将为这种致命疾病提供一种新的有效治疗方法。目的1将研究肝素酶在驱动骨髓瘤转移中的重要性，肝素酶在转移的阶段发挥作用，以及肝素酶对在骨髓中建立转移前生态位的影响。目的2将测试一种新的肝素酶抑制剂在体内的抗转移作用，无论是单独使用还是与地塞米松联合使用。公共卫生相关性：肝素酶是一种由癌细胞产生的蛋白质，在帮助癌细胞在全身生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，并测试一种新的抗肝素酶药物，以确定它是否能阻止癌症的扩散。

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.