Human pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in adults in the United States. As underscored by the NCI-sponsored Report of the Pancreatic Cancer Progress Review Group there is a tremendous need to develop novel biomarkers and novel therapeutic strategies. Thus, it is important to determine whether there are informative molecular biomarkers that can be identified for diagnostic purposes. This proposal focuses on microRNAs (miRNAs) as potential biomarkers in PDAC. miRNAs are a recently- discovered class of short non-coding RNA genes, which act as post-transcriptional negative regulators of gene expression. Altered expression of specific subsets of miRNAs has been linked to different types of leukemias and solid tumors, and they appear to have potential clinical value as biomarkers for early detection, diagnosis and/or prognosis. Moreover, their small size makes them less sensitive than messenger RNAs (mRNAs) of protein-encoding genes to degradation often associated with processing of tissue for formalin-fixation and paraffin-embedding (FFPE) or cell preparation obtained by endoscopic ultrasound-guided (EUS) fine needle aspiration (FNA). Thus, miRNAs may be more suitable biomarkers than mRNAs for expression characterization in archival tissue specimens and FNA cell samples obtained from the pancreas. Our preliminary studies (and/or reports from other groups) have linked a small subset of miRNAs to PDAC. In addition, we have implemented a miRNA in situ hybridization (ISH) protocol that permits the quantification of miRNA expression within individual cells in paraffin-embedded pancreatic tissue or in cell suspension. This pioneering technique will allow us to evaluate whether changes of miRNA expression occur within the cancer cells in PDAC and/or within the ad- joining stromal and parenchymal elements, and whether these changes are already manifested at early stages of malignancy such as pancreatic intraepithelial lesions. Here, we propose to conduct a thorough investigation aimed at: 1) Identifying the best subset of miRNAs to discriminate PDAC from benign lesions and chronic pancreatitis; 2) Assessing the clinical value of this selected subset in a sample of 150 archival patient cases; and 3) Implementing ISH methodology for potential clinical application of miRNAs as early detection or diagnostic biomarkers on FNA samples.

Public Health Relevance

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy in which mortality virtually equals incidence, yet for which there are no early diagnostic markers. miRNAs are a novel class of regulatory RNAs with great importance in cancer biology. We propose that changes in miRNA expression are linked to the initiation and/or progression of PDAC, and that characterization of these changes will provide the basis for assessing in a clinical setting the value of these miRNAs as novel biomarkers for early detection and diagnosis of PDAC when used in conjunction with endoscopic ultrasonography. ? ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA133715-01A1
Application #
7535727
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Thurin, Magdalena
Project Start
2008-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$251,843
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Sempere, Lorenzo F; Korc, Murray (2013) A method for conducting highly sensitive microRNA in situ hybridization and immunohistochemical analysis in pancreatic cancer. Methods Mol Biol 980:43-59
Preis, Meir; Gardner, Timothy B; Gordon, Stuart R et al. (2011) MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma. Clin Cancer Res 17:5812-21
Sempere, Lorenzo F; Preis, Meir; Yezefski, Todd et al. (2010) Fluorescence-based codetection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumors. Clin Cancer Res 16:4246-55
Szafranska, Anna E; Doleshal, Martina; Edmunds, Hayward S et al. (2008) Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. Clin Chem 54:1716-24