Abstract 2781: Elimination of PanIn2/3 in a GEMM for pancreatic cancer with disrupted p16 and activated Kras

Abstract

Abstract When treated with clinically achievable concentrations of arsenic trioxide, ascorbic acid and antabuse (disulfiram) (AAA), we found that four human pancreatic cancer cell lines underwent robust cell death associated with ATP decline and ROS accumulation. In these cells, early apoptosis shifted to aponecrosis, and was dependent on VDAC since shRNA antagonistic to 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 a full spectrum of pancreatic intraepithelial neoplasia (PanIN) lesions, pancreatic ductal adenocarcinoma (PDA), and frequent metastases. Eight week old mice were treated for 8 weeks, 3 times/week with AAA, sacrificed, and assessed for the development of pancreatic cancer. Little or no toxicity was observed in the AAA-treated mice. The development of frank pancreatic tumors was decreased from 37% in controls to 0% in AAA-treated mice. The mean number of PanIN 3 lesions/mouse declined from 14.2 in controls to 1.6 in AAA-treated mice (p=0.004); the mean number of PanIN 2 lesions declined from 5.8 in controls to 1.7 in AAA-treated mice (p=0.029), and the mean number of PanIN 1 lesions in control mice was 14.2 and in AAA-treated mice was 16.0 (p=0.82), indicating no difference in PanIN 1 occurrence between control and AAA-treated mice. The data also suggests that PanIN 2 and PanIN 3 lesions are killed after exposure to AAA, since mice prior to treatment had high levels of PanIN 2 (8.1 lesions/mouse) and PanIN 3 (11.4 lesions/mouse), similar to controls at 4 months of age. Therefore, AAA may have eliminated pre-existing PanINs rather than blocking their development. 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 the murine model, as we see in vitro. This is the first treatment that has shown potential to kill existing PanIN lesions and arrest the development of tumors in this pancreatic cancer murine model. Citation Format: Richard D. Dinnen, Wanglong Qiu, Gloria H. Su, Daniel P. Petrylak, Robert L. Fine. Elimination of PanIn2/3 in a GEMM for pancreatic cancer with disrupted p16 and activated Kras. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2781. doi:10.1158/1538-7445.AM2014-2781