Markers and therapeutic strategies for overcoming chemoradiotherapy resistance

克服放化疗耐药性的标志物和治疗策略

• 批准号: 8509639
• 负责人: John V. Heymach
• 金额: $ 26.76万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509639
• 关键词: Address; Antibodies; Candidate Disease Gene; Cetuximab; Cisplatin; Clinical; Collaborations; DNA Repair Pathway; Data; Data Set; Databases; Disease; Distant Metastasis; Distress; Double Strand Break Repair; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Formalin; Funding; Gene Expression; Gene Expression Profile; Grant; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immunohistochemistry; In Vitro; Individual; Instruction; Lung; Malignant Epithelial Cell; Mesenchymal; Meta-Analysis; Outcome; Paraffin Embedding; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Physicians; Population; Postoperative Period; Prognostic Marker; Proteins; Proteomics; Radiation Therapy Oncology Group; Radioresistance; Randomized; Regimen; Relapse; Research Personnel; Resistance; Signal Pathway; Signal Transduction; Societies; Source; Specialized Program of Research Excellence; Specimen; Telomerase; Testing; Therapeutic; Tissues; Toxic effect; Validation; XRCC5 gene; base; candidate marker; chemoradiation; clinical application; clinical practice; combat; design; epithelial to mesenchymal transition; experience; genome-wide; improved; in vitro Model; novel; novel marker; pre-clinical; preference; programs; randomized trial; receptor expression; resistance mechanism; response; response marker; therapeutic target; tumor; working group

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.

化学放疗（CRT）是针对局部晚期和局部晚期患者的前线非手术治疗 颈部鳞状细胞癌（HNSCC）。该小组的事先工作，其他人证明了 表皮生长因子受体（EGFR）表达与CRT抗性有关，并增加 抗EGFR抗体西妥昔单抗（CET）可改善HNSCC患者子集的结局。 此外，HNSCC患者的人乳头瘤病毒（HPV）被确定为强烈的预后标记 用CRT处理。然而，很大一部分患者在局部遇到CRT抗性 复发或远处转移。没有验证的标记来识别哪些HNSCC患者 最有可能受益于CRT方案，以及对这些方案的耐药性的机制， 以及如何克服它，尚不清楚。这些需求对于HPV阴性患者特别重要 疾病。我们假设通过系统的基因表达和HNSCC肿瘤的蛋白质组学分析 接受CRT方案治疗的患者，可以鉴定出候选预测标记，然后随后 使用肿瘤注释的标本进行了验证，此外，我们 相信可以确定克服这种抵抗的治疗策略。我们的初步数据 支持这些假设。到目前为止，我们已经确定了与CRT相关的几个新颖标记 响应包括Ku80，是双链破裂蛋白的响应；术后RT（端口）签名；和 上皮到间质转变（EMT）签名。我们还确定了几个目标，包括 端粒酶和CHK2，用于克服放射线。因此，为了满足我们提出的未满足需求 以下目的：1）我们将开发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，然后将它们与我们的预定义候选人一起确定优先级 项目1和3的标记，用于进一步测试。 2）将测试最高优先级标记，并可能进行 使用来自两项大型III期CRT研究（RTOG 0129＆0522）的样品进行了验证。 3）我们将评估 哪种途径可以靶向以克服VITNO中HNSCC细胞的治疗性抗性。因此，这个 项目有可能产生验证的标记以及克服CRT的新策略 反抗。该项目还从项目1和3和其他主要专业的努力中受益并为 赠款计划调查包括HN和肺孢子在内的相关问题。