关键词： 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

来  源：   DOI：10.1016/j.jceh.2019.01.004   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
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.
摘要：
肝细胞癌（HCC）在全球范围内的患病率迅速增加，死亡率很高。肝癌患者的进展是由晚期纤维化引起的，主要是肝硬化,和肝炎。缺乏适当的预防或治愈性治疗方法鼓励针对HCC的广泛研究以开发新的治疗策略。食品和药物管理局批准的Nexavar（索拉非尼）用于治疗不可切除的HCC患者。2017年，Stivarga（regorafenib）和Opdivo（nivolumab）在接受索拉非尼治疗后获得批准用于HCC患者，2018年，Lenvima（lenvatinib）被批准用于不可切除的HCC患者。但是,由于快速的耐药性发展和毒性，这些治疗方案并不完全令人满意.因此,迫切需要针对不同信号机制的新的全身联合疗法，从而降低了癌细胞对治疗产生抗性的前景。在这次审查中,HCC病因和新的治疗策略，包括目前批准的药物和其他潜在的HCC候选药物，如Milciclib，palbociclib,galunisertib,ipafricept,和ramucirumab进行评估。
公众号