Abstract 3922: Deregulated thymidylate synthase promotes tumorigenecity in pancreatic neuroendocrine tumors

Abstract

Abstract The incidence of pancreatic neuroendocrine tumors (PNET) is rapidly increasing and the prevalence in the US is now estimated to be over 100,000. The lack of a suitable animal model that recapitulates the human disease has limited development of new treatment for PNET. We established a new mouse model by taking advantage of our discovery that elevated levels of Thymidylate Synthase (TS) plays a direct causal role in tumorigenesis in vitro and that overexpression of human TS (hTS) in transgenic mice promotes development of adenomas in the endocrine pancreas. We crossed hTS transgenic mice with conditional MEN1 null mice that were previously shown to develop pancreatic islet carcinoma upon long latency. MEN1 was recently shown to be the most commonly mutated tumor suppressor gene in sporadic PNETs (44% of PNET patients have MEN1 mutations). Our newly established hTS/MEN1 mice model developed aggressive PNET with 100% penetrance due to overexpressed TS in MEN1 null mice. Transgenic overexpression of TS induced islet carcinoma with shortened latency as compared to MEN1-/- mice. The hTS/fMen1-/- mice develop islet carcinoma as early as 6 month of age whereas MEN1-/- mice develop islet carcinoma at 8 months of age. The median age of onset of islet carcinoma in hTS/MEN1-/- and MEN1-/- mice was 10.38±2.45 vs. 13.06±0.48 months; p<0.001 respectively. We also observed significant decrease of overall survival in hTS/MEN1-/-mice as compared to MEN1-/- mice (p<0.001). The median survival time of hTS/MEN1-/- mice was 10.73±0.22 months as compared to 13.07±0.58 months in MEN1-/- mice. In addition, overexpression of TS results in the increase of mutational frequency in tumors derived from the hTS/MEN1-/-as compared to MEN1-/- mice. We crossed hTS/MEN1-/- mice with Big Blue® transgenic mouse that serves as a mutation detection system. We analyzed mutation frequency in tumors isolated from several 10-12 months old hTS/MEN1-/- and MEN1-/- mice. We observed that overexpression of TS increase mutational frequency ranging from 4.38 x10E-5 to 8.39 x10E-5 in hTS/MEN1-/- as compared to control MEN1-/- mice (2.15 x10E-5 to 3.01 x10E-5). Sequencing analysis demonstrated that mutations such as transitions, transversions, insertions and deletions were 3.2 fold higher in tumors isolated from hTS/MEN1-/- as compared to control MEN1-/- mice. In summary, our results suggest that high levels of TS increase mutational frequency that may result in accelerated growth of islet cells tumors in hTS/MEN1 mice. This novel animal model will allow development of new strategies for targeting TS in combination with other mutational driven-events that are critical for the treatment and prevention of PNET. Citation Format: Kyungah Maeng, Hye Seung Lee, Min Chen, Maria Zajac-Kaye. Deregulated thymidylate synthase promotes tumorigenecity in pancreatic neuroendocrine tumors. [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 3922. doi:10.1158/1538-7445.AM2014-3922