Abstract 200: Long lasting inhibition of TGF-β receptor Type 1 inhibitor (TGF-β R1) for treatment of pancreatic cancer

Abstract

Abstract Pancreatic cancer stroma is a high component of total tumor volume and activators of fibro-genesis such as Transforming growth factor-β (TGF-β) are abundantly secreted by pancreatic stellate cells (PSCs) to the tumor microenvironment. Aberrant TGF-β signaling pathways are associated with many human diseases, including bone diseases, immune-suppression, fibrosis, cancer progression and metastasis. However, the precise mechanism of this phenomenon in pancreatic cancer remains unclear. In this study we hypothesized that inhibition of TGF-β Type I receptor kinase (TGF-β R1) in pancreatic cancer and stellate cells regulates proliferation and fibrosis through the regulation of TGF-β R1 signaling pathway in PC cells, resulting in decreased migration, and decreased proliferation. We analyzed a TGF-β R1 data set of PC patients from the Cancer Genome Atlas. Furthermore, the analysis of a panel of pancreatic cancer cell lines showed that TGFR-B1 at mRNA and protein levels were higher in PC cells when compared with human pancreatic duct epithelial (HPDE) normal cells. In vitro cell viability, growth, cell-cycle progression, migration, invasion and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following the inhibition of TGF-β R1 in pancreatic cancer and stellate cells. The experimental validation identifies TGFR-β1 associated with PC survival. Significant inhibition of cell growth, invasion, migration, angiogenesis and fibro-genesis. Furthermore, treatment with LY-DMPC:DMPG-MSV inhibited growth of CAPAN-II tumors. These findings identify TGFR-β1 as a potential therapeutic target in pancreatic cancers expressing high levels of this oncogenic protein. Note: This abstract was not presented at the meeting. Citation Format: Cristian Rodriguez-Aguayo, Emine Bayraktar, Haifa Shen, Gabriel Lopez-Berestein. Long lasting inhibition of TGF-β receptor Type 1 inhibitor (TGF-β R1) for treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 200. doi:10.1158/1538-7445.AM2017-200