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：
8403534
负责人：
ALAN C RAPRAEGER
金额：
$ 36.57万
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/8403534
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 tumor microenvironment 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.

描述（由适用提供）：多发性骨髓瘤是第二大普遍的血液系统恶性肿瘤，占美国所有血液学癌症的10％以上。据估计，每年诊断出16,500例新的骨髓瘤病例，每年有11,000多例死亡。尽管在过去十年中在治疗方面取得了进展，但患者的总体前景是严峻的。多发性骨髓瘤是一种恶性血浆细胞侵入骨髓内肿瘤并形成肿瘤的疾病。它们与肿瘤微环境的相互作用导致了支持骨髓瘤细胞增殖的细胞因子的释放，刺激了支持骨髓瘤细胞生长和转移的血管生成，并通过过度刺激骨质细胞的分化及其确保骨骼破坏而触发骨裂解疾病。我们在所有这些过程中都发现了一种中心机制，涉及四个效应子，每个效应子都在骨髓瘤形成和进展中起作用 - 即基质受体Syndecan-1（SDC1）（SDC1），AV¿3和AV¿3整联蛋白，胰岛素样生长因子-1受体-1受体和乙酰肝素酶。中心机制是激活由SDC1，两个整合素和IGF1R组成的信号传导复合物，当SDC1通过乙酰肝素酶裂解其乙酰肝素链激活SDC1时。重要的是，该机制被靶向Syndecan-1上的活动位点的胡椒（称为Synstatin（SSTN））阻止。该建议将检查肝小瘤细胞上SDC1激活SDC1的机制，从而导致骨髓瘤的肿瘤发生，并在肿瘤微环境中增加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作为该机制对肿瘤细胞和微环境中细胞的抑制剂的有效性。这项工作的好处很可能是多发性骨髓瘤和其他癌症的新有效治疗方法。