Novel Platform linking cancer-specific glycosylation with cell signaling outcomes

摘要 糖基化异常是许多癌症的标志，导致肿瘤生长和侵袭。那里 是否有许多蛋白质受体在癌症中由于基因突变和/或改变而被异常调节 糖基化。将特定的糖基化变化与信号转导结果联系起来的研究主要集中在 对单个受体或特定途径的研究。可以将多种形式的肿瘤特异性连接起来的方法 需要糖基化对信号通路激活的全局影响，以更好地识别潜在的新的 治疗学的靶点。为了克服这一限制，我们使用了异双功能分子。 这将把蛋白质受体上的癌症特异性糖基化与邻近诱导的泛素化联系起来。至 展示这种方法的潜力和适用性我们正在使用一种新的单链抗体，它可以识别 存在于卵巢癌和胶质母细胞瘤细胞上的肿瘤特异性糖链已被证明具有 极佳的细胞渗透性。结合单链抗体和蛋白水解靶向分子将使我们能够识别 受体和信号的变化使用质谱学方法。这个项目的成功完成将 建立有利于基础科学研究和临床治疗发展的新平台。

ABSTRACT Abnormal glycosylation is a hallmark of many cancers that contributes to tumor growth and invasion. There are many protein receptors that are regulated abnormally in cancer due to mutations and/or alterations in glycosylation. Studies to link specific glycosylation changes to signaling outcomes have primarily focused on studies of individual receptors or specific pathways. Methods that can link forms of tumor-specific glycosylation to global effects on signaling pathway activation are needed to better identify potential new targets for therapeutics. To overcome this limitation we are employing the use of heterobifunctional molecule that will link cancer-specific glycosylation on protein receptors with a proximity- induced ubiquitination. To demonstrate the potential and applicability of this method we are using a novel scFv antibody that recognizes tumor-specific glycans present on ovarian cancer and glioblastoma cells that has been demonstrated to have excellent cell permeability. Combining the scFv with proteolysis targeting molecules will enable us to identify receptors and signaling changes using mass spectrometry methods. Successful completion of this project will establish a new platform useful for both basic science research and clinical therapeutic development.