Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.

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

“…Healthy mature hepatocytes do not express IGFIR 16. In HCC samples, up‐regulation of IGFIR is one of the most common alterations, occurring in 30% of patients 33.…”

“…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…”

Reports from the International Liver Cancer Association (ILCA) congress 2014

“…The authors used BI836845, a monoclonal antibody directed against the ligand IGF2, to decrease IGF2/IG1R pathway activation and, consequently, decrease tumor formation in this mouse model. However, toxicity as severe hypoglycemia has limited the use of other IGF inhibitors in clinical trials [13]. The authors concluded that if this monoclonal antibody targeting IGF2 showed no limiting toxicity, it could be tested for treating patients with HCC harboring IGF pathway activation.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…Another RTK ligand playing an important role in hypoxia-induced tumorigenesis is insulinlike growth factor 2 (IGF2), which exerts its biologic activity via binding to the insulin-like growth factor 1 receptor (IGF1R) tyrosine kinase [39]. Activation of IGF1R in tumors is very rarely caused by gene amplification or point mutations.…”