P53 Biomark er and Intervention in Occupational Cancer

P53 职业癌症生物标志物和干预

• 批准号: 7776597
• 负责人: Paul W Brandt-Rauf
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7776597
• 关键词: P53; Biomark; er; Intervention; Occupational

DESCRIPTION (provided by applicant): Research Methods for Occupational Cancer are needed to develop early markers of adverse health effects from workplace exposures and to devise ways for interrupting the pathways between workplace exposures and resultant cancers. In this revision of a competing continuation application, we propose to expand on the success in the prior funding period which focused on p53 as a target for both of these approaches. For example, we have demonstrated that p53 autoantibody biomarkers have significant predictive value for the development of subsequent cancer in asbestosis cases but that the sensitivity is somewhat low. Therefore, in this renewal, we propose to utilize proteomic technology for additional biomarker discovery in the banked serum samples from this asbestosis cohort to improve the sensitivity for cancer detection; preliminary results on a small sub-set of these samples indicate the existence of a unique proteomic profile in these samples of high sensitivity and specificity. Therefore, analysis of all the samples and correlation of protein patterns with the subsequent development of cancer in the cohort members should ultimately yield a battery of protein biomarkers with high sensitivity and specificity as well as predictive value for the carcinogenic effects of asbestos exposure. Furthermore, we have also demonstrated that a unique protein sequence from p53 (C terminal amino acids 353-393 repeated as a palindromic tetramer) can cause apoptosis in mutant p53 lung cancer cells, similar to those that occur in the asbestosis cohort, in cell culture when delivered as the peptide with a leader sequence for cellular uptake or as a mini-gene in a plasmid via transfection or an adenovirus vector. Therefore, in this renewal, we propose to demonstrate the effectiveness of this therapy (delivered directly as the peptide or by adenovirus as the mini-gene) in vivo in animal models of nude mice xenografted with the same mutant p53 lung cancer cells. Such as peptide therapy would be useful for interrupting the p53-dependent carcinogenic pathway between asbestos exposure and resultant cancers.

描述（由申请人提供）：需要职业癌症研究方法来开发工作场所暴露对健康造成不良影响的早期标记，并设计中断工作场所暴露与由此产生的癌症之间途径的方法。在对竞争性延续申请的本次修订中，我们建议扩大先前资助期间的成功，该资助期间重点关注 p53 作为这两种方法的目标。例如，我们已经证明 p53 自身抗体生物标志物对于石棉肺病例中后续癌症的发展具有显着的预测价值，但敏感性较低。因此，在本次更新中，我们建议利用蛋白质组学技术在该石棉沉着病队列的库存血清样本中发现额外的生物标志物，以提高癌症检测的灵敏度；这些样品的一小部分的初步结果表明，这些样品中存在独特的蛋白质组谱，具有高灵敏度和特异性。因此，对所有样本的分析以及蛋白质模式与队列成员随后癌症发展的相关性最终应产生一系列具有高敏感性和特异性的蛋白质生物标志物，并对石棉暴露的致癌作用具有预测价值。此外，我们还证明，来自 p53 的独特蛋白质序列（C 端氨基酸 353-393 作为回文四聚体重复）可以导致突变 p53 肺癌细胞凋亡，类似于细胞培养中石棉沉着病组中发生的细胞凋亡当作为具有用于细胞摄取的前导序列的肽或通过转染或腺病毒载体作为质粒中的小基因递送时。因此，在本次更新中，我们建议在移植有相同突变型p53肺癌细胞的裸鼠动物模型中证明这种疗法（直接作为肽或通过腺病毒作为小基因传递）的体内有效性。例如，肽疗法可用于中断石棉暴露与由此产生的癌症之间的 p53 依赖性致癌途径。