Abstract 973: Targeting cancer stem cells by a novel anti-frizzled antibody inhibits pancreatic tumor growth and induces differentiation

Abstract

Abstract Clinical management of pancreatic cancer over the past years has not been improved and this disease remains the fourth most common cause of cancer-related death. It has been suggested that cancer stem cells drive tumor growth and progression and are resistant to many current therapies. The WNT/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and co-receptors, plays an important role in regulating cell fate, stem cell self-renewal and maintenance. We have recently demonstrated that inhibition of WNT/beta-catenin pathway by an anti-FZD antibody 18R5 decreased tumorigenicity and induced differentiation in solid tumors. The present study evaluated the anti-tumor effect of OMP-18R5 in a panel of pancreatic tumors. In vivo studies using primary pancreatic xenograft tumor models showed that OMP-18R5 was efficacious against both high and low grade pancreatic tumors. Histologic and gene expression analyses indicated that the 18R5-mediated anti-tumor effect was associated with inhibition of WNT target genes while inducing of mucin expression and tumor cell differentiation. Furthermore, inclusion of OMP-18R5 delayed pancreatic tumor recurrence following termination of gemcitabine. The delay in tumor recurrence by OMP-18R5 treatment was associated with a decrease in cancer stem cell frequency. The combination of OMP-18R5 and gemcitabine further decreased cancer stem cell frequency compared to the single agents. Our findings provide a rationale to target cancer stem cells through interference with WNT/beta-catenin pathway as a therapeutic approach in pancreatic cancer treatment. 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 973. doi:10.1158/1538-7445.AM2011-973