Angiogenesis as a therapeutic target in malignant gliomas

Abstract

Currently, adult glioblastoma (GBM) patients have poor outcomes with conventional cytotoxic treatments. Because GBMs are highly angiogenic tumors, inhibitors that target tumor vasculature are considered promising therapeutic agents in these patients. Encouraging efficacy and tolerability in preliminary clinical trials suggest that targeting angiogenesis may be an effective therapeutic strategy in GBM patients. However, the survival benefits observed to date in uncontrolled trials of antiangiogenic agents have been modest, and several obstacles have limited their effectiveness. This article reviews the rationale for antiangiogenic agents in GBM, their potential mechanisms of action, and their clinical development in GBM patients. Although challenges remain with this approach, ongoing studies may improve upon the promising initial benefits already observed in GBM patients.

Figure 1

Histopathological hallmarks of glioblastomas. (A): Microvascular proliferations (arrow) appear as “glomeruloid tufts” and consist of multilayered, mitotically active endothelial cells and pericytes. (B): Pseudopalisading necrosis consists of dense arrays of radially oriented, fusiform glioma cells (arrow) that appear to palisade around a central area of fibrillary necrosis. The pseudopalisading cells have highly upregulated vascular endothelial growth factor expression and are proposed to induce microvascular proliferation in adjacent areas.

Figure 2

Disease progression without contrast-enhancement on magnetic resonance imaging (MRI). (A): The top row depicts a glioblastoma prior to treatment with cediranib using different MRI techniques: a T1-weighted anatomic image after i.v. administration of a contrast agent (gadolinium-DTPA) (T1 pGd, left panel), demonstrating a region of bright signal corresponding to the recurrent brain tumor in the right temporal lobe; a T2-weighted image acquired with a fluid-attenuated inversion recovery (FLAIR) sequence (middle panel), where bright signal is present in the area of the contrast enhancement evident in the left panel as well as in a small surrounding margin; and a map of Ktrans, a measure of blood–brain barrier permeability, demonstrating regions of bright signal corresponding to areas of high permeability. (B): The same tumor at day 112 of cediranib therapy (bottom row) has marked improvements in contrast enhancement (left panel) and permeability (right panel); however, a significant increase in the area of FLAIR signal abnormality (middle panel) represents noncontrast-enhancing disease progression. Note also the mass effect on the right midbrain.