Abstract B144: LY3039478, a novel Notch inhibitor, potentiates the antitumor effects of sorafenib 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: Notch pathway has been involved in cell fate determination, cell differentiation, proliferation, and death. Notch promotes cell survival, angiogenesis, and treatment resistance in numerous cancers, making it a promising target for cancer therapy. The role of the Notch pathways in HCC tumorigenesis has shown some controversies over time and across studies, being endowed with both oncogenic and tumor-suppressive properties. Besides sorafenib, new therapies are needed to improve outcomes in patients with advanced HCC. Our study aimed at investigating the antitumoral effects of combining LY3039478, a novel Notch inhibitor, with sorafenib in an in vivo transgenic model of HCC. Materials and Methods: Transgenic mice developing stage-defined HCC were treated for 8 consecutive weeks (W) from W8 to W16 with either vehicle, LY3039478 (8mg/kg, thrice weekly, oral gavage), sorafenib (30mg/kg, daily, oral gavage), or LY3039478 plus sorafenib. Tumor growth was evaluated by ultrasound (liver size), by the number of macronodules, and the number of micronodules on hematoxylin phloxine saffron (HPS) sections 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 LY3039478 by assessing Notch 1 expression before and after treatment. An 85% decrease in Notch 1 expression was observed in liver tumors treated by LY3039478 compared to placebo or sorafenib. Liver size and the number of liver tumor macronodules were significantly lower in all treatment arms compared to control placebo at both the W12 intermediate sacrifice and W16 final sacrifice; the combination of LY3039478 and sorafenib showed increased tumor control in the combination arm at W16 (4.39mm3 ±0,82 in mean liver volumes) vs sorafenib, LY3039478, and placebo arms (5.41±1,0, 5.84±0,47, 7.09±1,5 respectively). Tumor growth inhibition was confirmed in both the sorafenib and LY3039478 arms at W16 by a 22% and 32% decrease in the number of macronodules compared to placebo, respectively. This inhibition reached 52% in the combination arm compared to placebo. On Hematoxylin Phloxine Saffron (HPS) section, while the number of micronodules was similar between groups, their size was dramatically reduced, especially in the combination arm with a 65% 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, LY3039478 potentiated the effect of sorafenib, with a TCm decrease of 36% compared to 23% and 18% for the sorafenib and LY3039478 arms, respectively. CD31 confirmed the antiangiogenic effects of LY3039478 alone or in combination, with a 70% and 81% decrease in vessel number, compared to placebo. Conclusion: The combination of LY3039478 and sorafenib showed promising antitumor activity that was associated with decreased angiogenesis in a murine model of stage-defined HCC.

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. LY3039478, a novel Notch inhibitor, potentiates the antitumor effects of sorafenib 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 B144.