Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer.

Abstract

PURPOSE:

COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/erlotinib in preclinical models of pancreatic cancer.

EXPERIMENTAL DESIGN:

Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined.

RESULTS:

COX-2 inhibition reduced the IC(50) of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression.

CONCLUSIONS:

Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer.

• Authors: Amanda Kirane, Jason E Toombs, Katherine Ostapoff, Juliet G Carbon, Sara Zaknoen, Jordan Braunfeld, Roderich E Schwarz, Francis J Burrows, Rolf A Brekken
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 18 Pg. 5031-42 (Sep 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22829202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Pyrroles
• Quinazolines
• Sulfonamides
• apricoxib
• Erlotinib Hydrochloride
• Cyclooxygenase 2
• ErbB Receptors

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Metastasis
• Neovascularization, Pathologic (drug therapy)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Pyrroles (administration & dosage, pharmacology, therapeutic use)
• Quinazolines (pharmacology)
• Sulfonamides (administration & dosage, pharmacology, therapeutic use)