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.
Keywords: AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; ATP, adenosine 5′-triphosphate; BMF, Bcl2 modifying factor; BMI, body mass index; CDK, cyclin-dependent kinase; CTGF, connective tissue growth factor; CTL, cytotoxic T lymphocyte; CTLA, cytotoxic T-lymphocyte-associated protein; ECM, extracellular matrix; EFGR, endothelial growth factor receptor; EGFR, epidermal growth factor receptor; EMT, Epithelial–mesenchymal transition; ERK, extracellular signal-regulated kinase; FDA, Food and Drug Administration; GFG, fibroblast growth factor; HBV, hepatitis B virus; HBcAg, hepatitis B core antibody; HBsAg, HBV surface antigen; HCC, Hepatocellular carcinoma; HCV, hepatitis B virus; HDV, hepatitis D virus; HIF, hypoxia-inducible factor; HIV, human immunodeficiency virus; IGFR, insulin-like growth factor; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MDSC, myeloid-derived suppressor cell; NASH, nonalcoholic steatohepatitis; NK, natural killer; NKT, natural killer T cell; ORR, objective response rate; OS, overall survival; PAPSS1, 3′-phosphoadenosine 5′-phosphosulfate synthase 1; PD-L1, programmed death ligand1; PD1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor; PEDF, pigment epithelium-derived factor; PFS, progression-free survival; PI3K, phosphoinositide 3-kinases; PTEN, phosphatase and tensin homolog; PUMA, p53 upregulated modulator of apoptosis; RFA, radiofrequency ablation; Rb, retinoblastoma protein; SCF, stem cell factor; SHP1, src homology 2 domain–containing phosphatase 1; STAT3, signal transducer and activator of transcription 3; TACE, transarterial chemoembolization; TGF 1, transforming growth factor-1; TK, tyrosine kinase; TKI, Tyrosine kinase inhibitor; TRKA, tropomyosin receptor kinase A; Treg, regulatory T cells; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; bFGF, basic fibroblast growth factor; combination therapy; cyclin-dependent kinase inhibitors; hepatocellular carcinoma; hepatology; tyrosine kinase inhibitors.