Angiogenesis inhibitors appear to be promising therapies for highly vascularized tumors such as glioblastoma multiforme (GBM). Sunitinib is an oral multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities due to selective inhibition of various receptor tyrosine kinases, including those important for angiogenesis (vascular endothelial growth factor receptors and platelet-derived growth factor receptors). Here we evaluated the antitumor activities of sunitinib on orthotopic models of GBM in vitro and in vivo. Sunitinib potently inhibited angiogenesis that was stimulated by implantation of U87MG and GL15 cells into organotypic brain slices at concentrations as low as 10 nM. At high dose (10 mM), sunitinib induced direct antiproliferative and proapoptotic effects on GL15 cells and decreased invasion of these cells implanted into brain slices by 49% (p , 0.001). Treatment was associated with decreases in Src (35%) and focal adhesion kinase (44%) phosphorylation. However, anti-invasive activity was not observed in vivo at the highest dose level utilized (80 mg/kg per day). Survival experiments involving athymic mice bearing intracerebral U87MG GBM demonstrated that oral administration of 80 mg/kg sunitinib (five days on, two days off) improved median survival by 36% (p , 0.0001). Sunitinib treatment caused a 74% reduction in microves- Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastomaSophie de Boüard, Paulette Herlin, James G. Christensen, Edwige Lemoisson, Pascal Gauduchon, Eric Raymond, and Jean-Sébastien Guillamo GRECAN, Centre François Baclesse, Université de Caen Basse-Normandie, 14076 Caen, France (S.D.B., P.H., E.L., P.G., J.-S.G.) ; Pfizer Inc., San Diego, CA 92121 USA (J.G.C.); Hôpital Beaujon, 92118 Clichy, France (E.R.); CHU Côte de Nacre, Département de Neurologie, 14033 Caen, France (J.-S.G.) Received July 13, 2006; accepted January 4, 2007. Address correspondence to Sophie de Boüard, GRECAN, Centre François Baclesse, Avenue du Général Harris, 14076 Caen, France (sophie.debouard@free.fr).sel density (p , 0.05), an increase in tumor necrosis, and a decrease in number of GBM cells positive for MIB antibody. Sunitinib exhibited potent antiangiogenic activity that was associated with a meaningful prolongation of survival of mice bearing intracerebral GBM. These data support the potential utility of sunitinib in the treatment of GBM. Neuro-Oncology 9, 412-423, 2007 (Posted to Neuro-Oncology [serial online], Doc. D06-00109, July 10, 2007. URL http://neuro-oncology.duke journals.org; DOI: 10.1215 DOI: 10. /15228517-2007 Keywords: angiogenesis, antiangiogenic therapy, glioblastoma, invasion, sunitinib G lioblastoma multiforme (GBM), the most frequent and aggressive type of primary brain tumor, 1 is associated with a high degree of vascularization.2 This profuse angiogenesis, together with tumor cell dissemination in the brain, 3 is largely responsible for tumor recurrence and poor prognosis despite treatment. The median survival ti...

Background: Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a nondestructive way that suggests cooperation between glioma cells and their environment. Recent studies using an engineered rodent C6 tumor cell line have pointed to mechanisms of invasion that involved gap junctional communication (GJC), with connexin 43 as a substrate. We explored whether this concept may have clinical relevance by analyzing the participation of GJC in human glioblastoma invasion.