Synstatin Therapy for Multiple Myeloma

多发性骨髓瘤的合成他汀治疗

基本信息

批准号：
8190334
负责人：
ALAN C RAPRAEGER
金额：
$ 38.91万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8190334
关键词：
Accounting Active Sites Bone Marrow Cell Line Cell Proliferation Cell Survival Cell surface Cells Complex Core Protein Diagnosis Disease Disease Progression Enzymes Extracellular Domain Extracellular Matrix Goals Hematologic Neoplasms Heparan Sulfate Proteoglycan Heparitin Sulfate Home environment Human IGF1 gene Implant In Vitro Insulin-Like-Growth Factor I Receptor Integrins Invaded Lead Ligands Lytic Malignant - descriptor Malignant Neoplasms Modeling Multiple Myeloma Neoplasm Metastasis Osteoclasts Patients Peptides Plasma Cells Process Protein Tyrosine Kinase Resistance Role SCID Mice Signal Transduction Stromal Cells Surface Testing Therapeutic Tumor Promoters United States Vascular Endothelial Cell Work angiogenesis base bone cell growth cell type cytokine effective therapy efficacy testing heparanase in vivo inhibitor/antagonist macrophage neoplastic cell novel novel therapeutics potency testing progenitor public health relevance receptor response syndecan tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma is the second most prevalent hematologic malignancy and accounts for over 10% of all hematologic cancers in the United States. It is estimated that over 16,500 new cases of myeloma are diagnosed and over 11,000 die from this disease each year. Although progress has been made in treatment over the last decade, the overall outlook for patients is grim. Multiple myeloma is a disease in which malignant plasma cells invade to populate and form tumors within the bone marrow. Their interactions with the tumor microenvironment lead to the release of cytokines that support myeloma cell proliferation, stimulate angiogenesis that supports myeloma cell growth and metastasis, and trigger bone lytic disease by over-stimulating differentiation of osteoclasts and their ensuing destruction of the bone. We have discovered a central mechanism in all of these processes that involves four effectors, each known to have a role in myeloma formation and progression - namely, the matrix receptor syndecan-1 (Sdc1), the av¿3 and av¿3 integrins, the insulin-like growth factor-1 receptor, and heparanase. The central mechanism is activation of a signaling complex comprised of Sdc1, the two integrins and the IGF1R when Sdc1 is activated by cleavage of its heparan sulfate chains by heparanase. Importantly, this mechanism is blocked by a peptide (called synstatin (SSTN)) that targets the active site on syndecan-1. This proposal will examine the mechanism by which Sdc1 is activated by heparanase on the myeloma cells, leading to tumorigenesis of the myeloma and heightened activation of vascular endothelial cells and osteoclast progenitors in the tumor microenvironment. Next, we will test the efficacy of SSTN as an inhibitor of this mechanism on the tumor cells and the cells in their microenvironment. The benefit of this work is likely to be new and effective treatments for multiple myeloma and other cancers. PUBLIC HEALTH RELEVANCE: Multiple myeloma is the second most prevalent hematologic malignancy. A novel mechanism, based on the matrix receptor syndecan-1 that is highly expressed in multiple myeloma, will be targeted by a new therapeutic called synstatin. Synstatin will be tested for its efficacy on the myeloma tumor and on the tumor microenvironment.

描述（通过应用程序证明）：多发性骨髓瘤是第二个流行的下肢，占美国所有血液癌的10％。一年。在过去的十年中，一直在信任中，患者的整体前景是严峻的。通过过度刺激破骨细胞和骨骼的推力，支持骨髓瘤和转移。 3和av¿ 3整联蛋白，胰岛素样因子1受体，肝素机械是由SDC1组成的信号，当SDC1通过肝素硫酸盐链的裂解激活机理被肽（称为Synstatin（SSTN））阻塞，syndecan-1上的活性位点在骨髓瘤细胞上激活YWICH SDC1。肿瘤微环境。公共卫生的相关性：在多发性骨髓瘤中高度表达的Onde Synde CAN-1将由一种称为合成蛋白的新疗法对骨髓瘤和肿瘤微环境的功效。