Profiling Autoantibodies in Non-small Cell Lung Cancer with Fusion Protein-Peptid
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AbstractDESCRIPTION (provided by applicant): Approximately 135,000 new cases of non-small cell lung cancer (NSCLC) are diagnosed each year in the USA, yet only 20%-25% of those patients will be diagnosed at a sufficiently early stage to be cured by surgical or oth er procedures. When used in concert with radiographic imaging, a sensitive and specific blood test for NSCLC could be a clinically valuable and cost-effective tool for early diagnosis. The immune system responds to tumor-associated proteins by secreting au toantibodies long before metastasis occurs. Autoantibody profiling for this important group of circulating tumor markers in peripheral blood has lead us to the identification of appropriate target peptides. Using a T7 phage display library derived from the cDNA of a NSCLC line, we have developed a panel of eight peptides which were formatted as a protein microarray for use in a simple capture immunoassay (Zhong et al. 2006, J. Thoracic Oncol. 1(6), 513). When probed with a blood sample, the array can identi fy the presence of tumor-associated antibodies in NSCLC but not in normals with both sensitivity and a specificity exceeding 90% at early and later stages of the disease. As used to measure tumor-associated antibodies in serum from a cohort of cancer patie nts and risk- matched controls, this test affords predictive accuracy that exceeds that of currently available circulating NSCLC- associated protein markers. The overall purpose of this application is to achieve three aims: 1) subclone the DNA sequences en coding the eight peptides identified in our initial discovery effort into two fusion-expression vectors, 2) prepare microarrays of the fusion peptides described in aim 1 and demonstrate that they enable measurement of autoantibody profiles that can disting uish cancer from normal blood samples with unprecedented sensitivity and specificity. 3) Finally, we will acquire a cohort of 30 NSCLC and 30 at risk controls and validate the above peptides as bona fide lung cancer biomarkers using protein microarrays. Mi croarrays of the purified peptides will be used for rigorous optimization and standardization of all technical and clinical performance measures for the multi-target immunoassay. Our initial clinical application will be early detection of lung cancer, alth ough multiple applications in lung cancer management are rational. Our data shows feasibility and proof of concept that supports the rationale for further development and testing of this approach. A subsequent Phase II application will lead to use of an ap propriate platform for definitive marker validation trials for application to clinical screening of NSCLC. Thus the primary goal of this application is to develop a novel blood test for NSCLC that can be rapidly translated into clinical practice. PUBLIC H EALTH RELEVANCE: A blood test for early detection of lung cancer could provide a cost-effective screening approach, and in concert with CT scanning would enable a viable strategy for reducing the severe mortality rate of this disease.
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