Abstract 3483: Combining the multi-targeted tyrosine kinase inhibitor, vandetanib, with fulvestrant results in enhanced anti-tumorigenic effects for lung cancer

Abstract

Abstract Current average survival after a lung cancer diagnosis is only 8-12 months, with a 5-year survival rate of 15% with best available first-line chemotherapy regimens. Thus, innovative approaches to treat lung cancer utilizing molecular targets are necessary. We have previously shown that epidermal growth factor receptor (EGFR) and estrogen receptor β (ERβ) are present in non-small cell lung cancer (NSCLC) and show a functional interaction. This interaction provided the foundation for combinatorial targeting strategies incorporating anti-estrogens into NSCLC treatment in combination with growth factor signaling pathway inhibitors. Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that potently inhibits vascular endothelial growth factor receptor-2 (VEGFR-2) and shows additional inhibitory activity against Flt-4 (VEGFR-3) and EGFR tyrosine kinases. This inhibitor may be beneficial in tumors that are dependent upon VEGF-mediated angiogenesis or EGF mediated tumor growth and has shown promising anti-tumor activity in NSCLC in clinical trials. We demonstrated that NSCLC cells significantly secrete VEGF protein over time in culture (p<0.001) and that production of VEGF mRNA and protein can be stimulated 2- to 3-fold with 10nM estrogen (p<0.001), suggesting an interaction between the estrogen and VEGF signaling pathways. To confirm this interaction, we showed that vandetanib completely abolished estrogen-induced P-MAPK signaling. Furthermore, long-term treatment of NSCLC cells in culture with 2.5µM vandetanib resulted in a 7.2-fold up-regulation of ERβ expression. These data provide rationale to combine an ER inhibitor with vandetanib to interfere with cross-talk between multiple interdependent growth-stimulatory pathways. The combination of vandetanib (1.25µM) with fulvestrant (5µM) was found to maximally inhibit cell growth of NSCLC cells compared to single agents in vitro (p<0.0001). In an in vivo lung tumor xenograft model, the vandetanib (12.5mg/kg, once-daily p.o)/fulvestrant (30mg/kg, twice-weekly, s.c.) combination decreased tumor volume in athymic nude mice by 64% compared to 51% and 23% for vandetanib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by statistically significant increases (up to 2.5-fold) in apoptotic cells in the tumors from the combination treatment group compared to single agent treatment groups. Vandetanib can inhibit EGFR and VEGFR-3, which are expressed on lung tumor cells themselves, while effects inhibiting VEGFR-2 occur on tumor blood vessels that can respond to VEGF by the tumor. The combination of vandetanib and fulvestrant should have clinical efficacy for NSCLC patients. A phase I clinical trial of this combination in lung cancer is planned. This work was supported by P50 CA090440 SPORE in Lung Cancer, to JMS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3483.