Heparanase regulation of tumor host interactions in myeloma and breast cancer

乙酰肝素酶对骨髓瘤和乳腺癌肿瘤宿主相互作用的调节

• 批准号: 7682576
• 负责人: Ralph D Sanderson
• 金额: $ 29.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682576
• 关键词: Automobile Driving; Behavior; Biological Models; Biology; Cancer Patient; Cell surface; Cells; Cleaved cell; Clinical Data; Clinical Trials; Data; Employee Strikes; Enzymes; Event; Extracellular Matrix; Funding; Gelatinase B; Goals; Growth; Growth Factor; Heparan Sulfate Proteoglycan; Heparin; Heparitin Sulfate; Home environment; Human; In Vitro; Knowledge; Light; Link; Location; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Modeling; Multiple Myeloma; Neoplasm Metastasis; Osteolysis; Osteolytic; Pharmaceutical Preparations; Phenotype; Play; Probability; Proteins; Publishing; Regulation; Resources; Role; SCID-hu Mice; Signal Pathway; Staging; Structure; Testing; Therapeutic; Tumor Biology; Tumor Cell Invasion; Up-Regulation; Work; angiogenesis; base; bone; cancer cell; cancer therapy; cell behavior; chemokine; design; experience; heparanase; host neoplasm interaction; in vivo; in vivo Model; inhibitor/antagonist; insight; malignant breast neoplasm; mouse model; neoplastic cell; novel; pre-clinical; promoter; public health relevance; research study; success; syndecan; therapy development; tumor; tumor growth

DESCRIPTION (provided by applicant): The long-term objective of our work is to determine how the heparan sulfate/heparanase axis regulates tumor behavior and to use this knowledge to develop new therapies for cancer. We have demonstrated that the heparan sulfate proteoglycan syndecan-1 and heparanase work synergistically to condition the tumor microenvironment thereby promoting an aggressive tumor phenotype in myeloma and breast cancer - two devastating cancers that home to and degrade bone. Our goal now is to determine the mechanism of heparanase activity in tumors and to target heparanase therapeutically using novel drugs. Although work in the field suggests that heparanase functions to degrade extracellular matrix and thereby promote tumor metastasis, based on our new discoveries we hypothesize that heparanase expression and activity initiates broad downstream effects that dramatically alter the tumor microenvironment to stimulate growth, angiogenesis, metastasis and osteolysis of bone-homing tumors. Data from in vivo models indicates that these events occur largely via heparanase-mediated upregulation of syndecan-1 shedding, enhanced MMP-9 expression and activated destruction of bone. The following specific aims will define the function and mechanism of action of heparanase in myeloma and breast cancer and test novel anti-heparanase drugs with the aim of eradicating these cancers. Aim 1 will determine the functional link between heparanase, syndecan-1 and MMP-9; Aim 2 will determine how heparanase enhances osteolysis; Aim 3 will test the anti-tumor efficacy and mechanism of action of a new class of heparin-based inhibitors of heparanase against breast cancer. These studies will utilize well-developed in vitro and in vivo models including the SCID-hu model in which human tumor cells are grown within human bone. This work will generate novel insight into heparanase function and mechanism of action and provide pre-clinical data necessary to drive new heparanase inhibitors toward clinical trials. 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 provide a new understanding about how heparanase works in multiple myeloma and breast cancer and to test new anti-heparanase drugs to block cancer growth.

描述（由申请人提供）：我们工作的长期目标是确定硫酸乙酰肝素/肝素酶轴如何调节肿瘤行为，并利用这些知识来开发新的癌症治疗疗法。 我们已经证明，硫酸乙酰肝素蛋白聚糖联合syndecan -1和乙酰肝素酶协同作用以调节肿瘤微环境，从而在骨髓瘤和乳腺癌中促进了侵袭性的肿瘤表型 - 两种毁灭性的癌症，它们是家乡并降解骨骼。 我们现在的目标是确定肿瘤中肝素酶活性的机制，并使用新型药物靶向肝素酶治疗。 尽管该领域的工作表明，肝酶的作用可降解细胞外基质并从而促进肿瘤转移，但基于我们的新发现，我们假设肝素酶表达和活性会促进肿瘤微环境的广泛下游效应，从而刺激生长，血管生成，转移，转移，转移，骨化和骨化的肿瘤。 来自体内模型的数据表明，这些事件在很大程度上通过肝素酶介导的Syndecan-1脱落，增强的MMP-9表达和激活的骨骼破坏而发生。 以下特定目的将定义肝素酶在骨髓瘤和乳腺癌中的作用和机理，并测试新型抗肝酶药物，目的是消除这些癌症。 AIM 1将确定肝素酶，Syndecan-1和MMP-9之间的功能联系； AIM 2将确定肝素酶如何增强溶解度； AIM 3将测试一种新的基于肝素的肝素酶对乳腺癌的新型肝素抑制剂的抗肿瘤功效和作用机理。 这些研究将利用良好的体外和体内模型，包括人类肿瘤细胞在人骨内生长的SCID-HU模型。 这项工作将对肝素酶功能和作用机理产生新的见解，并提供临床前数据，以将新的肝素酶抑制剂推向临床试验。 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。 该项目旨在对肝素酶在多发性骨髓瘤和乳腺癌中的工作方式进行新的了解，并测试新的抗肝酶药物以阻断癌症的生长。