p53 Biomarker and intervention in occupational cancer.
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-007590, 2011 Jun; :1-8
One of NIOSH's stated needs in the area of research methods for occupational cancer has been developing early markers of adverse health effects from workplace exposures and devising ways for interrupting the pathways between workplace exposures and resultant cancers. A potential model population for studying these issues is provided by asbestos-exposed workers for which there is a critical need for ways to detect those workers most at risk for the development of asbestos-related cancers as well as interventions to successfully treat and prevent their cancers. Thus, the purpose of this research has been two-fold: (1) to develop new biomarkers which will have high predictive value for the subsequent occurrence of asbestos-related disease, with a particular emphasis on the tumor suppressor gene p53 which is known to be altered by asbestos in many cases; and (2) to develop new interventions that could treat and prevent asbestos-related cancers that have an altered p53 gene, such as many lung cancers and mesotheliomas. For the first goal, we utilized the banked serum samples from a cohort of Finnish asbestosis cases who have been followed up for the occurrence of cancer to examine p53 auto-antibodies, since in many cases where p53 is mutated individuals develop an immune response against the structurally altered mutant protein. We were able to demonstrate that p53 autoantibody biomarkers do have significant predictive value for the development of cancer in asbestosis cases and in fact correlated with the changes in p53 found in the subsequent cancers; however, the sensitivity of this single biomarker was somewhat low. Therefore, we proceeded to use proteomic technology for additional biomarker discovery in the banked serum samples to improve the sensitivity for cancer detection. Preliminary results on a small sub-set of these samples suggested a proteomic profile in these samples of high sensitivity and specificity. One specific peak corresponded to transforming growth factor beta-1 (TGF beta1). An ELISA-based assay was then used to examine TGF beta1 in all samples, but statistical analysis showed that it was not specifically correlated with the development of cancer but rather with the severity and progression of the asbestosis. Subsequent proteomic analysis of all the samples from asbestos-related cancer cases and non-cancer controls yielded a different battery of protein biomarkers with high sensitivity and specificity as well as predictive value for the carcinogenic effects of asbestos exposure. Two of these peaks were identified as kinesin-family proteins, which could be plausibly related to both asbestos exposure and altered cell division leading to cancer. For the second goal, we initially constructed unique protein sequences from p53 that can cause cell death in mutant p53 pre-malignant and malignant cells (including lung cancer cells similar to those that occur in the asbestosis cohort) in cell culture when delivered as the peptide or as a mini-gene. Subsequently, we demonstrated the effectiveness of the most promising of these p53 peptides as therapy in vivo in animal models of nude mice xenografted with the same mutant p53 cancer cells. Such peptide therapies could interrupt the p53-dependent carcinogenic pathway between asbestos exposure and resultant cancers. Taken together, these results can be utilized in the workplace for the improvement of secondary prevention of asbestos-related cancers. For example, workers in high-risk cohorts due to their exposure can be screened with a battery of biomarkers (including p53 antibodies and kinesin proteins) to detect those individuals with the greatest likelihood of developing subsequent malignant disease. Workers who are identified by the p53 biomarker would then be candidates for a preventive intervention based on the p53 peptide therapy before clinical cancer develops. The intervention could also be used for those asbestos workers who have already developed a cancer with altered p53. The success of the treatment or prevention could be monitored by following the biomarker status.
Biomarkers; Cancer; Carcinogens; Carcinogenesis; Carcinogenicity; Cancer-rates; Exposure-assessment; Lung-cancer; Lung-disease; Mutagens; Mutagenesis; Pulmonary-cancer; Pulmonary-system-disorders; Pathogenesis; Pathogenicity; Risk-analysis; Risk-factors;
Author Keywords: ELISA; enzyme-linked immunosorbent assay; SELDI-TOF MS; surface-enhanced laser desorption/ionization time-of-flight mass spectrometry; TGF beta1; transforming growth factor beta-1
Paul W. Brandt-Rauf, Dr.P.H., M.D., Sc.D., Office of the Dean, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street, Chicago, IL 60612
Final Grant Report
Research Tools and Approaches: Cancer Research Methods
National Institute for Occupational Safety and Health
Columbia University Health Sciences