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Projekt Druckansicht

Ein neuartiges murines Modell zur funktionellen in-vivo Analyse des cholangiozellulären Karzinoms: Durchführung eines Screens für neue Tumorsuppressorgene sowie detaillierte Charakterisierung des Modells.

Fachliche Zuordnung Gastroenterologie
Förderung Förderung von 2011 bis 2013
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 202496315
 
Erstellungsjahr 2014

Zusammenfassung der Projektergebnisse

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.

Projektbezogene Publikationen (Auswahl)

  • 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
 
 

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