Targeting Heparan Sulfate for Myeloma Therapy

这项工作的总体目标是将硫酸乙酰肝素作为一种治疗骨髓瘤的新方法。尽管硫酸乙酰肝素通常被认为可以抑制肿瘤的进展，但我们实验室和其他人最近的发现表明，硫酸乙酰肝素蛋白多糖有一个更险恶的作用-实际上是促进癌症的生长。骨髓瘤细胞释放高水平的Syndecan-1进入患者血清是预后不良的指标，我们发现体内可溶性Syndecan-1促进了骨髓瘤的生长和转移。因为脱落的Syndecan-1积聚在骨髓基质和骨髓中 血浆，它处于战略位置，以促进许多推动骨髓瘤进展的硫酸乙酰肝素结合生长因子的活动(例如，HGF、VEGF)。因此，硫酸乙酰肝素是骨髓瘤治疗的独特靶点。我们假设，干扰硫酸乙酰肝素的功能或在骨髓微环境中的可用性将抑制骨髓瘤的生长和扩散。虽然针对单一信号通路的治疗药物可能对某些癌症有效，但在骨髓瘤中不太可能如此，因为存在广泛的遗传和分子异质性。通过阻断硫酸乙酰肝素的正常功能， 有一个令人兴奋的机会来干扰推动骨髓瘤进展的多个信号通路。利用小鼠骨髓瘤模型，在目标1中，我们将确定是否修改或中和硫酸乙酰肝素的功能，或抑制正常的硫酸肝素表达是否会抑制骨髓瘤的生长和扩散。我们在体内针对硫酸乙酰肝素的策略包括：i)用酶修饰硫酸乙酰肝素的功能；ii)用硫酸乙酰肝素功能的抑制剂中和硫酸乙酰肝素；以及iii)抑制蛋白多糖或硫酸肝素的合成或表达，或抑制Syndecan-1从细胞表面脱落。在目标2中，将使用质谱学中的新技术来确定结构和配体结合 从个体患者中分离的Syndecan-1硫酸乙酰肝素的能力。结果将被挖掘为与其他疾病参数(例如，预后、治疗反应)和结构信息的相关性，用于设计针对特定硫酸乙酰肝素介导的信号通路的新疗法。总之，这些研究将确定以硫酸乙酰肝素为基础的治疗骨髓瘤的潜力。

The overall goal of this work is to target heparan sulfate as a novel therapeutic approach for myeloma. Although heparan sulfate is generally thought to inhibit tumor progression, recent discoveries by our lab and others point to a more sinister role for heparan sulfate proteoglycans---one of actually promoting growth of cancer. High levels of syndecan-1 shed by myeloma cells into the sera of patients is an indicator of poor prognosis, and we have discovered that soluble syndecan-1 promotes growth and metastasis of myeloma tumors in vivo. Because shed syndecan-1 accumulates within the marrow stromal matrix and in marrow plasma, it is strategically placed to facilitate the activities of many of the heparan sulfate-binding growth factors that drive myeloma progression (e.g., HGF, VEGF). Thus, heparan sulfate represents a unique target for myeloma therapy. We hypothesize that interfering with heparan sulfate function or availability within the bone marrow microenvironment will inhibit myeloma growth and dissemination. While therapeutic agents that target a single signaling pathway may work in some cancers, this will not likely be the case in myeloma where there exists extensive genetic and molecular heterogeneity. By blocking the normal function of heparan sulfate, there is an exciting opportunity to interfere with multiple signaling pathways that drive myeloma progression. Using murine models of myeloma, in Aim 1 we will determine if modifying or neutralizing heparan sulfate function, or inhibiting normal heparan sulfate expression will inhibit myeloma growth and dissemination. Our strategies for targeting heparan sulfate in vivo include i) modifying heparan sulfate function with enzymes; ii) neutralizing heparan sulfate with inhibitors of heparan sulfate function; and iii) inhibiting synthesis or expression of proteoglycans or heparan sulfate, or inhibiting shedding of syndecan-1 from the cell surface. In aim 2, new techniques in mass spectrometry will be employed to define the structure and ligand-binding capabilities of syndecan-1 heparan sulfate isolated from individual patients. Results will be mined for relatedness to other disease parameters (e.g., prognosis, response to treatment) and structural information used for design of new therapies that target specific heparan sulfate-mediated signaling pathways. Together, these studies will determine the potential of heparan sulfate-based therapeutics for myeloma.