Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs

Abstract

// Isabel Ben-Batalla 1,2 , Miguel Cubas-Cordova 1,2 , Florian Udonta 1,2 , Mark Wroblewski 1,2 , Jonas S. Waizenegger 1,2 , Melanie Janning 1,2 , Stefanie Sawall 1,2 , Victoria Gensch 1,2 , Lin Zhao 1,2 , Iñigo Martinez-Zubiaurre 3 , Kristoffer Riecken 4 , Boris Fehse 4 , Klaus Pantel 2 , Carsten Bokemeyer 1 and Sonja Loges 1,2 1 Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 3 Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway 4 Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Sonja Loges, email: // Keywords : breast cancer, anti-angiogenic therapies, Cox-2, CAFs Received : September 28, 2014 Accepted : January 21, 2015 Published : January 31, 2015 Abstract Anti-angiogenic therapies were approved for different cancers. However, significant primary and secondary resistance hampers efficacy in several tumor types including breast cancer. Thus, we need to develop clinically applicable strategies to enhance efficacy of anti-angiogenic drugs. We report that anti-angiogenic therapies can induce upregulation of cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE 2 ) in breast cancer models. Upon Cox-2 inhibition PGE 2 levels were normalized and efficacy of anti-vascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib was enhanced. Interestingly, both treatments exerted additive anti-angiogenic effects. Following Cox-2 inhibition, we observed reduced infiltration of tumors with cancer-associated fibroblasts (CAFs) and lower levels of pro-angiogenic factors active besides the VEGF axis including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2). Mechanistic studies indicated that Cox-2 inhibition reduced PGE 2 -induced migration and proliferation of CAFs via inhibiting phosphorylation of Akt. Hence, Cox-2 inhibition can increase efficacy of anti-angiogenic treatments and our findings might pave the road for clinical investigations of concomitant blockade of Cox-2 and VEGF-signaling.