SU11248 (Sunitinib) does inhibit tumor growth and angiogenesis in an ovarian cancer murine xenograft model

Abstract

16557 Background: Ovarian cancer is newly diagnosed in∼ 22,000 cases each year in the US. Standard treatment is cyto reductive surgery followed by a platinum based chemotherapy. Some patients do not respond to primary chemotherapy and the majority of patients suffer from disease recurrence and eventually succumb to platinum-resistant tumors. The establishment of new strategies which target molecules and signaling pathways may provide new treatment options for the treatment of ovarian cancer. Sunitinib is an oral multitargeted tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, FLT3, KIT. Signaling blockade of these pathways is associated with anti-tumor and anti- angiogenesis activity. The aim of this study is to evaluate the efficacy of SU11248 in inhibiting ovarian tumor growth and angiogenesis in a xenograft mouse model. Methods: 5 million Skov3 ovarian cancer cells - which are in vitro platinum resistant - stably transfected with luciferase were injected i.p. into SCID beige mice. 28 days after implantation one group of mice were treated with a clinically relevant dosage of 40mg/kg SU11248 (orally/daily) and another group given vehicle control only. Tumor development was monitored weekly by measuring luciferase activity in vivo using a Peltier cooled charged-coupled device camera (NightOWL LB 983; Berthold). After 80 days of treatment all mice were sacrificed and CD31 staining was performed to measure micro-vessel density (MVD). Results: We report here for the first time that SU11248 does inhibit tumor growth and angiogenesis in an ovarian cancer murine xenograft model. Treatment with SU11248 showed a 1.6 fold reduction in tumor growth as visualized and measured by bioluminescence. Histological examination of tumors from treated mice showed a 2.5 fold reduced MVD when compared with the control mice. The control mice developed clinically relevant amount of ascites when compared to the SU11248 treated group. Conclusions: The inhibition of selective tyrosine kinases in an ovarian cancer mouse model significantly reduced tumor growth and angiogenesis. These results suggest that SU11248 is a small molecule drug which can potentially be utilized to target primary tumors with intrinsic platinum-resistance and recurrent tumors with acquired platinum-resistance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer