The overall goal of this project is to develop new serum and pancreatic juice markers of pancreatic cancer that can be used to diagnose patients with symptoms of their disease and to identify patients with early asymptomatic pancreatic cancer. The NCI Program review group (PRO) cited as a research priority- """"""""to identify and develop surveillance and diagnostic methods for the early detection of pancreatic cancer and its'precursors'"""""""". A panel of sensitive and specific markers of pancreatic adenocarcinoma would greatly facilitate the early diagnosis and early detection of this disease. We will examine three marker strategies that aim to detect pancreatic neoplasia in serum or in pancreatic juice.
Each aim focuses on specific, well-characterized protein or DNA markers that have already been the subject of phase 2 studies. One marker, serum MIC-1 (aim #l) has superior overall diagnostic sensitivity to CA19-9.
For aim #2 we will re-evaluate a well-known marker of pancreatic cancer, mutant KRAS. Previous studies have found that its detection in the pancreas lacks the necessary specificity to differentiate pancreatic cancer from pancreatitis. To overcome this lack of disease specificity, we have developed a novel, highly sensitive and specific assay (""""""""LigAmp"""""""") to detect and quantify point mutations such as mutant KRAS. Our preliminary phase 2 studies indicate that quantifying mutant KRAS significantly improves its diagnostic utility.
For aim #3 we will use a novel mutation detection approach that can detect unknown mutations in genes such as p53 and pi 6 when they are present at low concentration in clinical samples such as pancreatic juice (limiting dilution-PCR, or """"""""LD-PCR"""""""" and heteroduplex analysis (HA)). We will compare the results of 3A with those obtained using p53 Gene chips.
The specific aims we will pursue are:
Aim; 1: To determine the sensitivity and specificity of serum MIC-1;1A: as a marker of early pancreatic cancer. IB: as a predictor of asymptomatic pancreatic cancer in a population at high risk of developing this disease, and 1C;to determine the biological and clinical significance of pancreatic cancers that do not overexpress MIC-1.
Aim 2 A: To develop and validate five KRAS and one BRAF LigAmp assays to produce a panel for use in aim 2B. 2B: To demonstrate the diagnostic utility of LigAmp to detect and quantify KRAS2 and BRAF mutations in pancreatic juice and in serum from patients with pancreatic cancer and appropriate controls. 3A;To demonstrate the diagnostic utility of a novel assay (Limiting dilution PCR or LD-PCR with Heteroduplex analysis (HA)) to detect and quantify low abundance p53 and pi 6 mutations in the pancreatic juice of patients with pancreatic disease or undergoing pancreatic cancer screening. 3B;To compare the results of aim 3A (LD/PCR/HA) with p53 GeneChip for their ability to detect p53 mutations in pancreatic juice. We will also determine the diagnostic utility of combining the results of the markers derived from these 3 Aims.
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