Exploring the Past, Present, and Future of Anti-Angiogenic Therapy in Glioblastoma

Simple Summary Glioblastoma is the most common malignant primary brain tumor. Despite technological advancements and modern therapeutic agents used for treatment, the prognosis remains extremely poor. One unique characteristic of glioblastoma is its highly vascularized nature, enabling the tumors to grow and invade the surrounding brain tissue. This process is known as "angiogenesis" which is critical for growth of glioblastoma cells and has been a topic of interest for scientists. A critical protein that facilitates new blood vessel formation is vascular endothelial growth factor-A (VEGF-A), therefore, bevacizumab, a medication that specifically targets VEGF-A has been approved for treatment of recurrent glioblastoma. However, despite its theoretical potential, bevacizumab has failed to offer significant survival improvement. Furthermore, other agents with mechanisms of action comparable to that of bevacizumab have also not been able to demonstrate favorable results. Herein, we review the current state of anti-vascularization therapeutic agents, and the future of this therapeutic approach. Glioblastoma, a WHO grade IV astrocytoma, constitutes approximately half of malignant tumors of the central nervous system. Despite technological advancements and aggressive multimodal treatment, prognosis remains dismal. The highly vascularized nature of glioblastoma enables the tumor cells to grow and invade the surrounding tissue, and vascular endothelial growth factor-A (VEGF-A) is a critical mediator of this process. Therefore, over the past decade, angiogenesis, and more specifically, the VEGF signaling pathway, has emerged as a therapeutic target for glioblastoma therapy. This led to the FDA approval of bevacizumab, a monoclonal antibody designed against VEGF-A, for treatment of recurrent glioblastoma. Despite the promising preclinical data and its theoretical effectiveness, bevacizumab has failed to improve patients' overall survival. Furthermore, several other anti-angiogenic agents that target the VEGF signaling pathway have also not demonstrated survival improvement. This suggests the presence of other compensatory angiogenic signaling pathways that surpass the anti-angiogenic effects of these agents and facilitate vascularization despite ongoing VEGF signaling inhibition. Herein, we review the current state of anti-angiogenic agents, discuss potential mechanisms of anti-angiogenic resistance, and suggest potential avenues to increase the efficacy of this therapeutic approach.