Abstract LB-229: Arsenic trioxide, ascorbic acid and disulfiram (AAA) arrests pancreatic cancer development in a transgenic mouse model with p16 knockout and activated Kras

Abstract

Abstract Previously, we found that four human pancreatic cancer (PC) cell lines underwent robust cell death associated with dramatic ATP decline and ROS accumulation when treated with clinically achievable concentrations of arsenic trioxide, ascorbic acid and disulfiram (AAA). Early apoptosis was shifted to aponecrosis, and dependent on the voltage-dependent anion channel (VDAC), since shRNA directed against VDAC-1 abrogated the ROS accumulation and blocked cell death. In this study, assessment of AAA was performed in Pdx1-Cre transgenic mice with a conditional p16 knockout (p16flox/flox), and oncogenic KrasG12D. The KrasG12D, p16flox/flox; LSL-KrasG12D; Pdx1-Cre mice develop the full spectrum of pancreatic intraepithelial neoplasia (mPanIN) lesions, pancreatic ductal adenocarcinoma, and hepatic and peritoneal metastases. Over 95% of human PC have p16 deficiency and Kras mutation. Eight week old mice were treated for 8 weeks, 3 times/week with AAA, sacrificed, and the development of PC assessed. Little or no toxicity of the mice to the AAA treatment was observed. Frank PC was zero in AAA-treated mice and 31% in controls. The mean number of PanIN-3 lesions/mouse declined from 14.1 in controls to 1.58 in AAA-treated mice (p=0.008). The mean number of PanIN-2 lesions declined from 5.18 in controls to 1.67 in AAA treated mice (p=0.06). The mean number of PanIN-1 lesions in control mice were 14.2 and in AAA-treated mice were 16.0, p=0.51 indicating no difference in PanIN-1 occurrence. Preliminary results from immunohistochemical staining of the PanIN lesions for VDAC, indicated that PanIN-1 lesions have low, and PanIN-2 and 3 lesions have high, VDAC expression. This result parallels the in vitro human cell line data showing VDAC expression is critical to AAA sensitivity, and suggests a similar mechanism of action in vivo as in vitro. Although collection of data is ongoing, this is the first treatment that has been shown to arrest PanIN and tumor development in any a genetically-engineered mouse model for PC. The data suggests AAA either arrests the development of pre-cancerous lesions after the PanIN-1 stage, or the PanIN-2 and PanIN-3 lesions are destroyed by AAA in a VDAC-dependent manner. 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 LB-229. doi:10.1158/1538-7445.AM2011-LB-229