Abstract 2927: Antitumor and antiangiogenesis activities of E7386, an orally active CBP/β-catenin modulator, as a single agent and in combination with lenvatinib in human HCC xenograft models

Abstract

Abstract E7386 is a novel orally active CBP/β-catenin modulator that has showed anti-tumor activity in human tumor xenograft models with aberrant activation of Wnt/β-catenin signaling pathway. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. In HCC, it has been reported that aberrant activation of the canonical Wnt/β-catenin signaling pathway frequently occurs (20-40%). In this study, we investigated anti-tumor activity of E7386 as monotherapy or in combination with lenvatinib in human HCC xenograft models. Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors and oncogenic kinases. A recent Phase III study demonstrated the treatment effect of lenvatinib on OS by statistical confirmation of non-inferiority as compared with sorafenib patients with unresectable HCC. We evaluated the anti-tumor activity of E7386 as a single agent and in combination with lenvatinib in 4 human HCC cell lines (SNU398, HepG2, Hep3B2.1-7 and Huh-7) xenograft models. These cell lines were injected subcutaneously into male nude mice, and tumors were allowed to grow to 150-200 mm3 in size. Then, the mice were given oral administration of E7386 and/or lenvatinib for 14 days. Single treatment of E7386 demonstrated statistically significant anti-tumor effect in HepG2 and SNU398 xenograft models with β-catenin mutation; delta T/C value (dT/C) of 60% at 100 mg/kg qd in HepG2 model, dT/C of 74% and at 50 mg/kg qd in SNU398 model. On the other hand, no tumor growth inhibition was observed in Hep3B2.1-7 and Huh-7 xenograft models with wild type β-catenin. Lenvatinib at 10 mg/kg showed the anti-tumor effect in all 4 xenograft models, dT/C of 68%, 43%, 52% and 70% in SNU398, HepG2, Hep3B2.17 and Huh-7, respectively. E7386 at 50 mg/kg in combination with 10 mg/kg of lenvatinib showed more potent anti-tumor effects compared with each single treatment irrespective of β-catenin mutation status, dT/C of 35%, 14%, 9% and 17% in SNU398, HepG2, Hep3B2.17 and Huh-7, respectively. Similar combined activities were observed at the range of 6.25-50 mg/kg of E7386 with lenvatinib at 10 mg/kg. Next, we examined the effect on tumor angiogenesis. Each 50 mg/kg of E7386 and 10 mg/kg of lenvatinib decreased the microvessel density (MVD) in SNU398, reduction ratio of 37% and 79%, respectively. The combination treatment significantly decreased MVD more than each single treatment (reduction ratio of 91.4-95.1% at 12.5-50 mg/kg of E7386 with lenvatinib at 10 mg/kg). Similar combination effects were also observed in HepG2 and Huh-7 xenograft models.In conclusion, these results indicate that the combination of E7386 with lenvatinib exerted enhanced anti-angiogenic activity against tumor vessels and demonstrated the potent anti-tumor activity in HCC preclinical models. Citation Format: Kazuhiko Yamada, Yusaku Hori, Hiroshi Kamiyama, Takayuki Kimura, Yasuhiro Funahashi, Junji Matsui, Yoichi Ozawa. Antitumor and antiangiogenesis activities of E7386, an orally active CBP/β-catenin modulator, as a single agent and in combination with lenvatinib in human HCC xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2927.