It is now well known that the undifferentiated PDX1+ pancreatic progenitors proliferate and differentiate into endocrine, ductal, and acinar cells, thanks to the expression of numerous transcription factors, which can be used to better characterize pancreatic tumors.
Increasing Hh expression in neoplastic cells added desmoplastic stroma accumulation in orthotopic tumors, and Hh inhibitors that target the stroma have an ability to prolong the overall survival of Pdx-1-Cre/KrasG12D/p53R172H mice models via deleting the stromal components and increasing vascularity in pancreatic tumor.
We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008).
We disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors.
Deletion of Lfng resulted in downregulation of Tgfb1, Tgfb2 and Tgfbr2 expression in the wild-type pancreas at all ages examined, and in the Kras(LSL-G12D/+);Pdx1-Cre pancreas after PDAC onset, as well as reduced phospho-Smad2 levels in pancreatic tumors.