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Zhang et al. Hepatoma Res 2019;5:14 I http://dx.doi.org/10.20517/2394-5079.2018.117 Page 5 of 9

[59]
in cytotoxic T-cell inhibition and 6.3-fold increase in risk for HCC development . Using HBV infection
[60]
models in vitro and in vivo, new targets and compounds will be available .

[61]
HBx plays a crucial role in the various signal transduction pathways and HBV-induced hepatocarcinogenesis .
[62]
HBx accelerates the development of hepatoma . HBx-elevated male-specific lethal 2 can strengthen HBV
[63]
replication by regulating cccDNA in liver cancer cells, resulting in the development of HCC . Moreover,
we report that anti-HBx in sera may serve as one of the markers involving HBV-related liver cirrhosis and
[64]
liver cancer . Developing drugs targeting HBx is crucial for HBV-related HCC therapy. Two types of drugs,
conventional interferon, and nucleoside analogs, have become available for the treatment of chronic hepatitis
B infection. We also report that anti-HBV drugs such as entecavir, telbivudine and IFN-α2b inhibit the
[65]
tumor growth of HBV-related HCC through depressing HBx . The finding gives innovative insights into
the mechanisms of anti-HBV drugs in HCC therapy.

Molecular targets for the immunotherapy
The research about a cohort of 956 HCC patients, 25% had high expression of programmed death-
ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) in HCC tissues. Moreover, the study found
[66]
+
that infiltrating CD8 TILs (tumor-infiltrating lymphocyte) could induce PD-L1 expression via IFN-γ .
Icotinib decreases the growth of hepatoma cells in vitro and in vivo, relying on EGFR activation and PD-
[67]
L1 expression . Thus, the PD-1/PD-L1 pathway is available for prognosis and therapy in HCC. Patients
with positive PD-L1 expression had significantly poorer DFS and overall survival (OS) than PD-L1 negative
patients. The median DFS and OS were 14.9 and 29.6 months for PD-L1 positive patients compared with
not reached and 59.4 months for PD-L1 negative patients, thus confirming the findings of the prognostic
[68]
value of PD-1/PDL-1 in HCC . Currently, nivolumab, a monoclonal antibody targeting PD-1, obtained an
accelerated FDA approval in view of tumor response and durability for the therapy of HCC patients already
[69]
treated with sorafenib in the phase 1/2 single-arm CheckMate 040 study . Nivolumab and pembrolizumab
[70]
targeted PD-1 are ongoing in clinic .
Clinical trial status of molecular-targeted agents
Tivantinib as the first drug was used to a phase III trial grounded in receptor overexpression analyses after
[71]
disease progression on sorafenib in HCC . Lenvatinib as an oral multikinase inhibitor for differentiated
thyroid cancer and renal cell cancer treatment initially was approved. In a phase 2 trial of HCC patients
in Japan and South Korea, lenvatinib treatment was obtained with a 37% response rate (by mRECIST), a
[72]
median TTP of 7.4 months, and an available toxicity profile . In addition, Regorafenib as the first agent
[73]
showed a good survival benefit over placebo in patients progressing on sorafenib . Regorafenib acting as
an oral multikinase inhibitor, largely interdicted the activity of multiple protein kinases including tumor
proliferation, metastasis, angiogenesis, microenvironment, and tumor immunity. Regorafenib exhibited a
[74]
favorable survival regardless of the last dose of prior sorafenib (HR 0.67 for 800 mg/day; 0.68 for < 800 mg/day) .
Further approvals are coming, with good results from phase 3 trials evaluating cabozantinib and
ramucirumab in the second-line setting. Cabozantinib, a small-molecule multikinase inhibitor was better
[75]
than the placebo in the randomized phase 3 CELESTIAL trial . Based on the trial analyses 707 advanced
HCC patients previously received sorafenib treatment, cabozantinib distinctly increased OS over placebo
[76]
(10.2 months vs. 8.0 months, respectively, P = 0.0049) , as shown in Table 2.
Sorafenib
Sorafenib as a molecular-targeted agent can attenuate HCC proliferation and angiogenesis by inhibiting RAF
serine threonine kinase and VEGF, PDGF, Flt-3, c-Kit receptor tyrosine kinase, getting approved in Europe
and North America in 2007 and in Japan on May 20, 2009. To our delight, a subanalysis of the SHARP
study, such as sorafenib in combination with resection, ablation, transcatheter arterial chemoembolization
or hepatic arterial infusion chemotherapy, will overtly extend the overall survival in early-, intermediate- or