Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma
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Chinthalapally V. Rao1, Naveena B. Janakiram1, Venkateshwar Madka1, Vishal Devarkonda1, Misty Brewer1, Laura Biddick1, Stan Lightfoot1, Vernon E. Steele2, Altaf Mohammed1
1Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
2Division of Cancer Prevention, Chemopreventive Agent Development Research Group, National Cancer Institute, Bethesda, MD, USA
Chinthalapally V. Rao, e-mail: [email protected]
Altaf Mohammed, e-mail: [email protected]
Keywords: chemoprevention, inflammation, EGFR, pancreatic cancer
Received: July 31, 2015 Accepted: September 16, 2015 Published: September 28, 2015
Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders. Pancreata of mice receiving combination treatment showed significantly fewer Dclk1-positive cancer stem-like cells, inhibition of COX-2, 5-LOX, PCNA, EGFR and β-catenin expression (p < 0.05–0.0002), increased p21 expression. Significant changes in tumor immune responses and desmoplastic reaction was observed by NGS analysis in combination treatment (p < 0.05). In summary, early simultaneous targeting of 5-LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC.
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