Abstract 3339: Elimination of cancer stem cells in pancreatic cancer cell lines by a combinatorial therapy

Abstract

Abstract Cancer stem cells (CSC) are tumor initiating cells and considered resistant to current conventional chemo and radio therapies. Consequently, novel strategies are needed to target these cells. Tumor cells expressing elevated levels of aldehyde dehydrogenase 1 family member A1 activity (ALDHbright cells) have been shown to have many properties attributed to CSC, including tumorigenicity in immunodeficient mice. We used FACS analysis to identify and sort ALDHbright cells from several human pancreatic cell lines using ALDEFLUOR (Stem Cell Technologies, Vancouver Canada). We show that ALDHbright but not ALDHnegative cells sorted from the human MiaPaCa-2 pancreatic adenocarcinoma cell are highly tumorigenic at low inoculum of 500 cells in immunodeficient NOD.SCID mice, a critical property of CSC. Previously, we identified the ALDH1A188–96 peptide as an HLA-A2-restricted, cytotoxic T cell (CTL)-defined tumor antigen. Using a flow cytometry-based assay, ALDHbright cells in the HLA-A2+ MiaPaCa-2 cell line were selectively eliminated in vitro by ALDH1A188–96 peptide-specific CTL. The Hedgehog (Hh) stem cell signaling pathway has been shown to play a critical role in invasion and metastasis in pancreatic cancer. Treatment of the MiaPaCa-2 cell line with the Hg inhibitor, cyclopamine, significantly eliminated ALDH+ MiaPaCA-2 cells compared to treatment with conventional chemotherapeutic agents. The efficacy of a combinatorial therapy consisting of adoptive transfer of ALDH1A1-specific CTL combined with systemic administration of cyclopamine in vitro and in vivo on ALDHbright cells and in vivo growth inhibition of MIA PaCa-2-derived xenografts is detailed. 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 3339.