Targeting cytosolic helicases with modified siRNA for immunotherapy of hepatocellular carcinoma

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Immune responses are able to influence tumor growth in HCC. Type I interferon (IFN) in conjunction with other inflammatory cytokines plays a key role in tumor immune surveillance and boosts tumor immunity. The ubiquitously expressed RIG-I-like helicases (RLH) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein-5 (MDA-5) are immunoreceptors that signal the presence of viral RNA in the cytosol of cells and activate innate and adaptive immunity via type I IFN. Furthermore, RLH activate the intrinsic, mitochondrial pathway of apoptosis in tumor cells. The combination of immune activation and apoptosis induction via RLH ligands has great potential in cancer therapy. Synthetic RNA molecules containing a triphosphate group at the 5' end (ppp-RNA) induce RIG-I signaling. Modifying siRNA to ppp-siRNA allows to combine gene silencing with RIG-I activation and has shown therapeutic efficacy in several tumor models. The proposed project aims at evaluating RLH as targets and specific RLH ligands as therapeutic agents for HCC. Bi-functional ppp-siRNA molecules designed to specifically silence tumor promoting targets regulating angiogenesis, proliferation and immune suppression will be developed and validated in mouse models of HCC. In addition, means for optimizing siRNA delivery for effective tumor targeting will be investigated. Our goal is the preclinical development of bi-functional siRNA molecules as novel therapeutic option for patients with HCC.