Edema Control by Cediranib, a Vascular Endothelial Growth Factor Receptor–Targeted Kinase Inhibitor, Prolongs Survival Despite Persistent Brain Tumor Growth in Mice

Abstract

Purpose Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. Methods We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers. Results We show by intravital microscopy that cediranib significantly decreased tumor vessel permeability and diameter. Moreover, cediranib treatment induced normalization of perivascular cell coverage and thinning of the basement membrane, as mirrored by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation—as measured by MRI and by dry/wet weight measurement of water content—but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage infiltration and significant but minor changes in tumor cell proliferation and apoptosis. Systemically, cediranib increased plasma VEGF and placenta growth factor levels, and the number of circulating CXCR4+CD45+ cells. However, by controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth. Conclusion Anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth.

Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

“…This is challenged by the fact that the area infiltrated by these tumor satellites [8,14,26] may not exceed the area of the untreated control tumors.…”

“…Further, treatment with anti-angiogenic agents nevertheless results in impressive effects on OS in animal models [8,15,27]. This allows the differential hypothesis of antiangiogenic therapy failing at the tumor-vascular interface, probably because of altered physiological, metabolic conditions in close proximity to the vessel.…”

“…Anti-VEGF/VEGF receptor (VEGFR) compounds [5] at least as part of their mode of action induce normalization of the vasculature [6] by inhibiting pathological proliferation of endothelial cells and immature vessel formation. Secondly, as early as 1-2 days after initiation of therapy, a reduction of the permeability of the blood-brain-barrier results in decreased contrast enhancement and edema and high objective radiological response rates of 25-60% [1,2,5,7,8]. The makeup of the current as well as novel revised response criteria do not allow to easily differentiate this effect on the barrier permeability from a direct antitumor effect [9,10].…”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…For example, VEGF induces the formation of VEGFR-PDGFRb complexes in pericytes, which impede PDGFRbmediated adherence of ECs to pericytes . Finally, the perivascular basement membrane (BM) is also structurally abnormal in tumors-excessively thin or absent in certain regions and abnormally thick in others (Inai et al 2004;Tong et al 2004;Winkler et al 2004;Kamoun et al 2009).…”

Linearization improves the repeatability of quantitative Dynamic Contrast-Enhanced MRI

“…1 Several studies have shown evidence that K trans can be used to differentiate tumors from 10 normal tissue, [6][7] and to monitor anti-cancer treatment in fibrosarcoma, 8 breast, 9-10 and brain 11 neoplasms. [11][12] . Unfortunately, these results are inconsistent with other studies, which showed 12 that K trans offers little to no utility to monitor anti-cancer treatment in breast and brain cancers.…”