Abstract 3473: Beta catenin inhibitor ICG-001 attenuates proliferation of hepatic tumor initiating cells in Pten deficient models

Progenitor or tumor initiating cells (TICs) are “altered” stem cells with the capacity to form solid tumors. Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten) is aberrantly expressed in liver cancers. Liver specific Pten (Pm) mice develop liver cancer following an extensive phase of chronic lipid accumulation and demonstrate escalating levels of hepatic injury markers from 6-12M, prior to hepatic progenitor cell proliferation. In addition, TUNEL analysis revealed that hepatocytes from Pm mice undergo extensive apoptosis relative to control mice. We hypothesize that hepatocyte cell death induced by hepatic injury presents an opportunity for TICs to proliferate and consequently form mixed lineage tumors. Attenuation of hepatic injury by Akt2 deletion reduces progenitor cell proliferation and delays tumor development. Our analyses also revealed that the Wnt/β-Catenin signaling pathway is the likely molecular mediator of TIC proliferation in our Pm model. Wnt ligands including 7a and 10a as well as Wnt signaling receptor Fzd 2 are induced. In this study, we investigate the role of the Wnt/β-Catenin pathway in the activation of hepatic progenitor cells in the Pten deletion liver cancer model using novel Wnt/β-catenin inhibitor ICG-001. ICG-001 is a small molecule which specifically inhibits β-Catenin/CBP interaction. Coactivator CBP/β-Catenin/T cell factor (TCF) mediated transcription has been reported as critical for stem cell/progenitor cell proliferation. Here we demonstrate that ICG-001 significantly attenuates proliferation of hepatic cancer stem cell line P0 in vitro and also inhibits hepatotoxin induced proliferation of hepatic TICs in vivo in liver Pten null mice. Our preliminary results indicate that targeting the cancer stem cell niche may prove to be a viable approach to inhibit liver tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3473. doi:1538-7445.AM2012-3473