Ninety percent of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). PDAC diagnosis is difficult, usually occurring in the late stages of disease. Patients with these advanced tumors typically respond poorly to therapy. Post diagnosis, median survival is 6 months and the five-year survival rate is <4%. Five-year survival is <1% for those with advanced cancer. Progression to advanced disease occurs with few, if any, symptoms but studies have shown that there is a long period of time during which early detection may be possible. There appears to be a timeline for detection of specific biomarkers during the disease's development: (1) in Stage 1a, mutations in K-RAS occur early when there are minimal visible cytological, morphological or symptomatic changes; (2) in Stages1b and 2, additional genetic mutations occur that lead to Her-2 overexpression and p16 inactivation; (3) in Stage 3, mutations occur in the TP53, DPC4, and BRCA2 genes. The lack of symptoms in the early stages means that patients go undetected until the later stages when treatments may not be as effective. It is not feasible to routinely test pancreatic tissues for markers of early disease and it has been difficult to identify disease markers in plasma, serum and/or urine that might enable early disease detection. The discovery of the accumulated mutations in many human pancreatic tumors, specifically in K-RAS and TP53, has suggested that pancreatic cancer animal models are useful for the study of disease development. These mouse models will be used to test the application of Ice COLD-PCR to the high sensitive detection of K- RAS and Trp53 mutations in urine and blood. Further, this model system will allow the study of pancreatitis- related progression to pancreatic cancer stage 1 in a mutant K-RAS background. Pancreatitis will be induced in these mice models which will enable a time-line investigation of early detection of K-RAS and Trp53 mutations in murine samples. The method will be further validated in several tissues from well-characterized human pancreatic autopsy samples, including pancreas, blood and urine. If promising results are obtained from these Phase I studies, a Phase II STTR application will include more comprehensive studies of Ice COLD-PCR detection of DNA mutations associated with early and late stage pancreatic cancer in humans. This could ultimately lead to a simple, highly sensitive diagnostic assay for the early detection of pancreatic ductal adenocarcinoma.
Public Health Relevance: Pancreatic cancer is difficult to diagnose at an early stage. In the disease's late stage response to therapy is poor with an average survival of 6 months after diagnosis and a five-year survival rate of less than 4%. We aim to develop a highly sensitive genetic test that can detect pancreatic cancer biomarkers in blood or urine, enabling much earlier diagnosis and more effective treatment.
Public Health Relevance Statement: Pancreatic cancer is difficult to diagnose at an early stage. In the disease's late stage response to therapy is poor with an average survival of 6 months after diagnosis and a five-year survival rate of less than 4%. We aim to develop a highly sensitive genetic test that can detect pancreatic cancer biomarkers in blood or urine, enabling much earlier diagnosis and more effective treatment.
NIH Spending Category: Cancer; Digestive Diseases; Genetics; Pancreatic Cancer; Prevention; Rare Diseases
Project Terms: advanced disease; Advanced Malignant Neoplasm; Animal Model; Animals; Ascites; Autopsy; base; Biological Assay; Biological Markers; Biological Models; Blood; BRCA2 gene; Breeding; Caerulein; Cancer Patient; Collection; Detection; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Disease; Disease Marker; Disease Progression; DNA; DNA Sequence; Early Diagnosis; effective therapy; Epithelial Cells; ERBB2 gene; ES01; Evaluation; Gene Mutation; Genes; Genetic screening method; Genetically Engineered Mouse; Genotype; Histology; Human; human tissue; Ice; improved; Investigation; Lead; Lesion; Liquid substance; Liver; MADH4 gene; Malignant neoplasm of pancreas; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Methodology; Methods; Modeling; Monitor; mouse model; Mucin-1 Staining Method; Mucous body substance; Mus; mutant; Mutation; Mutation Detection; Nature; Neoplasm Metastasis; overexpression; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; pancreatic neoplasm; Pancreatitis; Patients; Phase; phase 1 study; Plasma; Point Mutation; Primary Neoplasm; Process; Production; progression marker; Promotor (Genetics); recombinase; response; Sampling; Serum; Serum Markers; Services; Small Business Technology Transfer Research; Staging; Survival Rate; Symptoms; Testing; Time; TimeLine; Tissues; tool; TP53 gene; Transgenes; Transgenic Mice; Transgenic Organisms; tumor; Urine; Validation
