Abstract #1070: Targeting cancer stem cells and vasculatures by a novel anti-dll4 antibody inhibits pancreatic tumor growth and delays tumor recurrence Free

Clinical management of pancreatic cancer is very challenging and this disease remains the fourth most common cause of cancer-related deaths. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to current therapies. Delta-like 4 ligand (DLL4) is an important component of Notch-mediated 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 with potent binding and blocking activities that recognize either human or murine DLL4 to investigate the role of DLL4 in pancreatic cancer. In vivo studies using primary pancreatic xenograft tumor models showed that anti-DLL4 was efficacious as a single agent and in combination with gemcitabine against both high and low grade pancreatic tumors. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Histologic analysis indicated that the anti-DLL4-mediated anti-tumor effects were associated with a decrease in cell proliferation and an increase in vascular density, hypoxia, apoptosis and differentiation. These effects were further enhanced by the combination treatment with gemcitabine. Furthermore, inclusion of anti-DLL4 delayed pancreatic tumor recurrence following termination of gemcitabine. A tumorigenicity study indicated that treatment with anti-DLL4 decreased cancer stem cell frequency as measured by in vivo limiting dilution assay, whereas gemcitabine alone was ineffective. The combination of anti-DLL4 and gemcitabine further decreased cancer stem cell frequency compared to single agents. Our findings provide a rationale for targeting cancer stem cells and the vasculature through interference with the DLL4/Notch pathway as a therapeutic approach in cancer treatment.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1070.