Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma

Abstract

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies.

Keywords: angiogenesis; antiangiogenic treatments; glioblastoma (GBM); immunotherapy; resistance.

Figure 1

Overview mechanisms of resistance to antiangiogenic therapies in GBM. Despite primary angiogenic signal suppression, GBM tumors activate alternate angiogenic pathways to maintain blood supply and tumor growth. GBM cells become more invasive in response to antiangiogenic therapy, allowing them to colonize distant brain regions and avoid localized therapeutic effects. Antiangiogenic treatment causes tumor microenvironment hypoxia. Hypoxia stabilizes HIFs, which activate genes that promote survival, angiogenesis, and therapeutic resistance. GBM cells transdifferentiate into endothelial-like cells, producing vessel-like structures without angiogenesis and sustaining nutrition supply. Antiangiogenic treatment changes tumor microenvironment immunity. This can recruit immunosuppressive cells and generate immunosuppressive cytokines, allowing tumor cells to avoid immune monitoring and elimination. The figure was drawn by Biorender 16 July 2024.

Figure 2

Mechanisms of antiangiogenic resistance in GBM. Anti-VEGF therapies inhibit VEGF, but tumors adapt by activating alternative proangiogenic factors such as FGF, PDGF, HGF, angiopoietins, and interleukins, promoting angiogenesis through VEGF-independent pathways. Hypoxia induced by antiangiogenic therapy triggers HIF-1α, which stimulates various proangiogenic factors, creating complex signaling networks that circumvent VEGF inhibition. Understanding these redundant pathways highlights the challenge of effectively targeting angiogenesis in GBM and underscores the need for combination therapies to manage GBM progression more effectively. The figure was drawn by Biorender 18 July 2024.

Figure 3

Antiangiogenic immune modulation in GBM. Myeloid-derived suppressor cells (MDSCs) inhibit T cell activation and growth, while tumor-associated macrophages (TAMs) secrete immunosuppressive cytokines IL-10 and TGF-β, impairing immune responses. Antiangiogenic therapy induces hypoxia, stabilizing hypoxia-inducible factors (HIFs) which upregulate PD-L1 on cancer cells, leading to T cell exhaustion. Hypoxia-induced immunosuppression significantly hampers the efficacy of antiangiogenic treatments, highlighting the critical role of immune regulation in glioblastoma (GBM) resistance to these therapies. The figure was drawn by Biorender 18 July 2024.