Pancreatic cancer is one of the deadliest forms of
cancer and effective treatment remains a clinical challenge.
Transforming growth factor-beta (
TGF-beta) has important roles in primary
tumor progression and in promoting
metastasis, and has become an attractive target for
therapy. Previously, we reported that treatment of
pancreatic cancer cells in vitro with
SD-208, a small molecule inhibitor of the
TGF-beta receptor I
kinase (TGF-betaRI), inhibited expression of genes associated with
tumor progression and inhibited invasiveness in a cell-based assay. In a demonstration of efficacy of
TGF-beta signaling inhibition in an in vivo model of
pancreatic cancer, we showed significantly reduced primary
tumor weight and decreased incidence of
metastasis in the Panc-1 orthotopic xenograft model of established
pancreatic cancer. In this report, we extend these in vivo findings to examine the mechanistic consequences of TGF-betaRI inhibition on Panc-1 primary
tumors and their microenvironment in situ. In a longitudinal study of TGF-betaRI inhibition in the Panc-1 orthotopic model, we show that
SD-208 treatment significantly reduced
tumor growth measured as bioluminescence intensity throughout the study. Histological evaluation revealed that
SD-208 treatment reduced proliferation and induced apoptosis in the primary
tumors, and reduced
fibrosis in the tumor microenvironment. An immune contribution (greater B-cell infiltration in SD-208-treated
tumors) was also suggested by the histological analyses.
SD-208 not only blocked direct
TGF-beta signaling in Panc-1 primary
tumors (reduced phospho SMAD2/3), but also down-regulated the expression of
TGF-beta-regulated genes (PAI-1 and COL7A1). Taken together, our results indicate that a TGF-betaRI
kinase inhibitor has a potential therapeutic benefit for
pancreatic cancer patients.