Review Article
Hepatocellular Carcinoma: Etiology and Current and Future Drugs

https://doi.org/10.1016/j.jceh.2019.01.004Get rights and content

Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration–approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.

Section snippets

Etiology

Several factors associated with the etiology of HCC have a direct influence on disease progression and on the characteristic of patients.4 The greatest global HCC incidence has been reported from sub-Saharan Eastern and Western Africa, Mongolia, China, and Asia-pacific regions.5 However, the pervasiveness of HCC is lower in developed countries excluding France, Japan, and Italy. HBV, HCV, and hepatitis D virus (HDV) have a strong link with the progression of HCC; therefore, the global incidence

Regulation of kinases in HCC

Two major kinase types are dysregulated in HCC, namely the tyrosine kinases (TKs) and cyclin-dependent kinases (CDKs). These groups of kinases play a crucial role in cell growth and metabolism and are emerging targets for the treatment of HCC.

Current drugs for HCC

The development of HCC involves dysregulation of the cell cycle, apoptosis, and many other cellular pathways. Tumor cell progression involves mutations in various proteins responsible for the regulation of cell cycle.80 Hence, the recent advances in the treatment of HCC include molecules that target proteins such as CDKs or growth factors to suppress the tumor development.91

Prospects for future research

Molecular studies of HCC have determined abnormal activation of different signaling pathways, which illustrate key targets for novel molecular therapies. Other agents such as linifanib, ramucirumab, bevacizumab, axitinib, cediranib, dovitinib, vandetanib, oratinib, nintedanib etc. have demonstrated potential results in clinical phase 1-2 trials, but further studies are required to indicate their efficacy. Overall, combination therapies that would provide a synergistic effect and reduce drug

Conclusion

In conclusion, genetic alteration leads to hepatocarcinogenesis that affects multiple signaling cascades and results in uncontrolled growth of the hepatocytes. There are systemic targeted therapies that focus on the critical steps of the carcinogenic pathways but limits in the widespread systemic toxicity. Hence, drugs such as Milciclib seem to be a promising candidate for combination therapies in patients with cancer. On account of the heterogeneity of HCC, proper combinative targeted therapy

Conflicts of interest

All authors have none to declare.

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