| Breaking the barrier: a guidelines-based review of antiangiogenesis drug resistance in pediatric cancer therapy |
Nader Shakibazad1,2 
, Mahdi Shahriari2
, Mani Ramzi3
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1Pediatric Hematology Oncology, Bushehr University of Medical Sciences, Bushehr, Iran
2Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
3Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran |
Correspondence:
Nader Shakibazad, Email: nshakibazad@gmail.com
Mahdi Shahriari, Email: drmahdi.shahriari@gmail.com
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Received: 9 August 2025 • Accepted: 26 September 2025 |
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| Abstract |
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The growth and metastatic potential of most solid and hematological tumors are angiogenesis-dependent. Antiangiogenic therapies have demonstrated clinical advantages in the treatment of numerous tumor types. Nevertheless, resistance to antiangiogenic therapy has emerged over time. This study aimed to review physiological blood vessel growth, angiogenesis, tumor vasculature, the role of vascular endothelial growth factor and its receptor in tumor angiogenesis, antiangiogenesis, resistance to antiangiogenic therapy, and mechanisms of resistance to antiangiogenic treatment while also providing guidance for the development of antiangiogenic therapies. We reviewed Google Scholar and PubMed for studies examining antiangiogenesis therapy, resistance to antiangiogenic agents, and strategies for overcoming them, thereby creating a guidelines-based approach. This review discusses a novel adaptive resistance mechanism involving metabolic adaptability of tumor cells. We found that personalized medicine may enhance the angiogenic mechanisms utilized by tumors. Thus, antiangiogenic therapy should be personalized by incorporating insights into tumor-specific vascularization and metabolism along with biomarker-guided treatment strategies. In addition to developing new pharmaceuticals, we must prioritize the identification of reliable markers for pathway activation and response. Addressing these challenges enables the optimization of antiangiogenic treatments within a precision oncology framework, thereby enhancing the prediction of therapeutic benefits and minimizing the risk of resistance in pediatric malignancies. In addition to conventional or salvage chemotherapy, antiangiogenic agents may serve as adjunctive chemotherapeutic agents, particularly for solid tumors. We also provide a guidelines-based approach to pediatric cancer therapy using antiangiogenic agents in countries with limited resources. |
| Key Words:
Angiogenic proteins, Angiogenesis inhibitors, Drug resistance, Clinical practice guidelines, Vascular endothelial growth factor |
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