Markers and therapeutic strategies for overcoming chemoradiotherapy resistance

放化疗（CRT）是一种一线非手术治疗局部晚期头部和 颈部鳞状细胞癌（HNSCC）。该小组和其他人先前的工作表明， 表皮生长因子受体（EGFR）表达与CRT抵抗相关， 抗EGFR抗体西妥昔单抗（CET）对RT改善了HNSCC患者亚组的结果。 此外，人乳头状瘤病毒（HPV）被确定为HNSCC患者的强预后标志物 用CRT治疗。然而，相当比例的患者在局部应用CRT时会出现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 最有可能受益于CRT方案，以及对这些方案产生耐药性的机制， 以及如何克服它，仍然不清楚。这些需求对于HPV阴性的患者尤其重要。 疾病我们假设，通过HNSCC肿瘤的系统基因表达和蛋白质组分析， 对于用CRT方案治疗的患者，可以鉴定候选预测标志物，并且随后 使用来自两个大型随机III期试验的肿瘤注释标本进行验证，此外，我们 相信可以确定克服这种耐药性的治疗策略。我们的初步数据 支持这些假设。到目前为止，我们已经确定了几个新的标记物与CRT 包括Ku 80（一种双链断裂修复蛋白）的反应;术后RT（PORT）特征;和 上皮-间质转化（EMT）特征。我们还确定了几个目标，包括 端粒酶和Chk 2，用于克服辐射抗性。因此，为了解决未满足的需求，我们建议 本研究的主要目的如下：1）开发CRT抗性的候选基因表达和蛋白质组学标记 使用档案HNSCC标本，然后将优先考虑他们与我们预先确定的候选人， 项目1和项目3的标记，用于进一步测试。2)将测试最高优先级的标记， 使用来自两项大型III期CRT研究（RTOG 0129和0522）的标本进行验证。3)我们将评估 可以靶向哪些途径来克服体外HNSCC细胞的治疗抗性。因此本 该项目有可能产生经过验证的标记以及克服CRT的新策略 阻力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， 资助项目调查相关问题，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.