Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

Abstract

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer (HCC). Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors ("small molecule inhibitors") and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin (mTOR) upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation. mTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

Figure 1

Major growth factor receptor signalling pathways in HCC.

Figure 2

Antiproliferative effects of sorafenib-based combination treatment. A: Huh-7 and B: HEP-G2 cells were treated for 72 h with sub-IC₅₀ concentrations of sorafenib and the histone deactylase inhibitor MS-275. Combination of both agents resulted in synergistic growth inhibition of Huh-7 cells, while rather additive growth inhibitory effects were observed in HepP-G2 cells (mean ± SEM).

Figure 3

Antiproliferative effects of combination treatment with bortezomib and sorafenib in hepatocelluar carcinoma cells. A: Huh-7 and B: Hep-G2 cells were treated for 72 h with sub-IC₅₀ concentrations of sorafenib and the proteasome inhibitor bortezomib. Combination of both agents led to additive growth inhibition both in Huh-7 as well as in Hep-G2 cells (mean ± SEM).