EGFR/Radiation Response and Resistance Interactions

描述(申请人提供)：表皮生长因子受体(EGFR)，一种细胞表膜信号蛋白，已成为最有希望的抗癌治疗的分子靶点之一。这项研究提案的长期目标是获得新的信息，以指导癌症患者最佳使用EGFR分子抑制剂。这项拟议的研究将利用新建立的具有EGFR抑制剂抗性的人类肿瘤细胞来检查EGFR抑制剂与辐射之间的细胞相互作用，并探索克服对EGFR抑制剂治疗的内在或获得性耐药性的策略。来自肿瘤模型系统临床前发现的有希望的线索将通过对参加临床试验的患者的肿瘤样本的分子分析来进一步检验。第一个科学目标是确定耐EGFR抑制剂的肿瘤细胞和亲本肿瘤细胞在分子足迹和辐射反应方面的具体差异。这些体外和体内研究将检验耐EGFR抑制剂的肿瘤和敏感肿瘤之间的分子差异，并使用高通量分析确定基因和蛋白质表达的差异。第二个科学目的是探索改变的蛋白质和基因表达变化对随后的EGFR抑制剂和辐射反应的功能意义。这些临床前研究将包括对可能在耐药机制中发挥作用的有希望的分子靶点进行系统评估。第三个科学目标是研究这些表征EGFR抑制剂耐药特征的分子靶点，并将它们的表达与参加国家癌症试验的患者的人类肿瘤标本的最终临床结果相关联。预计这些研究将提供关于EGFR抑制剂的反应和耐药机制的有价值的信息，从而促进创新的癌症治疗策略的设计，以改善结果。公共卫生描述：我们的许多最有希望的抗癌药物只在少数晚期肿瘤患者中显示出有益的影响。大多数肿瘤对药物治疗表现出某种形式的抗药性。在这项研究提案中，我们寻求通过识别和禁用促进治疗耐药的特定肿瘤细胞分子来增加从主要抗癌药物中受益的癌症患者的比例。

DESCRIPTION (provided by applicant): The Epidermal Growth Factor Receptor (EGFR), a cell surface membrane signaling protein, has emerged as one of the most promising molecular targets for anti-cancer therapy. The long-term objective of this research proposal is to gain new information to guide the optimal use of molecular inhibitors of EGFR in cancer patients. The proposed studies will take advantage of newly established EGFR inhibitor-resistant human tumor cells to examine cellular interactions between EGFR inhibitors and radiation, and explore strategies to overcome intrinsic or acquired resistance to EGFR inhibitor therapy. Promising leads from preclinical findings in tumor model systems will then be further examined by molecular analysis of tumor specimens from patients enrolled in a clinical trial. The first scientific aim is to characterize specific differences between EGFR inhibitor-resistant and parental tumor cells with regard to their molecular footprint and radiation response profile. These in vitro and in vivo studies will examine molecular distinctions between EGFR inhibitor-resistant and sensitive tumors, and identify gene and protein expression differences using high-throughput analyses. The second scientific aim is to explore the functional significance of altered protein and gene expression changes with regard to subsequent EGFR inhibitor and radiation response. These preclinical studies will include systematic evaluation of promising molecular targets that may play a role in the resistance mechanism. The third scientific aim is to investigate these molecular targets that characterize the EGFR inhibitor-resistant profile, and correlate their expression with ultimate clinical outcome in human tumor specimens from patients enrolled in a national cancer trial. It is anticipated that these studies will provide valuable information regarding mechanisms of response and resistance to EGFR inhibitors, and thereby facilitate the design of innovative cancer treatment strategies to improve outcome. Public Health Description: Many of our most promising cancer drugs show beneficial impact in only a minority of patients with advanced tumors. The majority of tumors exhibit some form of resistance to drug treatment. In this research proposal, we seek to increase the percentage of cancer patients who benefit from leading cancer drugs through the identification and disabling of specific tumor cell molecules that promote treatment resistance.