Emerging Therapies for Hepatocellular Carcinoma (HCC)

Abstract

Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment.

Oncostatin M: From Intracellular Signaling to Therapeutic Targets in Liver Cancer

“…According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, HCC is the sixth-most-common cancer and the third-most-common cause of cancer-related mortality worldwide [ 3 ]. HCC has a very poor clinical outcome, often due to a delay in diagnosis (early stages being asymptomatic) and resistance to conventional chemotherapy and radiotherapy, with the majority of patients diagnosed at advanced stages and then not eligible for curative therapy [ 3 , 4 , 5 ].…”

“…According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, HCC is the sixth-most-common cancer and the third-most-common cause of cancer-related mortality worldwide [ 3 ]. HCC has a very poor clinical outcome, often due to a delay in diagnosis (early stages being asymptomatic) and resistance to conventional chemotherapy and radiotherapy, with the majority of patients diagnosed at advanced stages and then not eligible for curative therapy [ 3 , 4 , 5 ]. HCC develops on the background of a cirrhotic liver, is intimately related to persistent fibrogenesis and inflammatory response, and may be associated with chronic viral infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), non-alcoholic fatty liver disease (NAFLD), alcohol abuse, and, to a lesser extent, autoimmune disorders or exposure to aflatoxin B1 [ 3 ].…”

“…HCC has a very poor clinical outcome, often due to a delay in diagnosis (early stages being asymptomatic) and resistance to conventional chemotherapy and radiotherapy, with the majority of patients diagnosed at advanced stages and then not eligible for curative therapy [ 3 , 4 , 5 ]. HCC develops on the background of a cirrhotic liver, is intimately related to persistent fibrogenesis and inflammatory response, and may be associated with chronic viral infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), non-alcoholic fatty liver disease (NAFLD), alcohol abuse, and, to a lesser extent, autoimmune disorders or exposure to aflatoxin B1 [ 3 ]. HCC incidence and mortality are expected to increase in the near future as a consequence of the close association between the obesity pandemic and NASH, which is emerging as the most rapidly rising cause of HCC and is predicted to amplify the incidence of HCC up to 41% by 2040 [ 3 , 6 ].…”

“…HCC develops on the background of a cirrhotic liver, is intimately related to persistent fibrogenesis and inflammatory response, and may be associated with chronic viral infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), non-alcoholic fatty liver disease (NAFLD), alcohol abuse, and, to a lesser extent, autoimmune disorders or exposure to aflatoxin B1 [ 3 ]. HCC incidence and mortality are expected to increase in the near future as a consequence of the close association between the obesity pandemic and NASH, which is emerging as the most rapidly rising cause of HCC and is predicted to amplify the incidence of HCC up to 41% by 2040 [ 3 , 6 ]. Genetic (somatic mutations and chromosomal aberrations leading to chromosomal instability) and epigenetic alterations (DNA methylation) can contribute to HCC development [ 7 ].…”

Providing meaningful survival benefit to hepatocellular carcinoma patients: combination therapy of future

“…The review paper by Zhang et al discusses combinatorial treatments for advanced HCC ( 2 ). HCC at early stages, especially if the tumor is <5 cm in size, can be treated by transplantation, surgical resection in combination with radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) ( 3 ). Historically advanced HCC was treated with a chemotherapy cocktail, and following a landmark clinical trial, angiogenesis-targeting strategy using a broad-spectrum tyrosine kinase inhibitor (TKI) sorafenib became the first-line treatment for HCC with subsequent introduction of newer generation of TKIs, such as lenvatinib.…”