Targeting insulin-like growth factor axis in hepatocellular carcinoma

Abstract

The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC.

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

“…In vivo , A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis 14. Although several IGF1R inhibitors or blocking antibodies have been tested in preclinical models or clinical trials for patients with HCC,9, 14, 15, 16 none has been approved by the FDA, possibly because inhibition of IGF1R alone may not be sufficient to effectively inhibit HCC cell growth and survival. Our data support this hypothesis as inhibition of IGF1R by shRNA or ceritinib has only a modest suppression on HCC proliferation and survival (Figs.…”

“…Abrogation of IGF1R activation significantly but modestly decreases HCC cell viability and proliferation 14. Although several IGF1R inhibitors have been tested in clinical trials,9, 15, 16 none have been approved by the U.S. Food and Drug Administration (FDA). Intriguingly, ceritinib (Zykadia), a potent anaplastic lymphoma kinase (ALK) inhibitor that is FDA approved for treatment of non‐small cell lung cancer,17 has been reported to effectively inhibit IGF1R 18…”

BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

“…In fact, sorafenib was found to be a multi-targeted kinase inhibitor, which targets VEGFR, PDGFR, FGFR and other pathways. Its anti-angiogenic effect is the potential mechanism of action in renal cell carcinoma and hepatocellular carcinoma (Kudo and Ueshima, 2010;Stenner et al, 2012;Wu and Zhu, 2011).…”

“…Ongoing clinical trials are evaluating new BRAF inhibitors (Table 1). LGX818, a mutant RAF kinase inhibitor, demonstrated no inhibitory effect on WT B-Raf cell lines, and also showed activity in LGX818 Phase 1 trial currently recruiting patients (Wu and Zhu, 2011) Mutant BRAF selective inhibitor ARQ736 Phase 1 trial currently recruiting patients (Chapman et al, 2011;Hauschild et al, 2013) Pan-RAF inhibitor RAF265…”

SND1 Affects Proliferation of Hepatocellular Carcinoma Cell Line SMMC‐7721 by Regulating IGFBP3 Expression

“…The liver is the main source of IGF. Disorder of the IGF pathway has been shown to be closely related to the initiation and development of HCC, and expression of IGF pathway-related genes were also affected in HCC tissues (Wu and Zhu, 2011). Insulin-like growth factor-binding protein 3 (IGFBP3), a negative regulator of the IGF pathway, has been shown to decrease in HCC (Huynh et al, 2002).…”