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: 8703513
• 负责人: John V. Heymach
• 金额: $ 27.72万
• 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/8703513
• 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.

放化疗 (CRT) 是针对局部晚期头部和颈部疾病患者的一线非手术治疗方法。 颈部鳞状细胞癌（HNSCC）。该小组和其他人之前的工作表明 表皮生长因子受体 (EGFR) 表达与 CRT 耐药相关，并且添加 抗 EGFR 抗体西妥昔单抗 (CET) 联合放疗改善了部分 HNSCC 患者的预后。 此外，人乳头瘤病毒 (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。目前还没有经过验证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，仍不清楚。这些需求对于 HPV 阴性患者尤其重要 疾病。我们假设，通过对来自 HNSCC 肿瘤的系统基因表达和蛋白质组学分析， 对于接受 CRT 方案治疗的患者，可以识别候选预测标记物，然后 使用来自两项大型随机 III 期试验的肿瘤注释样本进行了验证，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，我们已经鉴定了几个与 CRT 相关的新标记物 反应包括 Ku80，一种双链断裂修复蛋白；术后 RT (PORT) 签名；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 Chk2，用于克服放射抗性。因此，为了解决未满足的需求，我们提出 目标如下： 1）我们将开发 CRT 耐药的候选基因表达和蛋白质组标记 使用存档的 HNSCC 标本，然后将它们与我们预定义的候选者一起进行优先排序， 来自项目 1 和 3 的标记，用于进一步测试。 2) 最优先的标记将被测试并可能 使用来自两项大型 III 期 CRT 研究（RTOG 0129 和 0522）的样本进行了验证。 3）我们将评估 可以针对哪些途径来克服 HNSCC 细胞在 vitno 中的治疗耐药性。因此，这 该项目有可能产生经过验证的标记以及克服 CRT 的新策略 反抗。该项目还受益于项目 1 和 3 以及其他主要项目的努力并为其做出贡献。 资助计划调查相关问题，包括 HN 和肺孢子。