Chemotherapy for Hepatocellular Carcinoma: Current Evidence and Future Perspectives

Abstract

Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor. The importance of this drug lies not only in the modest gain of patients' survival, but in having opened a roadmap towards the development of new molecules and targets. Unfortunately, after the introduction of sorafenib, during the last years, a wide number of clinical trials on antiangiogenic therapies failed in achieving significant results. However, many of these trials are still ongoing and promise to improve overall survival and progression-free survival. A recent clinical trial has proven regorafenib effective in patients showing tumor progression under sorafenib, thus opening new interesting therapeutic perspectives. Many other expectations have been borne from the discovery of the immune checkpoint blockade, already known in other solid malignancies. Furthermore, a potential role in hepatocellular carcinoma therapy may derive from the use of branched-chain amino acids and of nutritional support. This review analyses the biomolecular pathways of hepatocellular carcinoma and the ongoing studies, the actual evidence and the future perspectives concerning drug therapy in this open field.

Keywords: Branched-chain amino acids; Hepatocellular carcinoma; Immunotherapy; Molecular target therapies.

Fig. 1.. Main molecular pathways in HCC pathogenesis.

(A) The activation of Frizzled (WNT receptor) determines the recruitment of disheveled (DSH), preventing the destruction of β-catenin through the dissolution of a molecular complex composed by Axin, adenomatosis polyposis coli (APC), and glycogen synthase kinase 3β (GDK3B). (B) Growth factors bind their specific receptors, leading to their dimerization and activation of the tyrosine-kinase. From this point, it is possible to recruit two different groups of molecules: MAPK and PI3K pathways, culminating with modifications in cell-cycle regulation, protein synthesis, and gene transcription. (C) Stimulation of TGF-βR recruits the SMAD complex, leading to a negative regulation of the cellular cycle. (D) CTLA-4 and its ligands: CD-80/CD-86 transmit an inhibitory signal in the antigen presenting cells (APCs), while CD-28 represents an activating signal. Programmed cell death protein-1 (PD-1), through its binding to PD-L1 (B7-1) and PD-L2 (B7-2), down-regulates the immune system and promotes self-tolerance. Adapted from Harding et al.