Extension of Radiotherapy Research

项目总结 HPV/p16阳性的头颈部鳞状细胞癌患者总体生存率较高 (OS)发生率高于HPV/p16阴性患者。这种癌症的主要治疗方法也是放射治疗。 已知单独或联合化疗和HPV阳性可使肿瘤对RT更敏感。 然而，到目前为止，这种有利现象的潜在机制仍不清楚。建议数 这项研究旨在通过分子机制的体外研究、体内试验来解决这一重要问题 以及对人类肿瘤组织的分析。我们的长期目标是确定 控制HPV/p16阳性OPSCC预后良好的机制并利用这一信息改善 所有患者的治疗结果。为了实现这一目标，我们生成了识别一部小说的初步数据 辐射抗性的介体TRIP12被p16的表达抑制，导致对 放射治疗。这个应用程序的直接目标体现在三个具体目标上：i)建立 P16和TRIP12之间的调节联系并确定TRIP12在辐射敏感性中的作用，II) 检查TRIP12信号对辐射反应的下游影响，以及iii)验证TRIP12的表达 是HNSCC的预后标志物，也是靶向该信号的放射增敏剂的预测性标志物 路径。我们希望通过描绘新的p16-trip12信令网络，能够提供有价值的见解。 研究辐射抵抗现象，并开发合理的靶向放射增敏剂供临床使用。

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.