Current evidence and challenges of multitarget anti-angiogenic agents for glioblastoma: Results from clinical trials.

Glioblastoma (GBM) is a highly vascularized and aggressive brain tumor with a dismal prognosis. This systematic review critically appraises clinical evidence for multitarget anti-angiogenic agents, which inhibit pathways such as VEGFR, FGFR, and PDGFR. Most supporting data come from small, single-arm phase II trials or retrospective studies. Five challenges are highlighted: (i) translational shortcomings of current preclinical models, (ii) restriction of agent delivery by the blood-brain barrier (BBB), (iii) heterogeneity of tumor endothelial cells (TECs) driving intrinsic and adaptive resistance, (iv) angiogenic escape via vasculogenic mimicry (VM), and (v) a lack of consensus on late-line treatment for recurrent GBM (rGBM). Future research should prioritize robust biomarker development, brain-penetrant agents, strategies tailored to specific TEC subtypes, and disruption of VM to unlock the full therapeutic potential of anti-angiogenic agents in GBM. This review provides an evidence-based foundation and translational research guidance for clinicians and pharmaceutical researchers.