Abstract 15: Targeting cancer stem cells and vasculature by a novel anti-delta-like 4 ligand (DLL4) antibody inhibits triple-negative breast cancer tumor growth and delays tumor recurrence

Abstract

Abstract Triple negative breast cancer (TNBC, ER−, PR− Her2−) accounts for about 10% of all types of breast cancer and is known to particularly aggressive and refractory to current therapies. Chemotherapeutic agents, such as taxanes, are currently the only treatment option for this type of breast cancer, however, these treatments often result in high rates of local and systemic relapse. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to many current therapies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We hypothesized that targeting cancer stem cells and the tumor vasculature by interfering with the DLL4/Notch pathway will improve treatment outcome. We developed anti-DLL4 antibodies that recognize either the human or murine protein and have potent binding and antagonist activities. We used these antibodies to investigate the role of DLL4 in triple negative breast cancer and to probe the mechanism in tumor and stromal cells in xenograft models derived from primary breast tumors. These studies showed that anti-DLL4 was efficacious as a single agent and in combination with paclitaxel (Taxol) against TNBC xenograft tumors. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Inclusion of anti-DLL4 delayed breast tumor recurrence and decreased the growth rate of recurrent tumors following termination of paclitaxel treatment. Flow cytometric analysis showed that ESA+/CD44+/CD24low expressing breast cancer stem cells, BrCSC, were enriched followed by paclitaxel treatment, whereas the combination of anti-DLL4 and paclitaxel reversed paclitaxel-induced increase in this cell population. Further analysis indicated that blocking DLL4 signaling in tumor cells by anti-human DLL4 delayed tumor recurrence and decreased ESA+/CD44+/CD24low expressing BrCSC fraction and tumorigenic potential, whereas blocking DLL4 in host stroma and endothelial cells by anti-mouse DLL4 interfered with angiogenesis. The combination of both antibodies produced an additive effect. Our findings provide a rationale for targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch signaling for TNBC treatment. 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 15.