A novel murine model for the functional in-vivo analysis of cholangiocarcinoma: a screen for new tumor suppressor genes and a detailed characterization of the model.
Final Report Abstract
Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy with a poor prognosis due to limited response to chemotherapeutic regimens. To accelerate the functional annotation of cancer genes and therapeutic targets in this disease, we have generated and characterized a flexible orthotopic allograft mouse model of cholangiocarcinoma that is based on the in-vitro modification and transplantation of liver progenitor cells into recipient mice. We have used this model to validate the FIG-ROS fusion gene, which was found in a subset of cholangiocarcinoma patients, as a potent oncogene in cholangiocarcinogenesis. Moreover, we show that inhibition of FIG-ROS, either genetically or by small molecule inhibitors, exerts a potent anti-tumor effect, thus indicating that FIG-ROS and potentially other ROS fusions will be promising therapeutic targets in patients harboring such fusion events. A small molecule inhibitor screen unveiled that foretinib, a compound that is currently evaluated in clinical trials as a c-met inhibitor, is a highly potent ROS inhibitor with superior invitro and in-vivo efficacy as compared to crizotinib, the current goldstandard in the clinical treatment of ROS fusion patients.
Publications
- Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci USA. 2013 Nov 26;110(48):19519-24
Davare MA, Saborowski A, Eide CA, Tognon C, Smith RL, Elferich J, Agarwal A, Tyner JW, Shinde UP, Lowe SW, Druker BJ
- Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. Proc Natl Acad Sci USA. 2013 Nov. 26; 110(48):19513-8
Saborowski A, Saborowski M, Davare MA, Druker BJ, Klimstra DS, Lowe SW
- A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev USA. 2014 Jan 1;28(1):85-97
Saborowski M, Saborowski A, Morris JP 4th, Bosbach B, Dow LE, Pelletier J, Klimstra DA, Lowe SW
(See online at https://doi.org/10.1101/gad.232082.113)
