A Mouse Model That Mimics Human Men1 Tumor Is Effective In Preclinical Neuroendocrine Tumor Therapeutics

Abstract Conditional knockout of Men1 in β cells leads to development of pituitary adenomas and pancreatic neuroendocrine tumors (PanNETs) by the age of eight to twelve months. This suggests that other events, like loss of additional mutations, may be required for development of tumors in the absence of MEN1. Since it was reported that mutations in genes of PI3K/mTOR pathway are found in human neuroendocrine tumors, we hypothesized that double deletion of PTEN and MEN1 may accelerate neuroendocrine tumorigenesis. Mice with double deletion of PTEN and MEN1 in β cells were produced by crosses among mice with Cre gene under the control of Rat Insulin promoter (Rip-Cre), floxed allele Men1 (Men1fl/fl), and Pten (Ptenfl/fl). Then mice with the genotype of Men1fl/fl Ptenfl/fl Rip-Cre were monitored for development of tumors. Consistent with our hypothesis, mice with conditional deletion of PTEN and MEN1 leads to fully developed PanNETs and pituitary adenomas by three to four months old, much earlier than that with Men1 deletion alone. These tumors resemble human MEN1 tumors at a histological and molecular level. Activation of phospho-AKT was observed in these tumors and Rapamycin treatments lead to delayed PanNETs and pituitary adenomas for at least two months. This mouse model (Men1fl/fl Ptenfl/fl Rip-Cre) directly supports that PI3K/mTOR pathway plays a critical role in neuroendocrine tumorigenesis, and also provides a platform to study new therapeutic opportunities for PanNETs and neuroendocrine tumors of the pituitary through the targeting of PI3K/mTOR pathway and MEN1 pathway. This model represents an important tool for studying the biology and preclinical therapeutics of human neuroendocrine tumors. Citation Format: Chung Wong, Richard Clausen, Laura Tang, Christian Davidson, Evan Vosburgh, Arnold Levine, Eugenia Xu. A mouse model that mimics human MEN1 tumor is effective in preclinical neuroendocrine tumor therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1538. doi:10.1158/1538-7445.AM2017-1538