Abstract 1673: Galunisertib combined with sorafenib affects proliferation, EMT and delays tumor growth in mice and in hepatocellular carcinoma (HCC) patient samples ex vivo

Abstract

Abstract Introduction: The TGF-β pathway that has been associated with hepatocellular carcinoma (HCC) progression, can be targeted by galunisertib, a selective ATP-mimetic TGF-β receptor (TβR)-I inhibitor currently under clinical investigation in HCC patients after sorafenib failure or ineligible for sorafenib treatment. Our study aimed to investigate the tumor effects of galunisertib with or without sorafenib in different models of HCC and in freshly grown HCC specimens from patients. Material and methods: Transgenic mice developing stage-defined HCC were treated for 12 weeks (W) with either vehicle, sorafenib (30mg/kg), galunisertib (100mg/kg) or sorafenib plus galunisertib. Human hepatocarcinoma HUH7 cells were subcutaneously injected in nude mice and treated daily with either vehicle, sorafenib (60mg/kg) or sorafenib combined with galunisertib (100mg/kg). Ex vivo experiments were realized in surgical specimens from HCC patients that were cut into 300μM and grown in specific media. Slices were randomly exposed to galunisertib (10μM), sorafenib (5μM) and sorafenib plus galunisertib for 48h. At the end of treatments, tumor samples were analyzed by IF or IHC. Results: In transgenic mice, the number of liver tumor macronodules was significantly lower in all treatment arms compared to control placebo (p3 fold decrease in proliferation (Ki67 expression) and 3-5 fold increase in apoptosis induction (caspase-3 expression). Conclusion: In vivo and ex vivo, TGF-β signalling inhibition using galunisertib in combination with sorafenib in HCC models showed promising data on downstream signaling pathway, angiogenesis and tumor growth inhibition and may prevent sorafenib-induced EMT. Citation Format: Annemilai Tijeras-Raballand, Maria Serova, Cindy Neuzillet, Miguel Albuquerque, Nathalie Colnot, Matthias Barral, Anthony Dohan, Matthias Barral, Philippe Bonnin, Marc Pocard, Valérie Paradis, Eric Raymond, Sandrine Faivre, Armand de Gramont. Galunisertib combined with sorafenib affects proliferation, EMT and delays tumor growth in mice and in hepatocellular carcinoma (HCC) patient samples ex vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1673. doi:10.1158/1538-7445.AM2015-1673