Scheller, Tobias, Hellerbrand, Claus, Moser, Christian, Schmidt, Katharina, Kroemer, Alexander and Lang, Sven A. (2015) Improving the efficacy of targeting fibroblast growth factor receptor (FGFR) in hepatocellular carcinoma (HCC). British Journal of Cancer, 112 (5). pp. 841-850. ISSN 0007-09201532-1827

Abstract

Background & Aims
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. So far, systemic therapy has proven only marginal effects. The aim of this study was to evaluate the effects of targeting fibroblast growth factor receptor (FGFR) on tumor and stromal cells in HCC models.
Methods
Human (Huh-7, HepG2) and murine (Hepa129) cancer cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and hepatic stellate cells (HSCs) were used. Effectiveness of FGFR inhibitor BGJ398 on growth, motility, oncogenic signaling and expression of angiogenic markers was determined in vitro. In vivo FGFR inhibition was assessed in subcutaneous and, combined with an mTOR inhibitior, in syngenic orthotopic tumor models.
Results
In vitro, targeting FGFR showed significant growth inhibition, impaired oncogenic signaling (Akt, ERK, c-myc) and reduced tumor cell motility. Furthermore, recruitment and angiogenic signaling was diminished in ECs. Only minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. Moreover, daily (5mg/kg) treatment with BGJ398 led to significant growth inhibition in subcutaneous tumor models. In an orthotopic model, only combination of FGFR and mTOR blockade impaired tumor growth, which was paralleled by reduced tumor cell proliferation (BrdU), vessel area (CD31), pericytes (αSMA) and increased apoptosis (Tunel).
Conclusion
Targeting FGFR with BGJ398 demonstrates significant effects on tumor cells and ECs, whereas whereas only combination with mTOR inhibition impairs recruitment of VSMCs and HSCs in vitro and in vivo. Therefore, this study provides compelling evidence for combined FGFR and mTOR inhibition in HCC.

Item Type:	Article
Date Deposited:	13 Apr 2017 00:45
Last Modified:	13 Apr 2017 00:45
URI:	https://oak.novartis.com/id/eprint/11450