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Table 2. Overview of clinical trial agents for hepatocellular carcinoma therapy
Developmental
Agents Targets Outcomes
status
Nivolumab Phase III PD-1 [69] Ongoing [70]
Pembrolizumab Phase III PD-1 [76] Ongoing [70]
Ramucirumab Phase III VEGFR2 [77] Survival benefit for the subgroup with AFP ≥ 400 ng/mL [79]
Lenvatinib Phase III VEGFR1-3, FGFR1-4, PDGFRα, RET and KIT [70] Non-inferior OS, improved PFS, TTP, and ORR [70]
Cabozantinib Phase III TIE-1, TIE-2, FLT3, c-MET, KIT, RET and VEGFR [78] Significant improvement in OS, PFS, and ORR [75]
Tivantinib Phase III c-MET [71] Improved OS and PFS [71]

HCC: hepatocellular carcinoma; OS: overall survival; ORR: objective response rate; PFS: progression-free survival; TKI: tyrosine kinase
inhibitor; TTP: time to progression

[80]
advanced-stage HCCs . However, it increases the potential risk of invasion and metastasis of HCCalthough
it significantly delays tumor progression time .
[81]
FUTURE CHALLENGES
Although the effective diagnosis and therapies have been developed in HCC at present, it is unsatisfied to
improve the patients’ survival. The challenges in the field of diagnosis and therapy for HCC are still ongoing.
Therefore, developing new diagnostic approach and drugs are urgent. About gene diagnosis of HCC, high-
throughput means combined with bioinformatics methods will be used to find out the root cause of HCC in
large-scale sample research. Clinically, it is necessary to monitor the biomarkers in the development of HCC
involving treatment and prognosis, but not only in the early stage. It is vital to develop kits for determining
the replication activity of HBV (or HCV) and HBV cccDNA to evaluate the risk of HCC incidence. For HCC
therapy, identifying innovative targets and combination with multiple drugs are still needed in the treatment
strategy. Effective combination of antiviral therapies with anti-inflammation drugs involving inflammation
factors is available to treat chronic HBV-related HCC. It is necessary to examine the sensitivity, specificity,
predictive value positive, predictive value negative, and validity of any candidate biomarker in a large pool
of HCC patients with or without HBV infection, furthermore, it is also important to follow up large patients
with HBV or other risk factor exposure for the prediction of occurrence and postoperative recurrence of
HCC using representative markers. If biomarkers are valid, it is necessary to develop kits for molecular
diagnosis, monitoring the efficacy, prognosis and treatments of HCC patients.

CONCLUSION
In summary, this review lists the recent progresses in gene diagnosis and therapy for HCC. The achievements
include the recent novel biomarkers and novel therapeutic strategies for HCC, such as AFP, AFP-L3, GPC3,
HSP90, DKK1, PON1, etc. Moreover, epigenetic regulation, signal pathway, cellular and molecular targets
for the immunotherapy, tumor microenviroment and genome sequencing analysis may also serve as the
molecular expression signatures in clinical practice. More studies are necessary to find new biomarkers
for prognosis and treatment response in patients under standard treatment of sorafenib. The new clinical
trials for other molecular-targeted agents, including pembrolizumab, nivolumab, tivantinib, lenvatinib,
cabozantinib, and ramucirumab, are ongoing in clinic. Anti-HBV drugs are available in the therapy of HBV-
related HCC.

DECLARATIONS
Authors’ contributions
Drafted the outline of this review: Zhang XD
Drafted the manuscript: Zhang XD, Zhao M
Finalized the manuscript: Zhang XD, Zhao M