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

Abstract

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.

Keywords: angiogenesis; glioblastoma; tumor microenvironment.

Figure 1

Visual demonstration of the VEGF signaling pathway and various anti-angiogenic agents discussed in this review. Soluble VEGF binds to its receptors located on the cell surface. This interaction leads to receptor dimerization and phosphorylation of tyrosine residues, activating the downstream signaling cascade such as Src, Raf, and PI3K. This eventually causes increased cell motility, cell proliferation, and vascular permeability. This figure was created with Biorender.com. VEGF: vascular endothelial growth factor, VEGFR: vascular endothelial growth factor receptor, PlGF: placental growth factor, TKI: tyrosine kinase inhibitor.