Originally published as JCO Early Release 10.1200/JCO.2008.19.9356 on March 30 2009

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

Walid S. Kamoun, Carsten D. Ley, Christian T. Farrar, Annique M. Duyverman, Johanna Lahdenranta, Delphine A. Lacorre, Tracy T. Batchelor, Emmanuelle di Tomaso, Dan G. Duda, Lance L. Munn, Dai Fukumura, A. Gregory Sorensen, Rakesh K. Jain

From the Edwin L. Steele Laboratory, Department of Radiation Oncology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, and A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital; and Division of Health Sciences and Technology, Harvard Medical School, Boston, MA.

Corresponding author: Rakesh K. Jain, PhD, Massachusetts General Hospital, 100 Blossom St, MGH, Cox-734, Boston, MA 02114; e-mail: jain{at}steele.mgh.harvard.edu

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.

W.S.K., C.D.L., and C.T.F. contributed equally to this work. R.K.J. and A.G.S. are co-senior authors.

Supported in part by National Institutes of Health Grants No. P01-CA80124 and R01-CA115767 (to R.K.J.) and K24-CA125440 and R01-CA129371 (to T.T.B.), by postdoctoral fellowships from the Susan G. Komen Foundation (to W.S.K. and D.L.) and Damon Runyon Foundation (to J.L.), by a predoctoral fellowship from the United States Department of Defense (A.M.D.), and by gifts from AstraZeneca Pharmaceuticals and the Montesi Family Research Fund.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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