EGFR/Radiation Response and Resistance Interactions

EGFR/放射反应和耐药性相互作用

• 批准号: 7148320
• 负责人: PAUL M HARARI
• 金额: $ 26.09万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148320
• 关键词: neoplasm /cancer

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.

描述（由申请人提供）：细胞表面膜信号蛋白表皮生长因子受体（EGFR）已成为抗癌治疗的最有希望的分子靶标之一。该研究建议的长期目标是获得新信息，以指导癌症患者中EGFR分子抑制剂的最佳使用。拟议的研究将利用新建立的EGFR抑制剂耐药的人肿瘤细胞来检查EGFR抑制剂和辐射之间的细胞相互作用，并探索克服对EGFR抑制剂疗法的内在或获得性抗性的策略。然后，通过对参加临床试验的患者的肿瘤标本的分子分析，将进一步研究来自肿瘤模型系统中临床前研究结果的有希望的铅。第一个科学的目的是表征EGFR抑制剂和父母肿瘤细胞之间在其分子足迹和辐射反应曲线方面的特定差异。这些体外和体内研究将检查EGFR抑制剂耐药和敏感肿瘤之间的分子区别，并使用高通量分析鉴定基因和蛋白质表达差异。第二个科学目的是探索蛋白质改变的功能意义和基因表达在随后的EGFR抑制剂和辐射反应方面的变化。这些临床前研究将包括对可能在阻力机制中发挥作用的有希望的分子靶标的系统评估。第三个科学目的是研究这些分子靶标，这些靶标表征了EGFR抑制剂耐药性的特征，并将其表达与参加国家癌症试验的患者的人类肿瘤标本中的最终临床结果相关联。可以预料，这些研究将提供有关对EGFR抑制剂的反应机制和抵抗力的宝贵信息，从而促进创新癌症治疗策略的设计以改善预后。公共卫生描述：我们许多最有前途的癌症药物仅在少数晚期肿瘤患者中显示出有益的影响。大多数肿瘤表现出某种形式的对药物治疗的抵抗力。在这项研究建议中，我们试图通过鉴定和禁用促进治疗耐药性的特定肿瘤细胞分子而从领皮药中受益的癌症患者的百分比。