Extension of Radiotherapy Research

项目摘要 HPV/p16阳性头颈部鳞状细胞癌（HNSCC）患者的总生存率较高 (OS)HPV/p16阴性的患者。这种癌症的主要治疗方法是放射治疗（RT）， 已知单独或与化疗和HPV阳性组合使肿瘤对RT更敏感。 然而，迄今为止，这种有利现象的潜在机制仍然未知。拟议 本研究旨在通过体外分子机制研究、体内试验 肿瘤反应和人类肿瘤组织的分析。我们的长远目标是找出 控制HPV/p16阳性OPSCC良好预后的机制，并利用这些信息改善 所有患者的治疗结果。为了实现这一目标，我们已经生成了初步数据， 辐射抗性介质TRIP 12，其被p16表达抑制，导致对辐射抗性的反应增强。 放疗本申请的直接目标由三个具体目标反映： p16和TRIP 12之间的调节连接并确定TRIP 12在辐射敏感性中的作用，ii） 检查TRIP 12信号传导对放射应答的下游作用，和iii）证实TRIP 12表达 是HNSCC的预后标志物，也是靶向该信号传导的放射增敏剂的预测标志物 通路我们希望通过描绘新的p16-TRIP 12信号网络，我们可以提供有价值的见解 研究放射抵抗现象，开发合理的靶向放射增敏剂用于临床。

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.