P53 Biomark er and Intervention in Occupational Cancer

描述(申请人提供)：职业性癌症的研究方法需要开发工作场所暴露对健康不利影响的早期标记，并设计出阻断工作场所暴露与由此产生的癌症之间的途径的方法。在竞争延续申请的这次修订中，我们建议扩大前一个供资阶段的成功，该阶段侧重于将p53作为这两种方法的目标。例如，我们已经证明，在石棉肺病例中，P53自身抗体生物标记物对后续癌症的发展具有显著的预测价值，但敏感性较低。因此，在这次更新中，我们建议利用蛋白质组技术在来自石棉肺队列的银行血清样本中发现额外的生物标记物，以提高癌症检测的敏感性；对这些样本的一小部分的初步结果表明，在这些样本中存在着具有高敏感性和特异性的独特蛋白质组图谱。因此，对所有样本的分析和蛋白质模式与队列成员随后癌症发展的相关性最终应该会产生一系列具有高敏感性和特异性的蛋白质生物标记物，以及对石棉暴露的致癌影响的预测价值。此外，我们还证明了来自P53(C末端氨基酸353-393重复为回文四聚体)的独特蛋白质序列可以导致突变的P53肺癌细胞的凋亡，类似于在石棉肺队列中发生的情况，当作为带有细胞摄取的前导序列的多肽或作为微基因通过转染法或腺病毒载体在质粒中传递时，在细胞培养中发生的情况类似。因此，在这次更新中，我们建议在裸鼠移植相同突变的p53肺癌细胞的动物模型中证明这种治疗方法(直接作为多肽或通过腺病毒作为微基因)的有效性。例如，肽疗法将有助于阻断石棉暴露和由此导致的癌症之间依赖于P53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.