Targeting N-linked Glycosylation to Enhance Radiation Therapy

靶向 N-连接糖基化以增强放射治疗

• 批准号: 9089960
• 负责人: Joseph N. Contessa
• 金额: $ 40.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089960
• 关键词: Address; Anabolism; Animal Model; Animals; Asparagine; Cancer Biology; Cell Surface Receptors; Cell model; Cells; Central Nervous System Neoplasms; Clinical; Clinical Trials; Co-Translational Protein Processing; Complement; Data; Defect; Disease; Dose; Endoplasmic Reticulum; Enzymes; Epidermal Growth Factor Receptor; FGFR2 gene; Gene Targeting; Genetic; Glioblastoma; Glioma; Goals; Growth; Health; Human; Immunohistochemistry; In Vitro; Ionizing radiation; Life; Link; Malignant - descriptor; Malignant Glioma; Mannose; Measures; Mediating; Modeling; Modification; Mus; Normal Cell; Normal tissue morphology; Pathway interactions; Patients; Phenotype; Polysaccharides; Pre-Clinical Model; Protein Tyrosine Kinase; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regimen; Research; Role; Signal Transduction; Systemic Therapy; Testing; Therapeutic; Time; Toxic effect; Translations; Tumor Cell Invasion; Tumor Cell Line; Tumor Tissue; Tunicamycin; U251; Work; Xenograft Model; Xenograft procedure; adhesion receptor; angiogenesis; base; cancer cell; cell motility; cellular targeting; chemotherapy; cytotoxic; endoplasmic reticulum stress; glioma cell line; glycosylation; high throughput screening; imaging platform; improved; in vitro Model; in vivo; inhibitor/antagonist; insight; knock-down; lipooligosaccharide; migration; molecular imaging; molecular targeted therapies; neoplastic cell; novel; outcome forecast; pre-clinical; prevent; radiosensitizing; receptor; receptor expression; receptor sensitivity; receptor-mediated signaling; small molecule; small molecule inhibitor; targeted treatment; temozolomide; therapeutic target; tumor; tumor xenograft

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.

描述（由申请人提供）：受体酪氨酸激酶（RTK）是经过临床验证的靶标，可以通过阻断它来增强放射治疗的功效。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。我们已将蛋白质 N 连接糖基化 (NLG) 确定为一种共翻译蛋白质修饰，可用于减少多种过表达 RTK 的信号传导。 NLG 抑制在体外和体内均可使癌细胞放射增敏，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 和细胞表面受体存活信号传导并增强放射治疗。我们生成了具有 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电离辐射敏感性中的作用。我们还确定了一种阻断肿瘤细胞中 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 酶作为与放射治疗相结合的治疗抑制的基因靶标。该项目将为 NLG 对癌症生物学的贡献提供新的见解，并为增强放射治疗在恶性疾病的治疗中提供治疗靶点。