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

7.项目总结 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 在美国流行的血液系统恶性肿瘤。超过26,000例新病例被诊断和超过 每年有11000人死于骨髓瘤。骨髓瘤是一种毁灭性的癌症，以疲惫、顽固的骨骼为特征。 疼痛、肾功能衰竭和反复感染。新疗法的出现(例如，波特佐米、沙利度胺) 在过去的十年里极大地提高了存活率；然而，患者的总体前景仍然严峻，因为 这些疗法会减缓而不是治愈疾病，患者最终会复发，然后迅速下降。因此， 发现新的靶点及其抑制剂，特别是对复发患者来说，是当务之急。 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 刺激血管生成，支持肿瘤生长和转移。我们最近发现了三部小说 机制，辅之以三种极有希望的抑制剂，它们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。全 三种机制依赖于Syndecan-1(Sdc1，CD138)，一种细胞表面的硫酸乙酰肝素蛋白多糖 在骨髓瘤中高表达，与该病预后不良有关。三个机制 涉及胰岛素样生长因子受体(IGF1R)，它对骨髓瘤细胞的生存至关重要，VLA4( α4β1整合素)，骨髓瘤细胞依赖它进行外渗，骨髓中的相互作用是必要的 生长、存活和耐药性，以及血管内皮生长因子受体-2(VEGFR2)，其中 我们最近发现驱动乙酰肝素酶表达的骨髓瘤细胞的侵袭，但似乎也 抑制NK和细胞毒性T细胞的募集。在每一种情况下，机制也被表达出来 并活跃于内皮细胞，为肿瘤提供血液供应和转移出口。这其中的每一个 重要的受体偶联到Sdc1的胞外区，其功能被高度稳定的 我们正在开发的作为治疗骨髓瘤的潜在药物的多肽(Synstatins)。我们在此提出建议 应用来研究这些机制的分子基础，并测试我们的多肽作为 在严格的多发性骨髓瘤小鼠模型中潜在的新疗法。

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.