Abstract 1641: Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

Abstract

We aim to test the hypothesis that histone deacetylases (HDACs) and RNA polymerase III (Polr3) cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. This hypothesis is based on the observations that HDACs and POLR3 play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Using chemical inhibitors of HDACs and POLR3, we examined the effect on exocrine pancreas during morphogenesis, and then translated the developmental findings to human pancreatic adenocarcinoma cultured cells. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the clinical HDAC inhibitor suberoyl-anilide hydroxamic acid (SAHA) and ML-60218 produced enhanced suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive induction of a pro-apoptotic regulator and the cyclin-dependent kinase inhibitors. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators in zebrafish can be translated into a potential therapeutic approach in human cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity. 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 1641. doi:10.1158/1538-7445.AM2011-1641