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Published on: December 9, 2015
Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies
Justin N Bottsford-Miller1, Robert L Coleman, Anil K Sood
1Departments of Gynecologic Oncology and Cancer Biology, University of Texas MD Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230-1439, USA.
Abstract:
Angiogenesis has long been considered an important target for cancer therapy. Initial efforts have primarily focused on targeting of endothelial and tumor-derived vascular endothelial growth factor signaling. As evidence emerges that angiogenesis has significant mechanistic complexity, therapeutic resistance and escape have become practical limitations to drug development. Here, we review the mechanisms by which dynamic changes occur in the tumor microenvironment in response to antiangiogenic therapy, leading to drug resistance. These mechanisms include direct selection of clonal cell populations with the capacity to rapidly upregulate alternative proangiogenic pathways, increased invasive capacity, and intrinsic resistance to hypoxia. The implications of normalization of vasculature with subsequently improved vascular function as a result of antiangiogenic therapy are explored, as are the implications of the ability to incorporate and co-opt otherwise normal vasculature. Finally, we consider the extent to which a better understanding of the biology of hypoxia and reoxygenation, as well as the depth and breadth of systems invested in angiogenesis, may offer putative biomarkers and novel therapeutic targets. Insights gained through this work may offer solutions for personalizing antiangiogenesis approaches and improving the outcome of patients with cancer.
Insights
Antiangiogenic cancer therapy faces resistance due to complex tumor microenvironment changes. Understanding these mechanisms, including hypoxia and reoxygenation, is key to developing personalized treatments and improving patient outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Angiogenesis is a critical target in cancer therapy, with early strategies focusing on vascular endothelial growth factor (VEGF) signaling.
- Therapeutic resistance and tumor escape are significant challenges in antiangiogenic drug development due to the complexity of angiogenesis.
Purpose of the Study:
- To review the mechanisms of tumor microenvironment adaptation leading to resistance against antiangiogenic therapy.
- To explore the implications of vascular normalization and co-option of host vasculature.
- To identify potential biomarkers and therapeutic targets through a deeper understanding of hypoxia and angiogenesis.
Main Methods:
- Review of existing literature on angiogenesis, cancer therapy, and tumor microenvironment dynamics.
- Analysis of mechanisms driving therapeutic resistance, including clonal selection and pathway upregulation.
- Exploration of the role of hypoxia, reoxygenation, and vascular co-option.
Main Results:
- Antiangiogenic therapy can lead to drug resistance through selection of resistant cell clones and upregulation of alternative proangiogenic pathways.
- Tumor cells can develop increased invasive capacity and intrinsic resistance to hypoxia.
- Vascular normalization and co-option of host vasculature present complex implications for treatment efficacy.
Conclusions:
- Understanding the dynamic changes in the tumor microenvironment is crucial for overcoming resistance to antiangiogenic therapies.
- Hypoxia, reoxygenation, and systems biology approaches may yield novel biomarkers and therapeutic targets.
- Personalized antiangiogenesis strategies informed by these insights can improve cancer patient outcomes.
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