Treatment of pancreatic cancer with bifunctional siRNA silencing TGF-b and activating RIG-I (74.13)

Abstract

Abstract A hallmark of pancreatic cancer is deregulated transforming growth factor-b (TGF-b) signaling which promotes tumor growth and entertains a potent immunosuppressive network correlating with poor prognosis. To brake immune suppression, we designed siRNA molecules silencing TGF-b1 and introduced a 5’ppp-modification (ppp-TGF-b) to additionally activate the cytosolic helicase retinoic acid-inducible gene I (RIG-I). RIG-I recognizes ppp-RNA motives in viral RNA and triggers type-I IFN production. We found that human pancreatic cancer cells express functional RIG-I. Treatment with ppp-RNA resulted in IRF-3 phosphorylation, type-I IFN and CXCL10 secretion, and tumor cell apoptosis. Treatment of mice with syngeneic orthotopic pancreatic tumors with ppp-TGF-b (i.v.) resulted in reduced tumor-associated TGF-b levels, systemic immune activation and high IFN levels in serum and tumor. Furthermore, ppp-TGF-b induced caspase-9-mediated tumor cell apoptosis in vivo and significantly prolonged survival of tumor-bearing mice. The development of bifunctional ppp-siRNAs that combine TGF-b silencing and RIG-I activation in one molecule represents an innovative strategy for the treatment of pancreatic carcinoma.