Markers and therapeutic strategies for overcoming chemoradiotherapy resistance

放化疗(CRT)是治疗局部晚期颅脑损伤患者的一线非手术治疗方法。 颈部鳞癌(HNSCC)。这个小组和其他人之前的工作证明了 表皮生长因子受体(EGFR)的表达与CRT抵抗有关， RT的抗EGFR抗体西妥昔单抗(CET)改善了部分HNSCC患者的预后。 此外，人类乳头状瘤病毒(HPV)被认为是HNSCC患者的一个强有力的预后标志。 用CRT治疗。然而，相当大比例的患者经历了局部CRT抵抗 复发或远处转移。目前还没有有效的标志物来识别哪些HNSCC患者 最有可能从CRT方案中受益，以及对这些方案产生耐药性的机制， 以及如何克服它，目前尚不清楚。这些需求对于HPV阴性的患者尤其关键。 疾病。我们假设，通过系统的基因表达和蛋白质组学分析，HNSCC肿瘤来自于 接受CRT方案治疗的患者，可以识别候选预测标志物，并随后 使用来自两个大型随机III期试验的肿瘤注释样本进行验证，此外，我们 相信克服这种耐药性的治疗策略是可以确定的。我们的初步数据 支持这些假说。到目前为止，我们已经确定了几个与CRT相关的新标记 反应包括双链断裂修复蛋白Ku80；术后RT(PORT)信号；以及 上皮向间充质转化(EMT)的特征。我们还确定了几个目标，包括 端粒酶和Chk2，用于克服辐射抗性。因此，为了解决我们提出的未得到满足的需求 主要目标如下：1)寻找CRT抗性的候选基因表达和蛋白质组标记 使用HNSCC存档标本，然后与我们预定义的候选人和 来自项目1和3的标记，以供进一步测试。2)将测试最高优先级的标记，并可能 使用来自两个大型III期CRT研究(RTOG 0129和0522)的样本进行验证。3)我们将进行评估 哪些途径可以靶向克服HNSCC细胞在体内的治疗耐药。因此，这 该项目有可能产生有效的标志以及克服CRT的新策略 抵抗。该项目还受益于项目1和项目3以及其他主要项目的努力，并对其作出贡献。 研究相关问题的资助项目，包括HN和肺孢子。

Chemoradiotherapy (CRT) is a frontline non-surgical treatment for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Prior work from this group and others demonstrated that epidermal growth factor receptor (EGFR) expression was associated with CRT resistance, and that adding the anti-EGFR antibody cetuximab (CET) to RT improved outcomes in a subset of HNSCC patients. Furthermore, human papilloma virus (HPV) was identified as a strong prognostic marker in HNSCC patients treated with CRT. Nevertheless, a substantial percentage of patients experience CRT resistance with local relapse or distant metastases. There are cun-ently no validated markers to identify which HNSCC patients are most likely to benefit from CRT regimens, and the mechanisms underlying resistance to these regimens, and how to overcome it, remain unclear. These needs are particularly critical for patients with HPV-negative disease. We hypothesize that by systematic gene expression and proteomic profiling of HNSCC tumors from patients treated with CRT regimens, candidate predictive markers can be identified and subsequently validated using tumor annotated specimens from two large randomized phase III trials, Furthermore, we believe that therapeutic strategies for overcoming this resistance can be identified. Our preliminary data supports these hypotheses. Thus far we have identified several novel markers associated with CRT response including Ku80, a double-strand break repair protein; a post-operative RT (PORT) signature; and an epithelial-to-mesenchymal transition (EMT) signature. We have also identified several targets, including telomerase and Chk2, for overcoming radioresistance. Therefore, to address the unmet needs we proposed the following aims: 1) We will develop candidate gene expression and proteomic markers of CRT resistance using archival HNSCC specimens, and will then prioritize them together with our predefined candidates and markers from Projects 1 and 3, for further testing. 2) The top priority markers will be tested and potentially validated using specimens from two large phase III CRT studies (RTOG 0129 & 0522). 3) We will evaluate Which pathways can be targeted to overcome therapeutic resistance of HNSCC cells in vitno. Therefore, this project has the potential to yield validated markers of as well as new strategies for overcoming CRT resistance. The project also benefits from, and contributes to, the efforts of Projects 1 and 3 and other major grant programs investigating related issues including the HN and Lung SPOREs.