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

• 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
• 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

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浆细胞存在于骨髓中的疾病，是第二大多发性骨髓瘤。 在美国流行的恶性血液病。超过26，000个新病例被诊断出来， 每年有11,000人死于骨髓瘤。骨髓瘤是一种毁灭性的癌症，其特征是疲劳，顽固性骨 疼痛、肾衰竭和复发性感染。新疗法的出现（例如，硼替佐米、沙利度胺） 在过去的十年中，已经大大提高了生存率，但患者的整体前景仍然严峻， 这些疗法减缓而不是治愈疾病，患者最终复发，然后迅速衰退。因此，在本发明中， 发现新的靶点及其抑制剂，特别是对于复发患者，是一个高度优先事项。 骨髓基质内的关键相互作用对骨髓瘤细胞的侵袭和存活至关重要，包括 刺激支持肿瘤生长和转移的血管生成。我们最近发现了三个新的 机制，由三种非常有前途的抑制剂补充，这些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和肿瘤免疫抑制的新机制。所有 三种机制依赖于syndecan-1（Sdc 1，CD 138），一种细胞表面硫酸乙酰肝素蛋白聚糖， 在骨髓瘤中高度表达，并且与该疾病的不良预后相关。这三个机制 涉及胰岛素样生长因子受体（IGF 1 R），这对骨髓瘤细胞的存活至关重要，VLA 4（ α4β1整联蛋白），骨髓瘤细胞依赖于外渗，骨髓中的相互作用， 生长、存活和耐药性，以及血管内皮生长因子受体2（VEGFR 2）， 我们最近显示，heparanase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细胞募集。在每一种情况下，该机制也表示 并对内皮细胞有活性，为肿瘤提供血液供应和转移出口。这一切成功都 一种重要的受体与Sdc 1的胞外结构域偶联，它们的功能被高度稳定的 我们正在开发作为骨髓瘤潜在治疗药物的肽（synstatins）。我们在此建议 应用研究这些机制的分子基础，并测试我们的肽作为 在严格的多发性骨髓瘤小鼠模型中的潜在新疗法。