Abstract B33: Inhibition of stromal-derived CTGF sensitizes murine pancreatic adenocarcinoma to gemcitabine treatment.

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia contributing to tumor progression and therapeutic resistance. Here, we aim to therapeutically target the profibrotic connective tissue growth factor (CTGF) in an established genetically engineered mouse model of PDA to improve therapeutic response to the standard chemotherapy gemcitabine. Methods: Response to treatment was assessed by high resolution ultrasound in mice bearing endogenous PDA. Pharmacokinetic studies were performed by LC-MS/MS for gemcitabine metabolites. Molecular evaluation of treatment effects on tumor cells and the tumor microenvironment was conducted in vivo and in vitro using various approaches such as immunohistochemistry, co-immunofluorescence, and immunoblotting. Results: In the KPC model, CTGF is predominantly expressed by cancer associated fibroblasts and the combination of the monoclonal antibody FG-3019 and gemcitabine most effectively reduced tumor burden, liver metastasis, hemorrhagic ascites and significantly prolonged survival compared to gemcitabine single agent (p<0.05). Although intratumoral gemcitabine delivery was not elevated upon FG-3019 treatment, apoptosis in tumor cells but not α-smooth muscle actin positive fibroblasts was significantly increased. Conclusions: Inhibition of stromal derived CTGF sensitizes murine PDA to gemcitabine without increasing its intratumoral levels. The synergism of FG-3019 and gemcitabine is of immediate clinical significance and provides support for investigational trials with this therapeutic combination in PDA patients. Moreover, our data suggest that inhibiting CTGF may be a promising strategy to circumvent therapeutic resistance in PDA. Citation Format: Albrecht Neesse, Kristopher K. Frese, Tash E. Bapiro, Suzanne Spong, Duncan I. Jodrell, David A. Tuveson. Inhibition of stromal-derived CTGF sensitizes murine pancreatic adenocarcinoma to gemcitabine treatment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B33.