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Funktionelle Analyse des Pdk1 Signalwegs zur Entwicklung neuer therapeutischer Strategien für das duktale Pankreaskarzinom

Antragsteller Professor Dr. Dieter Saur, seit 7/2019
Fachliche Zuordnung Gastroenterologie
Förderung Förderung von 2017 bis 2021
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 360394750
 
Erstellungsjahr 2022

Zusammenfassung der Projektergebnisse

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 Kras-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 therefore 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. We used the novel DRS based model to investigating the role of tumor-cell autonomous functions of the Kras-PI3K-Pdk1 regulated signaling pathway for progression, maintenance and metastasis of PDAC. We sequentially inactivated critical effectors of Kras-PI3K-Pdk1 signaling genetically and investigated associated vulnerabilities by genetic gain and loss of function approaches as well as combinatorial drug screening. We analyzed PI3K-dependent effector signaling pathways in vitro and in vivo and demonstrated that blockade of Pdk1 effectively prevents the progression of premalignant PanIN lesions to invasive tumors. In Kras driven PDAC, the targeting of Pdk by genetic and pharmacological approaches blocks proliferation, without inducing cell death. This prompted us to perform genome-wide functional genetic screens as well as high-throughput drug screening in combination with Pdk1 inactivation (>400 therapeutics including "standard of care" chemotherapies). Thereby, we were able to identify genetic interactions as well as drug combinations that transform this cytostatic effect into a cytotoxic response by exploiting the concept of synthetic lethality. In sum, our in vitro and in vivo data provide strong experimental evidence that Pdk1 is a bona fide therapeutic target in PDAC that can be used as a backbone for novel synthetic lethal combination therapies that target a wide variety of cancer relevant biological processes, such as oncogenic signaling, metabolism, proteasomal degradation, mRNA splicing, DNA replication, damage and repair. Inhibitors of the PI3K-Pdk1 pathway are already clinically approved or in clinical development, demonstrating feasibility of our approach. In follow up projects we now aim at advancing the most promising and efficient combinations to in vivo models to spur the way for clinical translation.

Projektbezogene Publikationen (Auswahl)

 
 

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