Pancreatic cancer is a uniformly lethal disease because most patients have no symptoms until the cancer has spread and become inoperable. Moreover, once the cancer has formed, chemotherapy offers only minimal improvement in survival. Cancers that are 2 cm or smaller have a much better survival outcome than those that are larger. We propose to develop a serum based early detection test for pancreatic cancer. Nearly all serum cancer biomarker tests are based on the detection of proteins. Therefore, we will use proteomics technology to identify the proteins that are specific to pancreatic cancer and pre-cancer. Our preliminary data is exciting: 1) we have already identified and quantified 656 proteins in pancreatic cancer tissue, of which 90 proteins were up-regulated and 61 were down-regulated in cancer by at least a 2-fold change. 2) Validation studies to date suggest that the proteomics measurements are robust and accurate. The proteins have been analyzed with regard to function, nearly one quarter are extracellular/membrane proteins- thus excellent candidates for pancreatic cancer biomarker development (membrane proteins are shed into the blood). 3) Two of the discovered protein biomarkers, Annexin II and Integrin B1, have been further investigated;both of these proteins have marked over-expression in cancer cells, but not in normal pancreatic ducts or in non-ductal pancreatic cells when evaluated by tissue array and immunohistochemistry. 4) One of the proteins, Galectin 1, has been validated by western blotting and then developed into an ELISA. Galectin 1 could distinguish pancreatic cancer versus normal sera with 100% accuracy in preliminary testing. 5) We have developed a MALDI-TOF-TOF methodology for measuring proteins directly from serum, so that ELISA's would eventually not be necessary for biomarker detection. In this proposal, we describe our methods for the comprehensive development of candidate pancreatic cancer biomarkers and the algorithm that will be used to determine which biomarkers are best suited for development into a clinically useable test. The studies proposed here have the potential to significantly change the outcome in a disease that has made minimal headway in the past 100 years. The use of proteomics technology has enormous potential. Our proposed studies can lead to: earlier diagnosis- improving the prognosis of this deadly disease;better understanding of tumorigenesis in pancreatic cancer;targeted proteins for future therapeutic interventions including new drug/vaccine development;development of disease response markers.
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