Abstract
Abstract Introduction: Galunisertib is a selective ATP-mimetic TGF-β receptor (TGFβR)-I inhibitor and DC101 is a rat antagonist antibody to mouse VEGFR-2 and is used to model VEGFR-2 blockade in murine tumor models. Ramucirumab and galunisertib being independently under clinical investigation in HCC patients, our study aimed at exploring the anti-tumoral potency of a combination of galunisertib and DC101 in an in vivo transgenic model of HCC. Methods: Transgenic mice developing stage-defined HCC were treated for 8 weeks (W) from W8 to W16 with either vehicle, DC101 (40mg/kg, twice weekly, IP), galunisertib (100mg/kg, daily, oral gavage) or DC101 plus galunisertib. Tumor growth was evaluated by ultrasound (liver size) and by the number of macronodules at sacrifice. Angiogenesis was evaluated by doppler (blood flow in the coeliac trunk) and by CD31 staining. Results: Liver size and the number of liver tumor macronodules were significantly lower in all treatment arms compared to placebo control at both the W12 intermediary sacrifice and W16 final sacrifice; the combination of galunisertib and DC101 showing increased tumor control at W16 (4,43±0,55 mean liver volume (in mm3) in the combination arm vs 5,22±0,86, 5,68±0,78, 7,09±1,54 in the DC101, galunisertib and placebo arms respectively). Angiogenesis assessed by measuring the mean blood flow in the coeliac trunk (TCm), decreased in all treatment arms compared to placebo. At W16, galunisetib potentiated the effect of DC101 with a TCm decrease of 66% compared to 59% and 10% in the DC101 and galunisertib, respectively. These results will be confirmed by the assessment of micronodules number on HPS section for tumor growth and CD31 staining for angiogenesis analysis (number of vessels and the vessel lumen area). The effects of the combination versus monotherapies will be evaluated on the immune landscape. Conclusion: The combination of galunisertib and DC101 showed promising anti-tumor activities that were associated with decreased angiogenesis. Citation Format: Annemilai Tijeras-Raballand, Christian Hobeika, Elise Payen, Matthieu Martinet, Philippe Bonnin, Karim A. Benhadji, Clarisse Eveno, Marc Pocard, Sandrine Faivre, Eric Raymond, Armand de Gramont. Addition of Galunisertib to DC101 increased angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 29. doi:10.1158/1538-7445.AM2017-29
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