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.
