Inhibition of CD95 ligand as a novel therapeutic strategy interfering with tumor stroma driven progression of pancreatic ductal adenocarcinoma

• Applicant: Professor Dr. Jan-Hendrik Egberts
• Subject Area: General and Visceral Surgery
• Term: from 2010 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 191999737

In addition to the paradigmatic role of the CD95/CD95Ligand (CD95L) system for the control of apoptosis, additional, mostly pro-inflammatory functions of this "death signal" have emerged. We have previously observed a substantial stimulation of invasiveness upon CD95 activation of pancreatic ductal adenocarcinoma (PDAC) cells. Since these tumor cells express CD95L and are additionally subjected to paracrine stimulation under in vivo conditions within the tumor microenvironment, inactivation of this death ligand is supposed to be a promising therapeutic strategy. We will use two novel recombinant (di-/trimeric) inhibitor proteins against CD95L in our comprehensively characterized, clinically adapted pancreatic tumor models. This will enable us to directly compare neoadjuvant, adjuvant, and combined-extended therapeutic regimens using our established molecular imaging and further conventional tools as readout for overall therapeutic effects as well as for specific effects on tumor stroma interaction. Having shown previously that neutralization of PDAC-derived TNF has a positive adjuvant effect we will also combine both inhibitory tools and further assess their interplay with Gemcitabine chemotherapy for the sake of clinical translation. Fully immune competent murine PDAC models will finally allow us to study the impact of CD95L antagonists on regulatory T cells and other infiltrating immune cells in the tumor stroma.

• DFG Programme: Research Grants
• Participating Person: Professor Holger Kalthoff, Ph.D.