Abstract A5: Tivozanib, a selective VEGFR TKI, potently blocks angiogenesis and growth in tumors that express a high level of VEGF-C and are refractory to VEGF-A blockade

• Published in: Molecular cancer therapeutics 2011-11, Vol.10 (11_Supplement), p.A5-A5
• Main Authors: Winston, William, Shen, Luhua, Li, Guangmu, Abbott, Sandra, Chen, Ting, Jiang, Jinwei, Weiler, Solly, Perino, Samantha, O'Hagan, Ronan, Robinson, Murray O., Chiu, M. Isabel, Gyuris, Jeno, Lin, Jie
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-A5

Background: Scientific understanding of the role of VEGF-A in tumor angiogenesis has led to the development of antiangiogenic therapies, such as bevacizumab, that selectively target VEGF-A. However, clinical trials across multiple cancer types have resulted in limited positive outcomes. VEGF-C is thought to be a potent lymphangiogenic growth factor and plays a role in tumor angiogenesis through VEGFR3; it has also been shown to bind to VEGFR2, which is important in tumor angiogenesis. Nevertheless, a direct role of VEGF-C in driving tumor angiogenesis has not been established. To explore the potential of VEGF-C as a driver of tumor angiogenesis and its implication in developing antiangiogenic therapies, we assessed the activity of tivozanib, a potent and selective TKI for VEGFR1, 2 and 3, and a VEGF-A targeted antibody in animal tumor models that exhibit distinct VEGF-C and VEGF-A expression. Method: A total of 107 independently derived murine breast tumors were expanded in vivo to establish population-based primary tumor models. The tumors were characterized for their angiogenesis phenotypes, including expression of angiogenic factors, microvasculature (demonstrated by quantitative CD31 IHC analysis), and myeloid infiltration, a previously identified mediator of tivozanib resistance. To examine the role of VEGF-C vs. VEGF-A in tumor angiogenesis and in affecting response to anti-VEGF therapies, a panel of representative tumors were tested with the cross species anti-VEGF-A antibody B20–4.1 and tivozanib. Tivozanib was also compared with B20–4.1 in blocking VEGF-C stimulated VEGFR2 or VEGFR3 activation in endothelial cells, and in VEGF-C stimulated in vivo angiogenesis in matrigel assay. Results: Three distinct subtypes of tumors were identified: those that expressed high level of VEGF-A and low VEGF-C, or high VEGF-C and low VEGF-A, or both high VEGF-A and high VEGF-C. These tumors exhibited characteristic VEGF driven microvasculature. When treated with systemic administration of B20–4.1 or tivozanib, the tumors expressing high VEGF-A showed comparable response to both agents, while the tumors expressing high VEGF-C but low VEGF-A only responded to tivozanib. In tumors that express both high VEGF-A and high VEGF-C, B20–4.1 treatment resulted in only modest response, while tivozanib completely blocked tumor progression accompanied by vast central necrosis. Pharmacodynamic analysis in representative tumors revealed tumor death associated with progressive hy