Targeting N-linked Glycosylation to Enhance Radiation Therapy

描述（由申请人提供）：受体酪氨酸激酶（RTK）是临床验证的靶点，可通过阻断来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表达限制了这种治疗方法。我们已经鉴定了蛋白质N-连接糖基化（NLG）作为共翻译蛋白质修饰，其可以被靶向以减少多个过表达的RTK的信号传导。NLG抑制在体外和体内均使癌细胞放射增敏，因此需要优化NLG抑制的研究以将该策略推进到临床试验。基于我们的生物学数据，我们假设NLG生物合成机制中的离散步骤可以靶向阻断RTK和细胞表面受体存活信号传导并增强放射治疗。我们已经产生了具有NLG缺陷的新型人类细胞模型，以解决糖基化在介导受体信号传导和对电离辐射的敏感性中的作用。我们还确定了阻断肿瘤细胞中NLG的药理学策略。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神经胶质瘤异种移植肿瘤模型中的NLG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酶作为与放射疗法组合的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，并为增强恶性疾病治疗中的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.