Novel Platform linking cancer-specific glycosylation with cell signaling outcomes

摘要 异常糖基化是许多癌症的标志，有助于肿瘤生长和侵袭。那里 是许多蛋白质受体，由于突变和/或改变，在癌症中被异常调节， 糖基化将特定糖基化变化与信号传导结果联系起来的研究主要集中在 研究单个受体或特定途径。可以将肿瘤特异性 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 治疗的目标。为了克服这一局限性，我们正在使用异双功能分子 其将蛋白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。到 为了证明这种方法的潜力和适用性，我们使用了一种新的scFv抗体， 卵巢癌和胶质母细胞瘤细胞上存在的肿瘤特异性聚糖，已被证明具有 优异的细胞渗透性。将scFv与蛋白水解靶向分子结合将使我们能够鉴定 受体和信号转导的变化。该项目的成功完成将 为基础科学研究和临床治疗开发搭建了新的平台。

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.