Abstract 2135: TGFβRI inhibition results in reduced collagen expression in pancreatic ductal adenocarcinoma.

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a robust stromal component termed the desmoplastic reaction. Transforming growth factor β (TGFβ) has been implicated in the activation of the cancer-associated fibroblast (CAF) that leads to pancreatic desmoplasia and the increased deposition of extracellular matrix proteins. Desmoplasia and its effects are thought to contribute to poor drug efficacy in PDAC treatment. We therefore hypothesized that TGFβ receptor (TGFβR) inhibition may serve to improve the activity of chemotherapeutics in PDAC by reducing the effects of desmoplasia. Using the TGFβRI inhibitors, LY2157299 and SB431542, we assessed the effects of TGFβR inhibition on cell proliferation and collagen production in both mono- and co-cultured pancreatic tumor cells and CAFs. We found that although the TGFβRI inhibitors had moderate effect on the proliferation of PDAC cells and co-cultured CAF cells, they significantly inhibited collagen 1 expression in the co-culture of MIA PaCa-2 and SU86.86 cells with CAFs (2.3 and 6.0-fold at the mRNA level, respectively). Similar qualitative reductions were also observed in immunofluorescence microscopy and immunoblots probing for collagen 1 protein levels. We also sought to determine if TGFβR inhibition would result in a reduction in collagen expression in the more biologically relevant in vivo model for PDAC, the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse. KPC mice were treated orally, b.i.d., with 75mg/kg LY2157299 and by i.p., with gemcitabine (q3dx4) at 80mg/kg. Tumors in KPC mice treated with the combination of LY2157299 and gemcitabine showed a marked reduction in overall stromal content when compared to vehicle-treated mice. Our results suggest that TGFβR inhibition may be an effective means of ameliorating the effects of desmoplasia in PDAC, which may in turn improve the efficacy of current PDAC treatment regimens. Citation Format: Clifford J. Whatcott, Sabrina N. Dumas, Aprill Watanabe, Janine LoBello, Daniel D. Von Hoff, Haiyong Han. TGFβRI inhibition results in reduced collagen expression in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2135. doi:10.1158/1538-7445.AM2013-2135