Project Details
Projekt
Targeting metabolism and autophagy to treat pancreatic cancer
Applicant
Dr. Mathias Rosenfeldt
Subject Area
Hematology, Oncology
Term
from 2015 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
Every year pancreatic cancer is newly diagnosed in approximately 15000 patients in Germany alone. Pancreatic ductal adenocarcinoma (PDAC) is by far the most common type with a 5-year survival rate of less than 10% even after surgery and aggressive chemotherapy. To improve patient outcome novel therapeutic concepts are urgently needed. In recent years, several pre-clinical studies suggested that certain intricacies of PDAC metabolism are promising therapeutic targets. In my previous work we had shown that inhibition of a metabolic process termed autophagy prevents the de novo development of PDAC in certain genetic contexts. To evaluate a potential therapeutic impact of autophagy inhibition it is important to conduct proper treatment studies and not rely on results from tumor prevention studies. The former investigate effects in established tumors, whereas the latter investigate de novo tumor development from healthy tissue. Results from both study types are not per se interchangeable. Currently, no study has looked at the effect of genetic autophagy impairment in established tumors. In the previous funding period we have generated mouse models and cohorts to delineate the impact of autophagy ablation on PDAC development in the context of mutant Trp53. This is clinically relevant because in human PDAC TP53 is rather mutated than completely lost and has previously not been appreciated. Importantly, we now also have a mouse model in place that allows genetic blockage of autophagy in established PDAC via inducible RNA interference. Thereby, we can investigate the potential therapeutic effect of autophagy ablation in vivo, also in the context of mutant Trp53. Furthermore, we sought mechanisms that compensate for the loss of autophagy. To this extent, we conducted a shRNA drop-out screen to identify relevant genes. Additionally, unbiased mass spectrometry based profiling of intra- und extracellular metabolites showed that the semi-essential amino acid arginine accumulates in autophagy-deficient PDAC cells. Subsequent arginine depletion experiments surprisingly resulted in only very modestly increased cell death in autophagy deficient cells, but induced a strong senescence – like arrest in PDAC cells regardless of autophagy. Arginine-depleted PDAC cells are highly susceptible to a novel drug class, so called senolytics that specifically kill senescent cells. Furthermore, initial results imply that arginine depletion might induce the cytosolic DNA-sensor cGAS and therefore possibly an immune response. In summary, we have generated sophisticated tools and mouse models to unravel if, how and when autophagy deletion can be utilized for PDAC therapy. Furthermore, we have uncovered a potential novel therapeutic approach to treat PDAC irrespective of autophagy status that combines metabolic intervention, senolytic therapy and possibly an immune response.
DFG Programme
Research Units
