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Molecular Cancer Research
Molecular Cancer Research

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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 and Rolf A. Brekken
Yuqing Zhang
Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
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Amanda Kirane
Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.Division of Surgical Oncology, Department of Surgery, UC Davis Medical Center, Sacramento, California.
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Huocong Huang
Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
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Noah B. Sorrelle
Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
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Francis J. Burrows
Kura Oncology, Inc., La Jolla, California.
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Michael T. Dellinger
Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
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Rolf A. Brekken
Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
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  • For correspondence: rolf.brekken@utsouthwestern.edu
DOI: 10.1158/1541-7786.MCR-18-0427 Published February 2019
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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-associated CD8+ 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.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/2/348/F1.large.jpg.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received April 30, 2018.
  • Revision received August 2, 2018.
  • Accepted October 11, 2018.
  • Published first October 17, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Research: 17 (2)
February 2019
Volume 17, Issue 2
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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 and Rolf A. Brekken
Mol Cancer Res February 1 2019 (17) (2) 348-355; DOI: 10.1158/1541-7786.MCR-18-0427

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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 and Rolf A. Brekken
Mol Cancer Res February 1 2019 (17) (2) 348-355; DOI: 10.1158/1541-7786.MCR-18-0427
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