Synstatin Therapy for Multiple Myeloma

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，占美国所有血液肿瘤的10%以上。据估计，每年有超过16,500例新的骨髓瘤病例被诊断出来，超过11,000例死于这种疾病。尽管在过去的十年中治疗取得了进展，但患者的整体前景仍然严峻。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，刺激血管生成，支持骨髓瘤细胞生长和转移，并通过过度刺激破骨细胞分化和随后的骨破坏引发骨溶解性疾病。我们已经发现了所有这些过程的核心机制，涉及四种效应物，每一种效应物都在骨髓瘤的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受体和肝素酶。其主要机制是当Sdc1被肝素酶裂解其硫酸肝素链激活时，由Sdc1、两种整合素和IGF1R组成的信号复合体被激活。重要的是，这种机制被一种靶向syndecan-1活性位点的肽（称为synstatin (SSTN)）阻断。本研究将探讨Sdc1被骨髓瘤细胞上的肝素酶激活的机制，从而导致骨髓瘤的发生以及肿瘤微环境中血管内皮细胞和破骨细胞祖细胞的激活增强。接下来，我们将测试SSTN作为这一机制的抑制剂对肿瘤细胞及其微环境中的细胞的作用。这项工作的好处可能是新的和有效的治疗多发性骨髓瘤和其他癌症。

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.