Identification of biomarkers to predict individual radiosensitivity using pre-clinical pancreatic cancer models and development of innovative chemoradiation therapy concepts
Radiation therapy is an efficient anti-tumorigenic treatment option in a subgroup of pancreatic cancer patients. We have demonstrated that chemoradiation causes an effective tumor downsizing, a secondary resectability and thereby improves long-term prognosis in locally advanced pancreatic ductal adenocarcinoma (PDAC) patients with non-resectable tumors. Although strong differences in intrinsic radiosensitivity exist and only about one third of PDAC patients benefit from radiation, standard radiotherapy does not consider the individual differences in tumor radiosensitivity. Therefore, the aim of P15 is the development of innovative molecular markers that predict radiosensitivity. In the future, these biomarkers could be used to identify those patients, which might benefit from radiotherapy in the context of biologically guided personalized treatment strategies.
250 mouse PDAC cell lines (from S01) with various genetic backgrounds will be screened for their radiosensitivity. First data from 38 mouse PDAC cell lines reveal distinct differences in radiosensitivity and first molecular analyses suggest EGR-1 (early growth response-1) to be involved in radioresponse (P13, S02). In a hypothesis driven approach, the correlation between radioresistance and EGR-1 expression will be examined. Additionally, the association between radioresistance and histone deacetylases (HDAC) which play an important role in DNA repair will be investigated. In an unbiased approach, the genomic, transcriptomic, proteomic landscape (S02) and signaling pathways (phosphoproteomics) (P18) of radioresistant and radiosensitive murine PDAC cell lines will be compared. The respective genes/pathways that differ will be manipulated by genetic gain- and loss- of function experiments (S01). Organoids derived from human PDAC patients (P12/S01) who reflect better the clinical situation will be screened accordingly. To verify the in vitro data, an orthotopic allograft mouse model will be applied to analyze the radioresponse of murine pancreatic tumors after high precision irradiation, which is standardized, and quality assured within the SFB (P16). Patient derived organoids (S01) will be transplanted into mice to prove the molecular signature - that has been developed in mouse tumors - in patient tumors. To improve the treatment of radioresistant PDACs, drugs from the drug library (S01) targeting the respective pathways/genes will be tested for their radiosensitizing efficiency in vitro and in vivo.
In summary, the screening of radioresistance of murine PDAC cell lines and pancreatic cancer patient-derived organoids (PDOs) and the detailed information on the genomic landscape, transcriptomes, proteomes and phosphoproteomes as well as the drug response will contribute to the identification of predictive biomarkers for cell intrinsic radioresistance and the development of novel innovative treatment concepts.
Nguyen, L., Dobiasch, S., Schneider, G., Schmid, R. M., Azimzadeh, O., Kanev, K., Buschmann, D., Pfaffl, M. W., Bartzsch, S., Schmid, T. E., Schilling, D., and Combs, S. E. (2021). Radiother Oncol 159, 265-276
Nguyen, L., Schilling, D., Dobiasch, S., Raulefs, S., Santiago Franco, M., Buschmann, D., Pfaffl, M. W., Schmid, T. E., and Combs, S. E. (2020). Cancers (Basel) 12
Wiechmann, S., Saupp, E., Schilling, D., Heinzlmeir, S., Schneider, G., Schmid, R. M., Combs, S. E., Kuster, B., and Dobiasch, S. (2020). Mol Cell Proteomics 19, 1649-1663
Schwarz, K., Dobiasch, S., Nguyen, L., Schilling, D., and Combs, S. E. (2020). Sci Rep 10, 3815
Naumann, P., Eberlein, J., Farnia, B., Liermann, J., Hackert, T., Debus, J., and Combs, S. E. (2019). Cancers (Basel) 11
Naumann, P., Eberlein, J., Farnia, B., Hackert, T., Debus, J., and Combs, S. E. (2019). Cancers (Basel) 11
Dobiasch, S., Kampfer, S., Habermehl, D., Duma, M. N., Felix, K., Strauss, A., Schilling, D., Wilkens, J. J., and Combs, S. E. (2018). Strahlenther Onkol 194, 944-952
Dobiasch, S., Kampfer, S., Burkhardt, R., Schilling, D., Schmid, T. E., Wilkens, J. J., and Combs, S. E. (2017). Strahlenther Onkol 193, 1039-1047
Naumann, P., Liermann, J., Fortunato, F., Schmid, T. E., Weber, K. J., Debus, J., and Combs, S. E. (2017). PLoS One 12, e0180940