P53 Biomark er and Intervention in Occupational Cancer

描述（由申请人提供）：需要职业癌症的研究方法，以开发工作场所照射对健康不利影响的早期标记，并设计出阻断工作场所照射与由此产生的癌症之间的途径的方法。在这一竞争性延续申请的修订中，我们建议在之前的资助期内扩大成功，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石棉沉滞病例的后续癌症发展具有重要的预测价值，但敏感性有些低。因此，在本次更新中，我们建议利用蛋白质组学技术在石棉沉滞队列的血清样本中发现额外的生物标志物，以提高癌症检测的敏感性；这些样品的一小部分的初步结果表明，在这些样品中存在一种独特的蛋白质组学特征，具有高灵敏度和特异性。因此，对所有样本进行分析，并将蛋白质模式与队列成员随后癌症发展的相关性进行分析，最终应产生一系列具有高灵敏度和特异性的蛋白质生物标志物，以及对石棉暴露致癌作用的预测价值。此外，我们还证明了p53的一个独特的蛋白质序列（C端氨基酸353-393作为回文四聚体重复）可以引起突变型p53肺癌细胞的凋亡，类似于石棉沉滞症队列中发生的情况，在细胞培养中，当作为具有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微型基因传递时。因此，在这次更新中，我们建议在移植了相同突变p53肺癌细胞的裸鼠动物模型中证明这种治疗（直接作为肽或通过腺病毒作为迷你基因传递）的有效性。如肽治疗将有助于中断石棉暴露和由此产生的癌症之间的p53依赖的致癌途径。

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.