Cyclooxygenase-2 inhibition potentiates the efficacy of vascular endothelial growth factor blockade and promotes an immune stimulatory microenvironment in preclinical models of pancreatic cancer

Yuqing Zhang, Amanda Kirane, Huocong Huang, Noah B. Sorrelle, Francis J. Burrows, Michael T. Dellinger, Rolf A. Brekken

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Resistance to standard therapy remains a major challenge in the treatment of pancreatic ductal adenocarcinoma (PDA). Although anti-VEGF therapy delays PDA progression, therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. COX-2 inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in PDA. Here, we evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of PDA. In vivo, the combination therapy was more effective in limiting tumor growth and metastasis than single-agent therapy. Combination therapy also reversed anti-VEGF-induced epithelial-mesenchymal transition and collagen deposition and altered the immune landscape by increasing tumor-associatedCD8+ T cells while reducing FoxP3+ T cells and FasL expression on the tumor endothelium. Implications: Together, these findings demonstrate that COX-2 inhibition enhances the efficacy of anti-VEGF therapy by reducing hypoxia-induced epithelial plasticity and promoting an immune landscape that might facilitate immune activation.

Original languageEnglish (US)
Pages (from-to)348-355
Number of pages8
JournalMolecular Cancer Research
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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