Ozal Beylerli, Ilgiz Gareev, Andrey Kaprin, Aamir Ahmad, Vladimir Chekhonin, Shanshan Yang, Guang Yang
{"title":"Hemorrhagic and ischemic risks of anti-VEGF therapies in glioblastoma.","authors":"Ozal Beylerli, Ilgiz Gareev, Andrey Kaprin, Aamir Ahmad, Vladimir Chekhonin, Shanshan Yang, Guang Yang","doi":"10.1038/s41417-025-00914-8","DOIUrl":null,"url":null,"abstract":"<p><p>Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies-such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"762-777"},"PeriodicalIF":4.8000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer gene therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41417-025-00914-8","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies-such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.
期刊介绍:
Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair.
Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.