The objective of this project is to determine the role of aldo-keto reductase family 1 member B10 (AKR1B10) in pancreatic carcinogenesis and to establish an efficient strategy for the prevention of pancreatic cancer using a potent AKR1B10 inhibitor. AKR1B10 belongs to the aldo-keto reductase (AKR) family and is a unique tumor biomarker that is over-expressed in smoking-related carcinomas including pancreas. AKR1B10 exhibits more restricted substrate specificity than that of most human AKR: only farnesal, geranylgeranial, retinal and carbonyls are its specific substrates. AKR1B10 could promote carcinogenesis in several ways, including regulating cellular fatty acid synthesis and isoprenoid metabolism, metabolizing highly active carbonyls, and regulating retinal homeostasis in the tumor. Our preliminary data further indicate the importance of AKR1B10 in pancreatic carcinogenesis. 1) We have demonstrated that i) 23/36 (64%) pancreatic adenocarcinomas over-expressed AKR1B10 and 70% patients with AKR1B10 over-expression were smokers. AKR1B10 was over-expressed in early precancerous PanIN lesions and in mouse pancreatic carcinomas with mutant Kras allele. 2) Silencing AKR1B10 by siRNA in pancreatic carcinoma cells resulted in induction of apoptosis and inhibition of protein prenylation including Kras and HDJ2. 3) Diclofenac and Sulindac [non- steroidal anti-inflammatory drugs (NSAIDs)] are competitive inhibitors of AKR1B10. Our studies showed that diclofenac and sulindac inhibited AKR1B10 activity and reduced Kras protein prenylation in pancreatic carcinoma cells, and significantly inhibited pancreatic carcinogenesis and increased animal survival in the two genetically engineered mouse models of pancreatic cancers. 4) Transgenic flox-p AKR1B10fl/fl mice (AKR1B10fl/fl) and several powerful murine models of pancreatic carcinoma have been fully developed and well used in our lab. Our hypothesis is that knockout or inhibition of AKR1B10 will inhibit the development of pancreatic carcinoma, mechanistically through i) inhibiting activation of oncogenic Kras protein and other key prenylated proteins via metabolizing isoprenoids, ii) affecting carbonyl metabolism and/or iii) regulating retinal homeostasis in tumors. We will perform the following specific Aims to test this hypothesis:
Aim 1 : To determine the chemopreventive effects and mechanism of diclofenac on mutant Kras-driven and pancreatitis-enhanced carcinogenesis in Pdx1Cre-KrasG12D mice (called PanKras).
Aim 2 : To determine the role of AKR1B10 gene deficiency in pancreatic carcinogenesis using a most powerful mouse model of the tri-transgenic Pdx1Cre-KrasG12D-AKR1B10fl/fl mice (called PanKras/AKR1B10) that concurrently knockout AKR1B10 and activating KrasG12D allele in the pancreatic Pdx1+ progenitor cells.
Aim 3 : To determine the synergistic effect of retinol (vitamin A) and diclofenac on inhibiting pancreatic carcinogenesis in PanKras mice and to determine if the synergistic effect of vitamin A and diclofenac is via modulating retinal homeostasis in the tumor.

Public Health Relevance

Smoking and chronic pancreatitis are the most clearly established risk factors for the development of pancreatic cancer. Chronic pancreatitis leads to malabsorption and nutritional deficiency, particularly of fat-soluble vitamins including vitamin A. AKR1B10 is a unique tumor biomarker that is over-expressed in smoking related carcinomas such as pancreas and is involved in down-regulation of anti-neoplastic retinoic acid. Therefore, the importance of this project is to develop a new and efficient strategy for the prevention of highly lethal pancreatic cancer through targeting AKR1B10.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA164041-05
Application #
9093761
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Project Start
2012-08-09
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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