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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：
8010929
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010929
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（由申请人提供）：多发性骨髓瘤是第二常见的血液恶性肿瘤，占美国所有血液癌症的 10% 以上。据估计，每年诊断出超过 16,500 例新发骨髓瘤病例，并有超过 11,000 人死于这种疾病。尽管过去十年在治疗方面取得了进展，但患者的总体前景仍然严峻。多发性骨髓瘤是一种恶性浆细胞侵入骨髓并在骨髓内形成肿瘤的疾病。它们与肿瘤微环境的相互作用导致细胞因子的释放，支持骨髓瘤细胞增殖，刺激支持骨髓瘤细胞生长和转移的血管生成，并通过过度刺激破骨细胞的分化及其随后的骨质破坏而引发溶骨性疾病。我们发现了所有这些过程中的一个核心机制，涉及四个效应子，每个效应子都在骨髓瘤形成和进展中发挥作用，即基质受体 Syndecan-1 (Sdc1)、av¿3 和 av¿3 整合素、胰岛素样生长因子 1 受体和乙酰肝素酶。核心机制是当 Sdc1 被乙酰肝素酶裂解其硫酸乙酰肝素链激活时，由 Sdc1、两个整合素和 IGF1R 组成的信号复合物被激活。重要的是，这种机制被一种针对 syndecan-1 活性位点的肽（称为 Synstatin (SSTN)）阻断。该提案将研究骨髓瘤细胞上的乙酰肝素酶激活 Sdc1 的机制，从而导致骨髓瘤发生并增强肿瘤微环境中血管内皮细胞和破骨细胞祖细胞的激活。接下来，我们将测试 SSTN 作为该机制抑制剂对肿瘤细胞及其微环境中的细胞的功效。这项工作的好处可能是为多发性骨髓瘤和其他癌症提供新的有效治疗方法。公众健康相关性：多发性骨髓瘤是第二常见的血液恶性肿瘤。一种基于多发性骨髓瘤中高表达的基质受体 syndecan-1 的新机制将成为一种名为 Synstatin 的新疗法的目标。将测试 Synstatin 对骨髓瘤肿瘤和肿瘤微环境的功效。