A majority of pancreatic cancer (PC) patients (> 80%) present with an unresectable primary tumor withdistant metastasis at the time of diagnosis due to its asymptomatic nature and lack of methods for earlydetection. While the overall 5-year survival rate of PC is dismal, significantly better outcomes have beenreported for early stage smaller tumors. PC is believed to progress through a series of histologicalchanges and recent estimates indicate that these changes require 15-20 years to develop into invasivemetastatic disease, hence providing a window of opportunity to intervene. While early diagnosis is anobvious strategy to improve the survival of PC patients, lack of non-invasive biomarkers for risk predictionof precursor lesions or early stage invasive disease impedes our ability to diagnose PC during this?window. Premalignant cystic lesions of the pancreas offer unique opportunity for early diagnosis. To meetthe EDRN stated goal of performing a validation study for early cancer detection and risk assessmentlikely to yield meaningful results within 5 years, we propose an innovative approach that could lead to thedevelopment of a clinically useful biomarker in this time frame. Additionally, we propose to study cysticneoplasms since IPMN and MCN offer a unique opportunity to identify pancreatic premalignant lesionsand serve as a target for early detection strategies. The candidate biomarkers studies in our applicationhave been identified and evaluated over the past 5 years in EDRN-funded biomarker developmentallaboratories (BDLs). Studies from the laboratories of participating investigators have conclusivelyestablished that mucin overexpression is a hallmark of pancreatic cancer and have identified biomarkers(MUC5AC and its 2 glycoforms, MUC4 and a glycoform of endorepellin) that can effectively distinguish a)patients with resectable PC patients from patients with benign pancreatic diseases; b) mucinous and nonmucinouscysts; c) high-grade from moderate- and low-grade mucinous cysts and d). high-risk intestinaltype IPMNs and low risk gastric type IPMNs. The overall objective of this CVC proposal is to demonstratethe ability of the aforementioned biomarkers to distinguish pancreatic adenocarcinoma (PC) patients fromhealthy controls, patients with benign biliary obstruction and chronic pancreatitis (CP), and to identifythose cysts with high malignant potential. We have a large number of high quality, well-characterizedspecimens from patients with pancreatic disease and diseased controls that were collected and processedfollowing protocols developed through the EDRN.
Two specific aims are proposed.
Aim 1 will useavailable samples from our biospecimen repository to evaluate MUC5AC and MUC4 as biomarkers todistinguish pancreatic adenocarcinoma (PC) patients from healthy controls, and from patients with benignbiliary obstruction and chronic pancreatitis (CP).
Aim 2 will determine if our biomarkers can identify thosecysts with high lethal potential from those with a low risk for malignant transformation.
The objective of this Clinical Validation Center (CVC) proposal is to validate biomarkers (MUC5AC andMUC4) in blood; cystic fluids and tissues. While early diagnosis of pancreatic cancer (PC) can positivelyimpact prognosis; it remains challenging due to asymptomatic nature; lack of early biomarkers and limitedavailability of samples. Most importantly we propose to prospectively collect specimens from high risksubjects (pancreatic cystic neoplasms and PC) to evaluate biomarkers for risk diagnosis and prognosis.
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