Targeting N-linked Glycosylation to Enhance Radiation Therapy

描述(申请人提供)：受体酪氨酸激酶(RTK)是临床验证的靶点，可以被阻断以增强放射治疗的疗效。然而，多种RTK和其他细胞表面受体的共同表达限制了这种治疗方法。我们已经确定蛋白质N-连接糖基化(NLG)是一种共翻译的蛋白质修饰，可以靶向减少多个过度表达的RTK的信号转导。NLG抑制在体外和体内都能使癌细胞放射增敏，因此需要研究优化NLG抑制以将这一策略推向临床试验。根据我们的初步数据，我们假设NLG生物合成机制中的离散步骤可以靶向阻断RTK和细胞表面受体生存信号，并加强放射治疗。我们已经建立了具有NLG缺陷的新的人类细胞模型，以解决糖基化在介导受体信号和对电离辐射敏感性方面的作用。我们还确定了一种阻断肿瘤细胞中NLG的药理策略。这些研究的另一个组成部分将使用生物发光分子成像平台评估NLG在胶质瘤异种移植瘤模型中的活性。我们计划使用这些临床前模型来评估和测试特定的NLG酶，作为结合放射治疗进行治疗抑制的基因靶点。该项目将为NLG对癌症生物学的贡献提供新的见解，并为在恶性疾病治疗中加强放射治疗提供治疗靶点。

DESCRIPTION (provided by applicant): Receptor Tyrosine Kinases (RTKs) are clinically validated targets that can be blocked to enhance the efficacy of radiation therapy. However, the co-expression of multiple RTKs and other cell surface receptors limits this therapeutic approach. We have identified protein N-linked glycosylation (NLG) as a co-translational protein modification that can be targeted to reduce signaling of multiple over-expressed RTKs. NLG inhibition radiosensitizes cancer cells both in vitro and in vivo and research to optimize NLG inhibition is therefore required to advance this strategy to clinical trials. Based on our preliminry data, we hypothesize that discrete steps in the NLG biosynthetic machinery can be targeted to block RTK and cell surface receptor survival signaling and enhance radiation therapy. We have generated novel human cell models with NLG defects to address the role of glycosylation in mediating receptor signaling and sensitivity to ionizing radiation. We have also identified a pharmacologic strategy for blocking NLG in tumor cells. An additional component of these studies will evaluate NLG activity in xenograft tumor models of glioma using a bioluminescent molecular imaging platform. We plan to use these pre-clinical models to evaluate and test specific NLG enzymes as gene targets for therapeutic inhibition in combination with radiation therapy. This project will provide new insights into the contributions of NLG to cancer biology as well as provide therapeutic targets for enhancing radiation therapy in the treatment of malignant disease.