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

Abstract

The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as embolization and chemotherapy are not effective against advanced-stage liver cancer; therefore, continuous efforts focus on the development of novel therapeutic options, including molecular targeted agents and gene therapy. In this review, we will summarize the progress toward the development of gene therapies for liver cancer, with an emphasis on recent clinical trials and preclinical studies.

Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma

“…With the expansion of genetic information obtained by the NGS and the development of molecular analyses, basic research focusing on strategies that target tumor-related genes, proteins inducing tumor cell death are significantly increased. Among these novel focuses, cancer gene therapy for HCC is increasing in popularity [26]. This strategy includes the in vivo modification of tumor suppressor and oncogenes, induction of suicide genes into the tumor cells, and ex vivo gene transfer of T-cells, which attack the tumor cells targeting the proteins expressed on the tumor cell surface [17,24,25,27].…”

“…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].…”

Gene Therapy in Cancer Treatment: Why Go Nano?

“…Delivery of TNAs, such as genes, oligonucleotides, miRNAs or siRNAs to cancer cells has allowed to tackle cancer via the silencing oncogenes or restoring the expression of tumor suppressor genes [8][9][10][11][12][13][14][15][16][17][18][19]. Most of these approaches (e.g., antisense therapy, RNA interference (RNAi), gene editing) aim at gene alteration/modulation [16][17][18][19][76][77][78][79][80][81] -see Figure 3.…”

“…Table 5 highlights some strategies using exosomes for gene therapy. Nanoparticles showed good biocompatibility and higher affinity to lungs than similar nanoparticles coated with liposomes [248] 1 miRNA: microRNA; 2 TNBC: triple-negative breast cancer; 3 HCCs: hepatocellular carcinoma cells; 4 AMSC: adipose tissue-derived mesenchymal stem cells; 5 HUCMSC: miR-148b-3p-human umbilical cord mesenchymal stem cells overexpressing miR-148b-3p; 6 NSCLC: non-small cell lung cancer; 7 MSCs: mesenchymal stem cells; 8 LNA: locked nucleic acid; 9 siRNA: small interfering RNA.…”

“…The mounting knowledge on the characteristics of tumor cells and surrounding TME have sparked the use of gene therapy to tackle cancer molecular mechanisms. Gene therapy consists of the introduction of exogenous nucleic acids, such as genes, gene segments, oligonucleotides, miRNAs or siRNAs into cells envisaging a target gene edition, expression modulation of a target gene, mRNA or synthesis of an exogenous protein [8][9][10][11][12][13][14][15][16][17][18][19]. Gene transfer into tumor cells has been demonstrated via administration of therapeutic nucleic acids (TNAs) ex vivo and/or in vivo (Figure 1) [20].…”