Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma

Abstract

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.

Pancreatic Cancer Chemoprevention Translational Workshop

“…Targeting of the epidermal growth factor receptor (EGFR) by Gefitinib or Erlotinib during the mPanIN-2 stage blocks the progression to mPanIN-3 and invasive carcinoma in a dose-dependent manner 88 . Similar efficacious effects were observed with Licofelone, a duel COX-2/5-LOX inhibitor 89 , while the combination of low-doses of Gefitinib and Licofelone completely abolished mPanIN progression to invasive carcinoma 90 . Among other repurposed and Food and Drug Administration (FDA) approved agents that were tested, both statins and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, sulindac, and celecoxib showed effective chemoprevention 91–97 .…”

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…Gefitinib reduces EGFR, proliferating cell nuclear antigen, cyclin D1, C2GNT, RhoA, β-catenin, p38, phosphor-extracellular signal-regulated kinase, caveolin-1 and mucin and increases cyclin B1 [4,7]. Gefitinib inhibits the incidence of PDAC in male (90%) and female (85%) mice [110].…”

“…Celecoxib, a COX-2 inhibitor, induces the inhibition of growth and apoptosis of cells with COX-2 expression, but it bears the risk of cardiovascular events [55,109,110]. Celocoxib inhibits VEGF by the suppression of SP1 [66].…”

“…Licofeleone inhibits the incidence of PDAC in male (72%) and female (90%) mice [110]. The pancreatic tumour weights were reduced; PanIN lesions and carcinoma were inhibited, the tumour cell proliferation was suppressed, apoptosis was induced and Matrix metalloproteases were reduced [110].…”

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

“…Using experimental test systems, licofelone was found to inhibit the formation of tumors, such as spontaneous intestinal tumors in APC Min/+ mice (17,25) and spontaneous urothelial cell carcinoma growth and invasion in UPII-SV40T transgenic mice (26), squamous cell carcinomas of the tongue in male F344 rats receiving 4-nitroquinoline-1-oxide in the drinking water (27), and lung adenomas induced by benzo[a]pyrene in female A/J mice receiving licofelone via oropharyngeal aspiration (28). In addition, especially when combined with the epidermal growth factor receptor (EGFR) inhibitor gefinitib, licofelone inhibited the incidence of pancreatic intraepithelial neoplasms and their progression to pancreatic ductal adenocarcinoma using p48 Cre/+-LSL-Kras G12D/+ mice expressing the activated Kras G12D oncogene (29). In that model, miRNAs characteristics of pancreatic tumorinitiating/cancer stem cells and inflammation were modulated by this NSAID (30).…”