Abstract 4044: LY3039579, a novel Notch inhibit, potentiates the anti-tumoral effects of sorafenib in hepatocellular carcinoma (HCC)
Authors: Tijeras-Raballand Annemilai , Hobeika Christian , Payen Elise , Martinet Matthieu , Bonnin Philippe , Benhadji Karim A. , Patel Bharvin R. , Eveno Clarisse , Pocard Marc , Faivre Sandrine , Raymond Eric , Gramont Armand de 
Published: July 2017

Abstract
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. Our study aimed at investigating the anti-tumoral effects of combining LY3039478, a novel Notch inhibitor, to sorafenib 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, 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 HPS sections 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 control placebo at both the W12 intermediary sacrifice and W16 final sacrifice; the combination of LY3039478 and sorafenib showing increased tumor control at W16 (4,39±0,82 in mean liver volumes (in mm3) in the combination arm vs 5,41±1,0, 5,84±0,47, 7,09±1,5 in the sorafenib, LY3039478 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, LY3039478 potentiated the effect of sorafenib, with a TCm decrease of 36% compared to 23% and18% the sorafenib and LY3039478 arms, 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 LY3039478 and sorafenib 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, Bharvin R. Patel, Clarisse Eveno, Marc Pocard, Sandrine Faivre, Eric Raymond, Armand de Gramont. LY3039579, a novel Notch inhibit, potentiates the anti-tumoral effects of sorafenib 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 4044. doi:10.1158/1538-7445.AM2017-4044