Extension of Radiotherapy Research

放射治疗研究的延伸

• 批准号: 9308230
• 负责人: Heath Devin Skinner
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308230
• 关键词: Address; Affect; Affinity Chromatography; Basic Science; Biological Assay; Biological Markers; Calcium; Cells; Chemicals; Clinical; Clinical Research; Clinical Trials; Communities; Coupled; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; Data; Disease; Gene Expression Regulation; Genetic; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Human papilloma virus infection; In Vitro; Malignant Epithelial Cell; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Outcome; PARP inhibition; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Prognostic Factor; Prognostic Marker; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radioresistance; Radiosensitization; Radiotherapy Research; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Surrogate Markers; Survival Rate; Testing; Transcriptional Regulation; Translating; Translational Research; Treatment outcome; Tumor Suppressor Proteins; Tumor Tissue; University of Texas M D Anderson Cancer Center; Work; Xenograft Model; base; cancer therapy; cancer type; chemoradiation; chemotherapy; clinically relevant; improved; improved outcome; in vivo; inhibitor/antagonist; insight; mRNA Expression; novel; outcome forecast; predictive marker; protein expression; radiation response; radiosensitive; repaired; response; response biomarker; tumor; tumor growth; ubiquitin ligase; ubiquitin-protein ligase

PROJECT SUMMARY HPV/p16-positive head and neck squamous cell carcinoma (HNSCC) patients have higher overall survival (OS) rates than do HPV/p16-negative patients. The primary treatment of this cancer is radiotherapy (RT) either alone or in combination with chemotherapy and HPV positivity is known to render tumors more sensitive to RT. However, to date, the underlying mechanisms of this favorable phenomenon remain unknown. The proposed study is aimed at addressing this important question via in vitro studies of molecular mechanisms, in vivo tests of tumor response, and analyses of human tumor tissue. Our long-term objective is to identify the mechanisms that govern favorable prognosis in HPV/p16-positive OPSCC and use this information to improve treatment outcomes for all patients. To fulfill this goal, we have generated preliminary data identifying a novel mediator of radioresistance, TRIP12, which is inhibited by p16 expression leading to enhanced response to radiotherapy. The immediate goals of this application are reflected by three specific aims: i) establish the regulatory connection between p16 and TRIP12 and determine the role of TRIP12 in radiation sensitivity, ii) examine the downstream effects of TRIP12 signaling on radioresponse, and iii) verify that TRIP12 expression is a prognostic marker in HNSCC as well as a predictive marker for radiosensitizers that target this signaling pathway. We hope that by delineating the novel p16-TRIP12 signaling network we can provide valuable insight into the phenomenon of radioresistance as well as develop rationally targeted radiosensitizers for clinical use.

项目摘要 HPV/P16阳性头和颈部鳞状细胞癌（HNSCC）患者的总生存率较高 （OS）比HPV/P16阴性患者的率。该癌症的主要治疗方法是放疗（RT） 已知单独或与化学疗法和HPV阳性结合使用会使肿瘤对RT更敏感。 但是，迄今为止，这种有利现象的基本机制仍然未知。提议 研究旨在通过对分子机制的体外研究，体内测试来解决这个重要问题 肿瘤反应和人类肿瘤组织的分析。我们的长期目标是确定 在HPV/p16阳性OPSCC中控制有利预后的机制并使用此信息来改进 所有患者的治疗结果。为了实现这一目标，我们生成了识别小说的初步数据 放射线抗性的介体Trip12，该介体受到p16表达的抑制，从而增强了对 放疗。该应用程序的直接目标反映了三个特定目的：i）建立 p16和Trip12之间的调节连接，并确定Trip12在辐射灵敏度中的作用，II） 检查Trip12信号传导对辐射响应的下游效应，并iii）验证Trip12表达 是HNSCC中的预后标志物，也是针对此信号的放射增感器的预测标记 路径。我们希望通过描述新颖的P16-TRIP12信号网络，我们可以提供宝贵的见解 进入放射线的现象，并发展为临床用途的合理靶向放射增敏剂。