ayed by Restoration of Angiostatic Signaling

ownload tment of metastatic renal cell cancer (RCC) with antiangiogenic agents that block vascular endothelial h factor (VEGF) receptor 2 signaling produces tumor regression in a substantial fraction of patients; er, resistance typically develops within 6 to 12 months. The purpose of this study was to identify mor pathways involved in resistance. Treatment of mice bearing either 786-0 or A498 human RCC xenowith sorafenib or sunitinib produced tumor growth stabilization followed by regrowth despite ued drug administration analogous to the clinical experience. Tumors and plasma were harvested at of therapy and at the time of resistance to assess pathways that may be involved in resistance. Serial ion imaging, and plasma and tumor collections were obtained in mice treated with either placebo or ib alone or in combination with intratumoral injections of the angiostatic chemokine CXCL9. Sunitinib istration led to an early downmodulation of IFNγ levels as well as reduction of IFNγ receptor and stream angiostatic chemokines CXCL9 to 11 within the tumor. Intratumoral injection of CXCL9, gh producing minimal effects by itself, when combined with sunitinib resulted in delayed resistance accompanied by a prolonged reduction of microvascular density and tumor perfusion as measured by ion imaging relative to sunitinib alone. These results provide evidence that resistance to VEGF receptor y is due at least in part to resumption of angiogenesis in association with reduction of IFNγ-related therap angiostatic chemokines, and that this resistance can be delayed by concomitant administration of CXCL9. Mol Cancer Ther; 9(10); OF1–10. ©2010 AACR.