Antiangiogenic therapy for high-grade gliomas: current concepts and limitations

Abstract

Glioblastoma (GBM) is associated with a high degree of angiogenesis. Therefore, antiangiogenic therapy could have a role in the treatment of this tumor. The currently available treatment approaches acting against angiogenesis are mainly directed toward three pathways: VEGF pathway, VEGF-independent pathways and inhibition of vascular endothelial cell migration. It has been demonstrated that antiangiogenic therapy can produce a rapid radiological response and a decrease of brain edema, without significantly influencing survival. Future studies should consider that: animal models are inadequate and cells used for animal models (mainly U87) are deeply different from patient GBM cells; GBM cells may become resistant to antiangiogenic therapy and some cells may be resistant to antiangiogenic therapy ab initio; and angiogenesis in the peritumor tissue has been poorly investigated. Therefore, the ideal target of angiogenesis is probably yet to be identified.

Keywords::

• angiogenesis
• glioblastoma
• peritumor tissue
• VEGF
• trials
• tumor resistance

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Glioblastoma (GBM) is associated with a high degree of angiogenesis (endothelial cell proliferation, new vessel formation and remodeling of pre-existing vessels), determining an increased vessel permeability with blood–brain barrier disruption.

• • The currently available treatment approaches acting on angiogenesis are mainly directed toward three pathways: VEGF pathway through antibodies to VEGF (bevacizumab), a decoy VEGF (aflibercept) or direct inhibition of VEGF receptor (cediranib, sunitinib and sorafenib); VEGF-independent pathways, with inhibitors of PDGF (imatinib and tandutinib), FGF (lenalidomide and brivanib) or Cox 2 (celecoxib and rofecoxib); and inhibition of vascular endothelial cell migration (cilengitide).

• • Possible tumor cell mechanisms of resistance include: the recruitment of vascular progenitor cells (bone marrow-derived monocytic cells), which may be attracted by hypoxia-derived HIF-1 expression and may promote angiogenesis; an increase of tumor cell invasiveness through vessel co-option; the activation of other vessel-forming pathways.

• • Most trials using antiangiogenic drugs have been disappointing and have not substantially changed patient survival.

• • It has been demonstrated that antiangiogenic therapy can produce a rapid radiological response and a decrease of brain edema. The decrease in enhancement in MRI images after initiation of therapy may be at least in part due to the reintegration of the integrity of the blood–brain barrier and decreased vascular permeability, leading to less contrast leakage from the vasculature.

• • No cost–benefit studies on these drugs are available.

• • Future studies should consider that: animal models used to date are inadequate and cells used for animal models (mainly U87) are deeply different from patient GBM cells; the use of patient GBM stem cells could warrant better results; GBM cells may become resistant to antiangiogenic therapy and some cells may be resistant to antiangiogenic therapy ab initio; and angiogenesis in the peritumor tissue (which represents the site of GBM recurrence in most cases) has been poorly investigated.