Only 15 % of pancreatic cancer patients'tumors are manageable via surgical resection. However, chemotherapy is often not effective because of drug resistance. Searching for a molecule (or protein) that affects drug resistance has become a focused theme in pancreatic cancer research. Preliminary studies Our preliminary studies show that;1) Nrf2 protein levels are frequently increased in both nucleus and cytoplasm in pancreatic cancer tissues and cell lines;2) significantly more active DNA-binding Nrf2(s) are present in cancer cells (comparing to normal cells);3) there are a good correlation between Nrf2 expression level vs. drug resistance;4) Nrf2 expression level affects the numbers of Hoechst 33342 positive cells;5) PI-103 affects Nrf2 transcriptional regulation activity;and 6) PI-103 reduces drug resistance in combination with chemotherapeutic drug. Hypothesis 1) Controlling Nrf2 expression level in pancreatic cancer will alter anti-tumor drug sensitivity. 2) Pretreatment of PI-103 will enhance cytotoxic effects of antitumor agents on pancreatic cancer.
Aims We propose to;SA1) confirm if inhibition of Nrf2 activity reduces drug resistance in in vivo;SA2) identify the mechanism of PI-103 in sensitizing chemotherapeutic drug in pancreatic cancer cell lines;and SA3) test if PI-103 can sensitize chemotherapeutic drug in mice model. Significance Our study will provide a new treatment regimen for pancreatic cancer by suggesting Nrf2 as a target molecule and by testing a candidate small molecule that can increase drug sensitivity.

Public Health Relevance

Pancreatic cancer is the fourth most common human malignant tumor;less than 5 percent of patients can survive longer than 5 years after diagnosis. Although anti-tumor drugs and radiation therapies are current treatment options for these cancers, drug resistance frequently occurs. Little is known about the molecular mechanisms in which pancreatic cancers are resistance to chemotherapeutic drugs. We recently found potentially important clues about this drug resistance. We found significantly elevated levels of a certain protein, called as a "Master protein", in human pancreatic cancer tissues and cell lines. This mater protein has been once considered as "a good guy" that is induced in response to oxidative stresses and protects normal cells by regulating its target gene products that neutralize the stress-associated harmful toxins (e.g., Reactive Oxygen Species). However, our findings implicate the elevated levels of the master protein can be "a bad guy" from the therapeutic viewpoint, for this protein can confer drug resistance to pancreatic cancer cells. Since the master protein's target gene products (proteins) are known to have the capacity to destroy or eliminate chemotherapeutic drugs, the increased amounts of these target proteins could confer drug resistance. In addition, our preliminary studies identified a small molecule which inhibits master protein's activity. When cells preincubated with the small molecule were challenged with anti-tumor agents (e.g., Cisplatin), we observed enhanced cell killing effects and decreased of the expression of the master and its target proteins in in vitro cell culture system. Therefore, we propose to further investigate the therapeutic value of this small molecule with combination of clinically relevant anti- tumor agent(s) (e.g., Gemcitabine) in in vivo animal model. Our long-term goal is to increase our ability to kill pancreatic cancer cells by controlling the amounts of these proteins and by developing new drugs based upon our initial findings.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA152530-01
Application #
7977896
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2010-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$76,750
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Duong, Hong-Quan; Yi, Yong Weon; Kang, Hyo Jin et al. (2014) Combination of dasatinib and gemcitabine reduces the ALDH1A1 expression and the proliferation of gemcitabine-resistant pancreatic cancer MIA PaCa-2 cells. Int J Oncol 44:2132-8
Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong et al. (2013) Targeting mutant p53 by a SIRT1 activator YK-3-237 inhibits the proliferation of triple-negative breast cancer cells. Oncotarget 4:984-94
Duong, Hong-Quan; Hong, Young Bin; Kim, Jung Soon et al. (2013) Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine. J Cell Mol Med 17:1261-70
Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong et al. (2013) Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells. Mol Carcinog 52:667-75
Kim, Yeon Jeong; Hong, Young Bin; Cho, Chi Heum et al. (2012) Exploring protein kinase inhibitors: unveiling gemcitabine resistance in pancreatic cancer. Pancreas 41:804-5
Duong, Hong-Quan; Kim, Hee Jeong; Kang, Hyo Jin et al. (2012) ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human pancreatic adenocarcinoma cells to gemcitabine. Oncol Rep 27:182-8
Duong, Hong-Quan; Hwang, Jae Seok; Kim, Hee Jeong et al. (2012) BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis in human pancreatic cancer cells. Int J Oncol 41:2227-36
Kang, Hyo Jin; Hong, Young Bin; Kim, Hee Jeong et al. (2012) Bioactive food components prevent carcinogenic stress via Nrf2 activation in BRCA1 deficient breast epithelial cells. Toxicol Lett 209:154-60
Kim, Yeon Jeong; Hwang, Jae Seok; Hong, Young Bin et al. (2012) Transforming growth factor beta receptor I inhibitor sensitizes drug-resistant pancreatic cancer cells to gemcitabine. Anticancer Res 32:799-806
Hong, Young Bin; Kim, Jung Soon; Yi, Yong Weon et al. (2012) Exploring protein kinase inhibitors: potentiating gemcitabine efficacy in pancreatic cancer. Pancreas 41:496-8

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