Abstract 220: Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features

Abstract

Abstract Hepatocellular carcinoma (HCC) is known to demonstrate a morphological variety of macroscopic appearances, but their pathological and molecular differences remain unclear. First, the clinicopathologic characteristics as well as genome-wide gene expressions were analyzed in relation to the gross morphology of HCC. Among the patients with nodular type HCC, significantly poor prognosis was recognized in confluent multinodular (CM) type in overall survival as well as recurrence-free survival. Analysis of the genome-wide expression patterns revealed significant deference of CM-type HCC from other types of HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM-type HCC. Next, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU. Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13, VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13. In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control. Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control. Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and specific approach for the treatment of HCC with the poor prognostic phenotype. Citation Format: Shinji Tanaka, Kousuke Ogawa, Ayano Murakata, Kaoru Mogushi, Satoshi Matsumura, Arihiro Aihara, Daisuke Ban, Takanori Ochiai, Takumi Irie, Atsushi Kudo, Noriaki Nakamura, Hiroshi Tanaka, Shigeki Arii, Minoru Tanabe. Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 220. doi:10.1158/1538-7445.AM2014-220