Current Status of Gene Therapy in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at an advanced stage and there are not many treatment options for late stage HCC. First-line therapy for late stage HCC includes sorafenib and lenvatinib. However, these treatments provide only an approximate three month increase in survival. Besides, they cannot specifically target cancer cells that lead to a wide array of side effects. Patients on these drugs develop resistance within a few months and have to rely on second-line therapy that includes regorafenib, pembrolizumab, nivolumab, and cabometyx. These disadvantages make gene therapy approach to treat HCC an attractive option. The two important questions that researchers have been trying to answer in the last 2–3 decades are what genes should be targeted and what delivery systems should be used. The objective of this review is to analyze the changing landscape of HCC gene therapy, with a focus on these two questions.

Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma

“…Recently, cancer gene therapy has developed in parallel with the significant improvement of genomic information using next-generation sequencing (NGS) and advances in the techniques of molecular biology [16,17] that use two-dimensional culture systems and patient-derived primary cancer cells [18,19] to target and modify tumor-related genes [20][21][22][23]. Therefore, innovative basic research and clinical trials focusing on the development of gene therapy for HCC are becoming more common [23][24][25][26]. The following cancer gene therapies for HCC have been tested in both basic and clinical research: the modification of genes related to tumor suppressors, oncogenes, suicide genes, those encoding the proteins expressed on the tumor cell surface, and the T-cell receptor to target the tumor, as well as genetic immunotherapy [17,24,25,27].…”

“…Therefore, innovative basic research and clinical trials focusing on the development of gene therapy for HCC are becoming more common [23][24][25][26]. The following cancer gene therapies for HCC have been tested in both basic and clinical research: the modification of genes related to tumor suppressors, oncogenes, suicide genes, those encoding the proteins expressed on the tumor cell surface, and the T-cell receptor to target the tumor, as well as genetic immunotherapy [17,24,25,27]. Among these strategies, we focus on the suicide gene delivery strategy, which was recently reported to be elicited in a tumor-specific manner using transcriptionally targeted retroviral replicating vectors [28], targeting the genomic rearrangement in the tumor by using the genome-editing approach to insert the suicide gene [29].…”

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

“…On the basis of these significant developments and advances in the techniques of molecular biology [5,22], innovative basic research and clinical trials, focusing on the development of gene therapy for liver cancers, are increasing [23,24]; together, these have the potential to offer long therapeutic benefit and overcome the issue of heterogeneity.…”

“…Potential therapeutic targets for which inhibitors currently exist include the WNT signaling pathway, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and various immune checkpoint proteins [46]. On the basis of these findings, the modification of genes related to tumor suppressors, oncogenes, those encoding the proteins expressed on the tumor cell surface, and the T-cell receptor to target the tumor, as well as genetic immunotherapy, have been tested in both basic and clinical research [22][23][24]46].…”

“…Materials including lipids [126], polymers [127], proteins [128], and peptides [128] have been shown to be effective for gene delivery to tissues [129,130] and in HCC [131]. Non-viral vectors have been evaluated for gene therapy of a variety of liver diseases including hepatic fibrosis, viral hepatitis, and liver cancer [24]. Taking advantage of membrane receptors on hepatic stellate cells, liver-targeted gene delivery for hepatic fibrosis has been attempted using the mannose 6-phosphate/insulin-like growth factor-II receptor [132][133][134], integrins [135], high-affinity membrane receptor for retinol-binding protein, and the galactosyl receptor as targets [101].…”