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Overcoming resistance to antiangiogenic therapies
Sabine Tejpar1, Hans Prenen, Massimiliano Mazzone
1Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, Leuven B-3000, Belgium. sabine.tejpar@uz.kuleuven.ac.be
Abstract:
The concept of targeting new blood vessel formation, or angiogenesis, in tumors is an important advancement in cancer therapy, resulting, in part, from the development of such biologic agents as bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF)-A. The rationale for antiangiogenic therapy is based on the hypothesis that if tumors are limited in their capacity to obtain a new blood supply, so too is their capacity for growth and metastasis. Additional evidence suggests that pruning and/or "normalization" of irregular tumor vasculature and reduction of hypoxia may facilitate greater access of cytotoxic chemotherapy (CT) to the tumor. Indeed, for metastatic colorectal cancer, bevacizumab in combination with established CT regimens has efficacy superior to that of CT alone. Despite ~2-month longer progression-free and overall survival times than with CT alone, patients still progress, possibly because of alternative angiogenic "escape" pathways that emerge independent of VEGF-A, or are driven by hypoxic stress on the tumor. Other VEGF family members may contribute to resistance, and many factors that contribute to the regulation of tumor angiogenesis function as part of a complex network, existing in different concentrations and spatiotemporal gradients and producing a wide range of biologic responses. Integrating these concepts into the design and evaluation of new antiangiogenic therapies may help overcome resistance mechanisms and allow for greater efficacy over longer treatment periods.
Insights
Targeting tumor blood vessel formation (angiogenesis) with agents like bevacizumab improves cancer therapy. However, tumors can develop resistance through alternative pathways, necessitating new therapeutic strategies.
Area of Science:
- Oncology
- Cancer Biology
- Vascular Biology
Background:
- Targeting tumor angiogenesis, the formation of new blood vessels, is a key cancer therapy strategy.
- Bevacizumab, a VEGF-A inhibitor, has shown efficacy in combination with chemotherapy for metastatic colorectal cancer.
- Tumor vasculature normalization and hypoxia reduction may enhance chemotherapy delivery and efficacy.
Purpose of the Study:
- To explore the rationale and efficacy of anti-angiogenic therapy in cancer treatment.
- To investigate mechanisms of resistance to anti-angiogenic agents like bevacizumab.
- To highlight the need for integrated approaches to overcome therapeutic resistance.
Main Methods:
- Review of existing literature on angiogenesis, bevacizumab, and chemotherapy in cancer.
- Analysis of clinical outcomes for bevacizumab combined with chemotherapy.
- Discussion of tumor escape pathways and resistance mechanisms.
Main Results:
- Bevacizumab plus chemotherapy demonstrates superior progression-free and overall survival compared to chemotherapy alone in metastatic colorectal cancer.
- Despite initial benefits, patients eventually progress, indicating the emergence of resistance.
- Resistance may involve alternative angiogenic pathways independent of VEGF-A or driven by tumor hypoxia.
Conclusions:
- Anti-angiogenic therapy is a valuable addition to cancer treatment, but resistance remains a challenge.
- Understanding the complex network regulating tumor angiogenesis is crucial for overcoming resistance.
- Developing novel anti-angiogenic therapies that target multiple pathways may improve long-term efficacy.
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