PROJECT SUMMARY/ABSTRACT Pancreatic cancer presents a significant public health problem due to its short median survival of six months and projections that deaths from pancreatic cancer will exceed those occurring from breast and colon cancer by 2030. Diagnosing pancreatic cancer at an early stage in patients would enable more efficient and effective intervention, but is hampered by a lack of diagnostic tools. This lack of diagnostic and screening strategies is especially poignant for individuals with two or more first-degree relatives with pancreatic cancer, who have a 9- to 32-fold increased risk. Novel diagnostics would also improve detection of metastases and discrimination between pancreatic cancer and benign pathologies, such as chronic pancreatitis. In addition, improved surveillance methods enable more effective therapeutic intervention upon detection of relapse. Therefore, there remains a pressing need for diagnostic and staging strategies for pancreatic cancer. As such, my ultimate goal is to establish an independent pancreatic cancer research laboratory at a major medical center with an active pancreatic cancer patient program, where I can strategically focus on glycosylation changes as biomarkers of disease and mediators of malignancy. If awarded, the K99/R00 career award will facilitate my transition to research independence, enhance my training in mouse models of disease and mass spectrometric techniques, as well as augment my proficiency at developing clinical-grade diagnostic assays and designing clinical trials under the tutelage of my primary mentor, Dr. David Tuveson. This two-year transition period will also enable extensive training in multiple reaction monitoring methodology for the mass spectrometric-based quantification of biomarker candidates in sera under the guidance of my co-mentor, Dr. Darryl Pappin. The network of great investigators at Cold Spring Harbor Laboratory and established collaborations will enhance my training, accelerate completion of the mentored phase of my proposal, and help me gain the knowledge and experience needed to transition into an independent faculty position. The mentored phase of my research proposal will focus on designing diagnostics for pre-invasive pancreatic cancer and developing better models of pancreatic cancer. During the independent phase, I will identify glycosylation changes during pancreatic cancer progression, and determine their functional relevance to pancreatic cancer. The glycan epitope CA19-9 is the only biomarker for pancreatic cancer. While CA19-9 can be used to follow treatment response, it cannot be used for early detection because it cannot distinguish between inflammatory conditions, such as pancreatitis, and pancreatic cancer. I hypothesize that modifying the manner in which this biomarker is evaluated will enhance its diagnostic utility. Specifically, since CA19-9 is a modification found on many proteins, the test can be altered to detect the presence of CA19-9 on ...