P53 Biomark er and Intervention in Occupational Cancer

P53 职业癌症生物标志物和干预

• 批准号: 7657375
• 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: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657375
• 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）： 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志物，并设计中断工作场所暴露与由此产生的癌症之间的途径的方法。在竞争性继续申请的修订中，我们建议扩大前一个资助期的成功，该资助期将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肺病例中后续癌症的发展具有显著的预测价值，但灵敏度有点低。因此，在这次更新中，我们建议利用蛋白质组学技术在石棉肺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;这些样本的一小部分的初步结果表明，这些样本中存在独特的蛋白质组学特征，具有高灵敏度和特异性。因此，对所有样本的分析以及蛋白质模式与队列成员中随后癌症发展的相关性最终应产生一组具有高灵敏度和特异性以及石棉暴露致癌作用预测价值的蛋白质生物标志物。此外，我们还证明了来自p53的独特蛋白质序列（C末端氨基酸353-393作为回文四聚体重复）可以在细胞培养物中作为具有用于细胞摄取的前导序列的肽或作为质粒中的微型基因通过转染或腺病毒载体递送时引起突变型p53肺癌细胞的凋亡，类似于石棉肺组群中发生的凋亡。因此，在这次更新中，我们建议在裸鼠异种移植相同突变型p53肺癌细胞的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）的体内有效性。如肽疗法将有助于中断石棉暴露和由此产生的癌症之间的p53依赖性致癌途径。

项目成果

Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo.

• DOI: 10.3390/biomedicines11020258
• 发表时间: 2023-01-18
• 期刊: Biomedicines
• 影响因子: 4.7

Serum growth factors in asbestosis patients.

石棉肺患者的血清生长因子。

• DOI: 10.1080/13547500802676868
• 发表时间: 2009
• 期刊: Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals
• 作者: Li,Yongliang;Karjalainen,Antti;Koskinen,Heikki;Vainio,Harri;Pukkala,Eero;Hemminki,Kari;Brandt-Rauf,PaulW
• 通讯作者: Brandt-Rauf,PaulW