Abstract 5084: Overcoming the resistance to anti-angiogenic therapy: Itraconazole blocks blood vessel maturation and synergizes with anti-VEGF therapy.

Abstract

Abstract Background: Anti-angiogenic drugs, such as sunitinib, have been used as a first line therapy for renal cell carcinoma and some other cancers. However, the development of resistance to angiogenesis inhibitors targeting the VEGF pathway is common and impedes the efficacy of cancer treatments. Previously, we found it that blood vessel maturation is a common feature of tumors resistant to sunitinib. Thus, we hypothesized that novel approaches of inhibiting pericyte coverage of the tumor vasculature could be a successful approach to sensitize resistant tumors to sunitinib. Approach: An in vitro angiogenesis model was developed for screening the pericyte recruitment inhibitors. Itraconazole, an anti-fungal drug, was found to block the association of pericyte with newly-formed blood vessel endothelial cells. A sunitinib resistance animal model of Myc-Cap prostate cancer xenograft was used for studying the in vivo effect of treatment. Animals were dosed with itraconazole, sunitinib or the combination when tumors were well established. Result: through the in vitro angiogenesis model, the association of pericyte with endothelial cells was significantly reduced by itraconazole treatment. Its mechanism of action involved inhibition of focal adhesion kinase activity, a protein that plays a central role in cell spreading, differentiation, migration and cell death. Moreover, itraconazole treatment showed reduced pericyte coverage of tumor vasculature in vivo, and synergized with sunitinib treatments. Conclusion: These findings indicated that itraconazole is effective in inhibiting the pericyte coverage of the tumor vasculature and broaden the efficacy of sunitinib. Our results support further preclinical and clinical evaluation of itraconazole combination therapies in cancer treatment. Citation Format: Chenglai Fu, Stephanie Gerber, Richmond Castillo, Anita van der Zwan, Sushant Kachhap, Hans Hammers. Overcoming the resistance to anti-angiogenic therapy: Itraconazole blocks blood vessel maturation and synergizes with anti-VEGF therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5084. doi:10.1158/1538-7445.AM2013-5084