Dual-recombinase systems for combinatorial target identification in pancreatic cancer

• Applicant: Professor Dr. Dieter Saur
• Subject Area: Gastroenterology
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 219542602

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and heterogeneous cancer with a 5-year-survival rate <7%. PDAC is remarkably resistant to chemotherapies and almost invariably fatal. A better understanding of the biology and therapeutic vulnerabilities is needed to archieve progress in the clinic. Our data indicate that increased gene dosage of mutant oncogenic KRAS and associated modulation of the downstream signaling levels drive the biology and the clinical outcome of the disease. To investigate signaling requirements for tumor progression and maintenance as well as validating therapeutic targets, we have developed an inducible dual-recombinase system (DRS), by combining Flp/FRT and Cre/loxP, that overcomes major limitations of classical Cre/loxP based genetic mouse models of pancreatic cancer. In the proposed research project, we aim at deciphering the MAPK signaling pathway in KRAS-driven PDAC and exploit it for novel combinatorial treatment strategies. We will use the DRS to sequentially inactivate critical effectors of MAPK signaling genetically and investigate associated vulnerabilities using unbiased systematic pharmacological and genetic approaches. This will lead to important insights into the role of MAPK signaling in PDAC biology and pathophysiology and will open the horizon for novel combinatorial treatment strategies for this dismal disease.

• DFG Programme: Research Grants