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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs
Isabel Ben-Batalla1,2, Miguel Cubas-Cordova1,2, Florian Udonta1,2
1Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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 (PGE2) in breast cancer models. Upon Cox-2 inhibition PGE2 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 PGE2-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.
Insights
Blocking cyclooxygenase-2 (Cox-2) enhances anti-angiogenic therapies for breast cancer by normalizing prostaglandin E2 (PGE2) levels. This approach improves drug efficacy and reduces cancer-associated fibroblasts, offering a potential clinical strategy.
Area of Science:
- Oncology
- Cancer Research
- Pharmacology
Background:
- Anti-angiogenic therapies show promise but face resistance in cancers like breast cancer.
- Developing strategies to overcome resistance is crucial for improving treatment efficacy.
Purpose of the Study:
- To investigate the role of cyclooxygenase-2 (Cox-2) and prostaglandin E2 (PGE2) in resistance to anti-angiogenic therapy in breast cancer.
- To evaluate the efficacy of combining Cox-2 inhibition with anti-angiogenic treatments.
Main Methods:
- Breast cancer models were used to study the effects of anti-angiogenic therapies on Cox-2 and PGE2 levels.
- The impact of Cox-2 inhibition on the efficacy of anti-vascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib was assessed.
- Tumor infiltration of cancer-associated fibroblasts (CAFs) and levels of pro-angiogenic factors were analyzed after Cox-2 inhibition.
Main Results:
- Anti-angiogenic therapies upregulated Cox-2 and PGE2 in breast cancer models.
- Cox-2 inhibition normalized PGE2 levels and enhanced the efficacy of anti-VEGFR-2 antibodies and sunitinib.
- Combined treatment reduced CAF infiltration and levels of non-VEGF axis pro-angiogenic factors like HGF and FGF2.
- Cox-2 inhibition suppressed PGE2-induced CAF migration and proliferation by inhibiting Akt phosphorylation.
Conclusions:
- Cox-2 inhibition can overcome resistance and enhance the efficacy of anti-angiogenic therapies in breast cancer.
- Combined blockade of Cox-2 and VEGF signaling presents a promising strategy for clinical investigation.
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