Abstract 2448: Inhibiting the DLL4/Notch pathway delays tumor recurrence and decreases tumorigenicity in pancreatic cancer

Abstract

Abstract It is becoming increasingly evident that cancer stem cells drive tumor growth and progression and are preferentially resistant to chemotherapy. Previously, we demonstrated that interfering with the Delta-like 4 ligand (DLL4)/Notch signaling by anti-DLL4 antibodies decreased tumor growth in a pancreatic xenograft model, delayed tumor recurrence following chemotherapy, and reduced the pancreatic cancer stem cell (CSC) fraction. In this study, we evaluated the response of seven pancreatic xenograft tumors to anti-DLL4 antibodies as a single agent and when combined with gemcitabine. Utilizing an in vivo limiting dilution assay, we tested the ability of cells from previously treated xenografts to re-grow tumors after serial transplantation to quantify CSCs. We discovered that anti-DLL4 was efficacious as a single agent in all seven tumor models. In all seven models, when anti-DLL4 was combined with gemcitabine, the therapy provided significant efficacy over that of gemcitabine alone. This combination therapy resulted in tumor regression in three of these models. The antibody therapy reduced the CSC fraction, while gemcitabine treatment alone enriched for the CSC. The chemotherapy/antibody combination further reduced the CSC fraction compared to anti-DLL4 alone. To analyze the mechanism of action of inhibiting DLL4-Notch signaling in tumor cells and in the host vasculature, we tested a human specific DLL4 mAb and a murine specific DLL4 mAb as single agents. Anti-human DLL4 reduced the tumorigenicity of pancreatic tumor cells, while anti-murine DLL4 had no effect on tumor initiating cell frequency. In a tumor recurrence model, the human specific DLL4 mAb delayed tumor recurrence following the termination of gemcitabine while the murine specific DLL4 mAb decreased the growth rate of recurrent tumors. The combination of human and murine targeting DLL4 mAbs produced an additive effect in reducing tumor recurrence. These data support the rationale for targeting the DLL4/Notch pathway in pancreatic cancer and provide evidence of the therapeutic utility of targeting pathways, such as Notch, required for cancer stem cell self renewal. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2448. doi:10.1158/1538-7445.AM2011-2448