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：
10208798
负责人：
ALAN C RAPRAEGER
金额：
$ 36.97万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208798
关键词：
Adaptive Immune System 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 Endothelium Environment Enzymes Extracellular Domain Extravasation Fatigue Growth Hematologic Neoplasms Heparan Sulfate Proteoglycan Heparitin Sulfate Homing Human Immune Immunologic Surveillance Immunosuppression In Vitro 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 Prognosis Receptor Activation 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 migration mouse model novel novel therapeutics prevent receptor recruit recurrent infection relapse patients syndecan tumor tumor growth

Adaptive Immune System 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 Endothelium Environment Enzymes Extracellular Domain Extravasation Fatigue Growth Hematologic Neoplasms Heparan Sulfate Proteoglycan Heparitin Sulfate Homing Human Immune Immunologic Surveillance Immunosuppression In Vitro 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 Prognosis Receptor Activation 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 migration mouse model novel novel therapeutics prevent receptor recruit recurrent infection relapse patients syndecan tumor tumor growth

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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。项目摘要多发性骨髓瘤是一种恶性血浆细胞驻留在骨髓中的疾病，是第二种美国普遍的血液系统恶性肿瘤。已诊断出26,000多个新病例每年有11,000人死于骨髓瘤。骨髓瘤是一种毁灭性的癌症，以疲劳，棘手的骨骼为标志疼痛，肾衰竭和复发感染。新疗法的出现（例如硼替佐米，沙利度胺）在过去的十年中，生存率大大提高了。然而，患者的整体前景仍然严峻这些疗法缓慢而不是治愈疾病，并最终继承患者，然后迅速下降。那，发现新靶标及其抑制剂，尤其是针对接力患者的抑制剂，这是一个很高的重点。骨髓基质内的主要相互作用对于骨髓瘤细胞侵袭和生存至关重要，包括刺激支持肿瘤生长和转移的血管生成。我们最近发现了三本小说由三个高度有前途的抑制剂完成的机制，这些抑制剂控制着骨髓瘤细胞侵袭，生存，它们所依赖的血管生成和肿瘤免疫抑制的新机制。全部三种机制依赖于Syndecan-1（SDC1，CD138），一种细胞表面硫酸乙酰肝素蛋白聚糖，是在骨髓瘤中高度表达，与该疾病的预后不良相关。这三种机制涉及胰岛素样生长因子受体（IGF1R），这对于骨髓瘤细胞的存活至关重要 α4β1整联蛋白）表明，骨髓瘤细胞依赖于渗出，在骨髓中相互作用所需的相互作用生长，生存和耐药性，以及血管内皮生长因子受体2（VEGFR2），这我们最近显示，驱动了表达肝酶表达骨髓瘤细胞的侵袭，但似乎也似乎抑制NK和细胞毒性T细胞的募集。在每种情况下，机制也表示并在内皮细胞上活跃，为肿瘤提供血液供应和转移性出口。每个重要的受体与SDC1的细胞外结构域耦合，其功能被高度稳定阻塞我们正在作为骨髓瘤潜在疗法发展的肽（合成蛋白）。我们建议用于研究这些机制的分子基础的应用，并将我们的肽测试为多发性骨髓瘤的严格小鼠模型中的潜在新疗法。