Antiangiogenic Therapy for Malignant Brain Tumors: Does It Still Matter?

Abstract

Purpose of Review To summarize the mechanisms of tumor angiogenesis and resistance to antiangiogenic therapy, and the influence on tumor microenvironment. Recent Findings Several clinical trials have investigated the activity of anti-VEGF monoclonal antibodies and tyrosine kinase inhibitors in glioblastoma, shedding the light on their limitations in terms of disease control and survival. We have outlined the mechanisms of resistance to antiangiogenic therapy, including vessel co-option, hypoxic signaling in response to vessel destruction, modulation of glioma stem cells, and trafficking of tumor-associated macrophages in tumor microenvironment. Moreover, novel generation of antiangiogenic compounds for glioblastoma, including small interfering RNAs and nanoparticles, as a delivery vehicle, could enhance selectivity and reduce side effects of treatments. Summary There is still a rationale for the use of antiangiogenic therapy, but a better understanding of vascular co-option, vascular mimicry, and dynamic relationships between immunosuppressive microenvironment and blood vessel destruction is crucial to develop next-generation antiangiogenic compounds.

The proneural subtype is not associated with survival benefit from bevacizumab in newly diagnosed glioblastoma: a secondary analysis of the GLARIUS trial

“…While the monoclonal VEGF-antibody bevacizumab was approved for recurrent glioblastoma in some countries based on prolonged PFS and clinical benefit, such as the reduction of steroid need and neurological symptoms, it did not prolong OS in several phase 3 clinical trials - both in newly diagnosed and recurrent disease [ 3 , 4 , 11 , 14 ]. Following these disappointing results, different mechanisms of resistance to antiangiogenic therapy have been identified such as compensatory angiogenic signaling or vessel co-option [ 15 ]. Some initiatives set out to identify subgroups potentially deriving an OS benefit from bevacizumab, such as the report from Sandmann and colleagues associating the proneural subtype with increased OS from bevacizumab, which seems counterintuitive as the mesenchymal and not the proneural subtype shows elevated angiogenic markers including VEGF [ 7 ].…”

The role of angiogenic growth factors in the immune microenvironment of glioma

“…Standard treatment fails to improve glioma patient survival in an efficient way, when combining with anti-angiogenic therapy, the clinical results were still unsatisfactory ( 172 , 173 ). After a period of usage, resistance was shown in anti-angiogenic therapy which develops compensatory pathways to maintain glioma angiogenesis and growth ( 16 , 174 ).…”

“…Angiogenesis in glioma and GBM is particularly obvious among all tumors ( 13 , 14 ). Anti-angiogenic therapy by targeting AGFs or their receptors has become a hot topic in the treatment of glioma during the past decades ( 15 , 16 ). This therapy differs from the traditional anti-tumor therapies.…”

“…It aims to inhibit tumor growth rather than directly attack tumor cells. Unfortunately, most clinical trials of anti-angiogenic treatment to glioma ended with patients showing serious side effects or no significant benefits ( 16 , 17 ). Therefore, the anti-angiogenic treatment of glioma should be considered from a more comprehensive perspective than just focusing on the vessels.…”

Characterization of prevalent tyrosine kinase inhibitors and their challenges in glioblastoma treatment

“…The complete set of protein kinases (kinome) has emerged as an appealing target for therapeutic strategies for human malignancies ( Fleuren et al, 2016 ). Several studies reported that the tumor progression and therapy resistance are subsequently related to overexpression and mutation of TKs that activate many critical downstream pathways in GBM ( Bolcaen et al, 2021 ; Peller et al, 2023 ). In GBM, certain well-characterized mutated TKs are the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor-α (PDGFR-α) ( Fleuren et al, 2016 ; Brar et al, 2022 ).…”