Abstract 4116: Anti-tumor and anti-metastasis efficacy of a novel Notch inhibitor (PF-03084014) in hepatocellular carcinoma

Abstract

Abstract Hepatocellular Carcinoma (HCC) is well-known for its aggressive growth and highly metastatic potential. Efficacy of current therapy is limited by fast tumor growth and rapid metastasis. Cancer stem cells (CSCs) represent a distinct population that can be prospectively isolated from tumor tissues and have long-term clonal repopulation and self-renewal capacity. They are highly tumorigenic, metastatic, and resistance to conventional radiation and chemotherapy. Therefore, it is essential to identify effective therapy to target CSCs. In our prior study, Notch deregulation was correlated with poor outcome in HCC. In this study, we investigated anti-tumor and anti-metastatic efficacy of a novel Notch inhibitor (PF-03084014) in liver cancer spherical cells in vitro and sphere cell-derived orthotropic model in vivo. PF-03084014 significantly suppressed liver CSCs spheroid formation (derived from 97H HCC cells), with survival rate less than 20% by higher dose of PF-03084014. In accordance, CD90+, EpCAM+ and Oct4+ liver CSC populations significantly decreased, so as down-regulation the stem cell genes expression such as Sox2 and Nanog. These results suggest a suppressive effect of PF-03084014 on liver CSC self-renewal ability. Low dose PF-03084014 induced cancer spheroid cell differentiation leading to chemosensitization. Moreover, Notch inhibitor (PF-03084014) altered liver CSCs stemness properties and blocked spherogenesis of CSCs in vitro, leading to decrease tumorigenicity in vivo. In HCC spherical cell- and non-spherical cell-derived orthotropic model, PF-03084014 effectively inhibited tumor growth, with tumor size was 2570±690 mm3 in vehicle group vs. 800±500 mm3 in Notch inhibitor group (p < 0.001). More importantly, under PF-03084014 treatment, HCC tumor metastasis to lung was significantly reduced (87.5% metastasis rate in vehicle group vs. 18.75% in PF-03084014 group). To explore the potential mechanism, we found PF-03084014 was able to suppress phosphorylation of STAT3 and AKT, the kinases involving in self-renewal of stem cells. PF-03084014 also reversed endothelial mesenchymal transition (EMT) shown by down-regulation of Snail-1 and up-regulation of E-cadherin. Together, PF-03084014 shows a strong anti-cancer and anti-metastasis effect on HCC spherical cell derived in vitro and in vivo model, which provides a preclinical rational of the PF-03084014 to serve as a new novel drug in liver cancer therapy. Citation Format: Wu Chuanxing, Wang Xiaoqi. Anti-tumor and anti-metastasis efficacy of a novel Notch inhibitor (PF-03084014) in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4116.