Syndecan-1 (CD138) and its synstatins: targeting invasion, survival and angiogenesis in myeloma

Syndecan-1 (CD138) 及其 Synstatins：靶向骨髓瘤的侵袭、存活和血管生成

基本信息

批准号：
9383657
负责人：
ALAN C RAPRAEGER
金额：
$ 37.56万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9383657
关键词：
Adaptive Immune System Alpha Cell Angiogenesis Inhibitors Apoptosis Biological Assay Blood Vessels Bone Marrow Bone Pain Bortezomib CXCR4 gene Cell Adhesion Cell Survival Cell surface Cells Clinic Clinical Treatment Complement Complex Coupled Couples Cyclic AMP-Dependent Protein Kinases Cytotoxic T-Lymphocytes Diagnosis Disease Drug resistance Endothelial Cells Environment Enzymes Extracellular Domain Extravasation Fatigue Growth Hematologic Neoplasms Heparan Sulfate Proteoglycan Heparitin Sulfate Homing Human Immune Immunologic Surveillance Immunosuppression In Vitro Infection Insulin-Like Growth Factor Receptor Insulin-Like-Growth Factor I Receptor Integrin alpha4beta1 Integrins KDR gene Kidney Failure Link Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Multiple Myeloma Mus Natural Killer Cells Neoplasm Metastasis Patients Peptides Pharmaceutical Preparations Phosphorylation Plasma Cells Receptor Activation Recruitment Activity Recurrence Relapse Resistance Role Site Stromal Cells Survival Rate T-Lymphocyte Testing Thalidomide Therapeutic Translating Tumor Suppression United States Vascular Endothelial Cell Vascular Endothelium Vascular blood supply angiogenesis bone experience heparanase human disease improved in vivo inhibitor/antagonist killings migration mouse model novel novel therapeutics outcome forecast prevent receptor relapse patients syndecan tumor tumor growth

项目摘要

7. PROJECT SUMMARY Multiple myeloma, a disease in which malignant plasma cells reside in the bone marrow, is the second most prevalent hematologic malignancy in the United States. Over 26,000 new cases are diagnosed and over 11,000 die from myeloma each year. Myeloma is a devastating cancer marked by fatigue, intractable bone pain, renal failure and recurrent infections. The emergence of new therapies (e.g., bortezomib, thalidomide) over the past decade has greatly improved survival rates; yet the overall outlook for patients remains grim as these therapies slow rather than cure the disease and patients ultimately relapse, then rapidly decline. Thus, discovering new targets and their inhibitors, especially for relapsed patients, is a high priority. Key interactions within the bone marrow stroma are critical for myeloma cell invasion and survival, including stimulating angiogenesis that supports tumor growth and metastasis. We have recently discovered three novel mechanisms, complemented by three highly promising inhibitors, that govern myeloma cell invasion, survival, the angiogenesis upon which they depend and a novel mechanism of immune suppression by the tumors. All three mechanisms rely on syndecan-1 (Sdc1, CD138), a cell surface heparan sulfate proteoglycan that is highly expressed in myeloma and correlates with poor prognosis in this disease. The three mechanisms involve insulin-like growth factor receptor (IGF1R), which is critical for the survival of myeloma cells, VLA4 (the α4β1 integrin) that the myeloma cells rely on for extravasation, interactions in the bone marrow necessary for growth and survival and drug resistance, and vascular endothelial growth factor receptor-2 (VEGFR2), which we have recently shown drives the invasion of heparanase-expressing myeloma cells, but also appears to suppress recruitment of NK- and cytotoxic T-cells. In each of these cases, the mechanism is also expressed and active on endothelial cells providing the tumor with a blood supply and metastatic outlets. Each of these important receptors is coupled to the extracellular domain of Sdc1 and their function is blocked by highly stable peptides (synstatins) that we are developing as potential therapeutics for myeloma. We propose in this application to investigate the molecular underpinnings of these mechanisms, and to test our peptides as potential new therapeutics in rigorous mouse models of multiple myeloma.

7. 项目概要多发性骨髓瘤是一种恶性浆细胞驻留在骨髓中的疾病，是第二大常见疾病美国有超过 26,000 例新确诊的血液系统恶性肿瘤。每年有 11,000 人死于骨髓瘤。骨髓瘤是一种毁灭性的癌症，其特点是疲劳、难治性骨骼。新疗法的出现（例如硼替佐米、沙利度胺）。过去十年大大提高了生存率；但患者的总体前景仍然严峻这些疗法会减缓而不是治愈疾病，患者最终会复发，然后迅速衰退。发现新的靶点及其抑制剂，特别是对于复发患者来说，是当务之急。骨髓基质内的关键相互作用对于骨髓瘤细胞的侵袭和存活至关重要，包括我们最近发现了三项新发现。机制，辅之以三种非常有前途的抑制剂，控制骨髓瘤细胞的侵袭、存活、它们所依赖的血管生成以及肿瘤免疫抑制的新机制。三种机制依赖于 syndecan-1（Sdc1、CD138），这是一种细胞表面硫酸乙酰肝素蛋白聚糖，在骨髓瘤中高表达并与该疾病的不良预后相关。涉及胰岛素样生长因子受体（IGF1R），它对骨髓瘤细胞的存活至关重要，VLA4（ α4β1 整合素），骨髓瘤细胞依赖其进行外渗，在骨髓中相互作用是必要的生长、存活和耐药性，以及血管内皮生长因子受体 2 (VEGFR2)，其中我们最近发现驱动表达乙酰肝素酶的骨髓瘤细胞的侵袭，但似乎也抑制 NK 细胞和细胞毒性 T 细胞的募集在上述每种情况下，也都表达了该机制。并活跃于内皮细胞，为肿瘤提供血液供应和转移出口。重要的受体与 Sdc1 的胞外域偶联，其功能被高度稳定的我们正在开发的肽（合成他汀）作为骨髓瘤的潜在疗法。应用程序来研究这些机制的分子基础，并测试我们的肽严格的多发性骨髓瘤小鼠模型中潜在的新疗法。