SUMMARY:
Colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma remain among the leading causes of cancer-associated death worldwide. Through the use of targeted therapies that "attack" specific signaling pathway molecules in the tumor, progress has already been made in the overall survival of tumor patients, e.g. through the use of a monoclonal antibody against the growth factor receptor EGFR in CRC. The focus of our research is the identification of new active targeted therapies in both tumor types using established preclinical PDX models. Primary and secondary resistance mechanisms of the investigated targeted therapies are molecularly identified and potential new drug combinations to overcome resistance are tested in PDX models. The main question is to clarify whether PDX tumors represent an effective approach to generate an individualized therapy proposal for patients or to enable an optimization of the individualized therapy in the resistance situation. It will also be clarified whether the molecular data set collected in the PDX trials can be used to establish a bioinformatic model for predicting the causes of resistance and the resulting therapy options. Finally, we are investigating the so-called "drug tolerant persister cells" (DTPs) at the molecular level, i.e. those cells that survive the therapy and thus represent the cell reservoir for the development of secondary resistance. The aim is to find therapeutic targets to minimize drug tolerance in order to improve the response to therapy.
FIELD OF WORK AND METHODS:
Basic and translational research on pancreatic and colon adenocarcinoma. Methodological focus is on the production of transgenic cell models (established cell lines, primary cell lines) with lentiviral vector systems (overexpression, shRNA, TALEN, CRISPR/Cas9 systems, and expressed barcoding) for global and clone-specific gene function and signaling pathway analyses (e.g. via global or single cell gene expression analyses, protein and phosphoprotein analyses and gene sequencing). Production of primary cell lines from pancreatic and colon carcinomas using conditional reprogramming. Animal models: patient tumor-derived xenograft tumor system (also known as PDX; xenograft bank: colon carcinoma N>220, pancreatic carcinoma N>70) with a focus on testing targeted therapies and the identification of molecular causes forf the development of so-called "persister" cells as well as the development of therapy resistance (primary and secondary resistance) to targeted therapies. Production of in vivo secondary resistance models.
CURRENT TOPICS/PROJECTS:
1) Secondary resistance mechanisms to anti-EGFR therapy in colon carcinoma
2) Targeted therapies of KRAS mutated tumors in preclinical models of colon and pancreatic cancer.
3) Primary and secondary resistance mechanisms of the targeted therapies tested under 2.
4) Clonal developmental dynamics of resistant cells under targeted therapy.
5) Biology of the so-called "drug tolerant persister cells" (DTPs).
METHODEN:
