Abstract B145: Addition of galunisertib to DC101 improved angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC)
Authors: Tijeras-Raballand Annemilai , Hobeika Christian , Martinet Matthieu , Paven Elise , Bonin Philippe , Eveno Clarisse , Pocard Marc , Bouattour Mohamed , Faivre Sandrine , Raymond Eric , de Gramont Armand 
Published: August 2018

Introduction: Galunisertib, a selective ATP-mimetic TGF-β receptor (TGFβR)-I inhibitor, displays a very safe toxicity profile in clinical trials, making it suitable for combinations. Galunisertib showed activity as second-line treatment in advanced HCC patients with high baseline AFP &gt; 200 ng/mL. Patients experiencing &gt;20% reduction in AFP level during treatment with galunisertib presented an outstanding median overall survival of 21.4 months (Faivre et al., ASCO GI 2014). Poor-prognosis HCC patients require innovative combinations to improve outcomes observed with antiangiogenic therapies. DC101 is a rat antagonist antibody to mouse VEGFR-2, and is used to model VEGFR-2 blockade in murine model. Both therapies have been shown to be independently beneficial to some subpopulation of HCC patients. Our study aimed at exploring the antitumoral potency of a combination of galunisertib and DC101 in an in vivo transgenic mouse model of HCC. Materials and 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: First, we confirmed the mode of action of galunisertib by assessing pSMAD2 expression, the pharmacodynamics target of galunisertib, before and after treatment. An 87% decrease in pSMAD2 expression was observed in liver tumors treated by galunisertib compared to placebo or DC101. 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 improved tumor control at W16 in the combination arm (4.43 mm3±0,55 mean liver volume) vs in the DC101, galunisertib, and placebo arms (5.22±0,86, 5.68±0,78, 7.09±1,54 respectively). Tumor growth inhibition was confirmed at W16 by a 31% and 52% decrease in the number of macronodules compared to placebo, in the galunisertib- and DC101-treated mice, respectively. This inhibition reached 62% in the combination group compared to placebo. Moreover, on hematoxylin phloxine saffron (HPS) section, no decrease in the number of micronodules was observed, whereas the size of these micronodules was dramatically reduced, especially in the combination arm with a 72% decrease compared to placebo. Angiogenesis, assessed by measuring the mean blood flow in the coeliac trunk (TCm), decreased in all treatment arms compared to placebo. At W16, galunisertib potentiated the effect of DC101 with a TCm decrease of 66% compared to 59% and 10% in the DC101 and galunisertib arms, respectively. CD31 confirmed the antiangiogenic effects of galunisertib and DC101, with a 25% and 51% decrease in vessel number, respectively, compared to placebo. These effects on angiogenesis were potentiated in the combination arm with an 80% decrease compared to placebo. Conclusion: The combination of galunisertib and DC101 showed promising antitumor activities that were associated with decreased angiogenesis.

Citation Format: Annemilai Tijeras-Raballand, Christian Hobeika, Matthieu Martinet, Elise Paven, Philippe Bonin, Clarisse Eveno, Marc Pocard, Mohamed Bouattour, Sandrine Faivre, Eric Raymond, Armand de Gramont. Addition of galunisertib to DC101 improved angiogenesis inhibition and tumor growth control in hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B145.