CT322, a VEGFR-2 antagonist, demonstrates anti-glioma efficacy in orthotopic brain tumor model as a single agent or in combination with temozolomide and radiation therapy J. Dawn WatersCarlos SanchezAyguen SahinDiahnn Futalan • David D. GondaJustin K. ScheerJohnny AkersKamalakannan Palanichamy • Peter WatermanArnab ChakravartiRalph WeisslederBrent Morse • Nick MarshEric FurfineClark C. ChenIrvith CarvajalBob S. Carter

Glioblastomas are among the most aggressive human cancers, and prognosis remains poor despite pres- ently available therapies. Angiogenesis is a hallmark of glioblastoma, and the resultant vascularity is associated with poor prognosis. The proteins that mediate angiogen- esis, including vascular endothelial growth factor (VEGF) signaling proteins, have emerged as attractive targets for therapeutic development. Since VEGF receptor-2 (VEG- FR-2) is thought to be the primary receptor mediating angiogenesis, direct inhibition of this receptor may produce an ideal therapeutic effect. In this context, we tested the therapeutic effect of CT322, a selective inhibitor of VEGFR-2. Using an intracranial murine xenograft model (U87-EGFRvIII-luciferase), we demonstrate that CT322 inhibited glioblastoma growth in vivo and prolonged sur- vival. Of note, the anti-neoplastic effect of CT322 is aug- mented by the incorporation of temozolomide or temozolomide with radiation therapy. Immunohistochemi- cal analysis of CT322 treated tumors revealed decreased CD31 staining, suggesting that the tumoricidal effect is mediated by inhibition of angiogenesis. These pre-clinical results provide the foundation to further understand long term response and tumor escape mechanisms to anti-angio- genic treatments on EGFR over-expressing glioblastomas.