Dissecting the role of Pdk1 signalling in pancreatic cancer to develop novel therapeutic strategies

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease. It is extremely treatment resistant and almost invariably fatal. Therefore, novel therapeutic strategies are urgently needed. We have shown that the PI3K-Pdk1 signalling pathway is essential for KrasG12D-driven pancreatic cancer formation in a genetically engineered, Cre/loxP-based mouse model that faithfully recapitulates the human disease. Recently it has become clear that the signalling requirements for tumor progression and maintenance can be distinct from the pathways needed to transform a phenotypically normal cell into a cancer cell. Since tumor progression and maintenance is more important than tumor initiation for the treatment of human cancer, the relevance of a particular gene or pathway for tumor progression/maintenance is of paramount importance. Because the classical Cre/loxP based mouse models rely on a single Cre recombination step to activate mutant Kras expression in the pancreas, it is almost impossible to validate therapeutic targets in established tumors genetically. This is a significant bottleneck of the Cre/loxP system and rate limiting for pre-clinical research. We have developed a novel inducible dual-recombinase system (DRS) by combining Flp/frt and Cre/loxP to improve genetically engineered mouse models of pancreatic cancer. Our model enables the genetic validation of therapeutic targets in autochthonous tumors in vivo. In the proposed research project we aim at investigating the role of tumor-cell autonomous functions of the PI3K-Pdk1 regulated signalling pathway for progression, maintenance and metastasis of PDAC. We will use the novel DRS based model to sequentially inactivate critical effectors of PI3K-Pdk1 signalling genetically and investigate associated vulnerabilities. This approach will lead to important insights into the role of PI3K-Pdk1 signalling in pancreatic cancer biology, pathophysiology and therapeutic resistance and will open the horizon for novel treatment strategies for this dismal disease.