Background: Clear cell renal cell carcinoma (ccRCC), the most common form of renal cell carcinoma, is characterized VEGF driven tumor vascularization. However, in patients treated with anti-VEGF therapies inevitably tumor progression occurs, likely driven by up-regulation of alternative proangiogenic pathways including angiopoietins and c-MET. We hypothesized that angiopoietin inhibition has anti-tumor effect on RCC and may affect the development of resistance to anti-VEGF therapies. In the current study we utilized the dual angiopoietin inhibitor AMG 386 in murine models of RCC, and assessed the preclinical impact of this strategy. Methods: Seven week old female Balb/c mice were injected with 250,000 RENCA cells (luciferase expressing), one week later these mice were randomized, using bioluminescence imaging into two treatment groups: vehicle or Amgen 386 (5.6mg/kg/day, twice a week, subQ injection). Body weight measurements, tumor growth rate, and end point tumor weight measurements were used to evaluate possible side effects and the progression of RENCA tumors. Four weeks of treatment culminated in collection of tumor tissues for immunohistochemistry analysis of Ki67 and CD31. In addition we have ongoing studies utilizing patient derived xenografts (PDX) of ccRCC developed in our lab. Results: In the RENCA model AMG 386 induced a significant decrease of tumor weight by 44.0 percent (p = 0.0123). In addition, histological analysis of tumor sections revealed a high proportion of necrosis and decreased blood vessel density. Studies are ongoing with sunitinib sensitive PDXs and matched sunitinib resistant PDXs treated with AMG 386 in combination with a selective c-MET inhibitor. Results from these models will be available at the time of the meeting. Conclusions: Our preliminary results suggest that AMG 386 as a single agent is inhibiting both vascularization and tumor growth in an orthotopic renal cell carcinoma model. Ongoing studies with AMG 386 in combination with a selective c-MET inhibitor in sunitinib sensitive and resistant PDX models will provide guidance for the optimal clinical development of angiopoietin inhibitors in patients with ccRCC.

Citation Format: Ashley Orillion, Kiersten Marie Miles, Li Shen, Remi Adelaiye, Eric Ciamporcero, Swathi Ramakrishnan, Sheng Yu Ku, May Elbanna, Sreenivasulu Chintala, Roberto Pili. Angiopoietin 1/2 inhibition impairs tumor growth in an orthotopic model of renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1013. doi:10.1158/1538-7445.AM2014-1013