Infiltrating pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall five-year survival rate of less than five percent. The high mortality rate associated w/ith PDAC is primarily due to the late stage at which disease is diagnosed and the resistance of pancreatic cancer to traditional chemotherapy and radiotherapy treatment approaches. These observations highlight the critical need for early detection of pancreatic neoplasia at a stage where surgical resection can be curative. The major goal of this proposal will be to use state-of-the-art mass spectrometry and genetically engineered mouse models representing preinvasive or early, organ-confined stages of pancreatic neoplasia to identify a comprehensive set of biomarkers that can be used in combination to prospectively diagnose early neoplasic disease in humans.
In Aim 1, we will identify serum biomarkers in genetically inbred mice that express an activated allele of Kras (KrasG12D) in the pancreatic ductal epithelium and in mice with KrasG12D expressed on a p16lnk4a- or p53-deficient background. Constitutive activation of KRAS is observed in over 90% of PDAC cases and it likely represents one of the earliest genetic lesions in pancreatic cancer.
Aim 2 will utilize newly-derived pancreatic ductal cell lines from the same animal models described in Aim 1 to characterize the complete spectrum of changes that occur in the cell-surface proteome and in the secretome as neoplasia progresses from preinvasive lesions to fully metastatic disease.
In Aim 3, we will utilize histology-guided MALDI-TOF MS tissue profiling to identify biomarkers associated with early-stage pancreatic neoplasia using pancreatic tissue from the animal models. From these results, we expect to compile a comprehensive set of biomarkers for detection of early-stage pancreatic cancer. Finally, in Aim 4, we will test the specificity and sensitivity of the early-stage biomarkers identified in the murine system for their ability to diagnose pancreatic neoplasia using human serum samples collected from healthy donors and cases representing chronic pancreatitis and PDAC. The goal of these studies will be the development of an antibody-based diagnostic assay that can be used to screen high-risk patients for pancreatic cancer.

Public Health Relevance

Pancreatic cancer is the fourth leading cause of cancer death, accounting for approximately 33,000 deaths annually in the United States. Surgical resection ofthe tumor remains the best treatment option but this is often not possible given the advanced stage at initial diagnosis. The primary goal of this project is to use genetically engineered mouse models of early-stage pancreatic neoplasia to derive a comprehensive set of serum biomarkers that can be used to diagnose early-stage pancreatic cancer in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA101955-10
Application #
8707203
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Hwang, Chang-Il; Boj, Sylvia F; Clevers, Hans et al. (2016) Preclinical models of pancreatic ductal adenocarcinoma. J Pathol 238:197-204
Kim, Harrison; Samuel, Sharon; Lopez-Casas, Pedro et al. (2016) SPARC-Independent Delivery of Nab-Paclitaxel without Depleting Tumor Stroma in Patient-Derived Pancreatic Cancer Xenografts. Mol Cancer Ther 15:680-8
Baker, Lindsey A; Tiriac, Hervé; Clevers, Hans et al. (2016) Modeling pancreatic cancer with organoids. Trends Cancer 2:176-190
Tzou, Ywh-Min; Bailey, Sarah K; Yuan, Kaiyu et al. (2016) Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer. Bioorg Med Chem Lett 26:1237-44
Biffi, G; Öhlund, D; Tuveson, D (2016) Building up the tension between the epithelial and stromal compartment in pancreatic ductal adenocarcinoma. Cell Death Differ 23:1265-6
Chio, Iok In Christine; Jafarnejad, Seyed Mehdi; Ponz-Sarvise, Mariano et al. (2016) NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell 166:963-76
Schultz, Matthew J; Holdbrooks, Andrew T; Chakraborty, Asmi et al. (2016) The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype. Cancer Res 76:3978-88
Nam, Ki-Hwan; Kim, Peter; Wood, David K et al. (2016) Multiscale Cues Drive Collective Cell Migration. Sci Rep 6:29749
Jones, Jacqueline; Mukherjee, Angana; Karanam, Balasubramanyam et al. (2016) African Americans with pancreatic ductal adenocarcinoma exhibit gender differences in Kaiso expression. Cancer Lett 380:513-22
Ho, Yen-Yi; Starr, Timothy K; LaRue, Rebecca S et al. (2016) Case-oriented pathways analysis in pancreatic adenocarcinoma using data from a sleeping beauty transposon mutagenesis screen. BMC Med Genomics 9:16

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