Current discovery strategies for hepatocellular carcinoma therapeutics

ABSTRACT

Introduction: The global incidence of hepatocellular carcinoma (HCC) is not expected to decline significantly over the next 30 years. And although the latest gene sequencing studies have established its genetic map, the potentially targetable drivers of HCC are, so far, difficult to identify. To date, only seven drugs have been approved by the FDA for unresectable HCC treatment; thus, effective therapeutic breakthroughs are still needed urgently.

Areas covered: In this review, the authors discuss both genetic and epigenetic alterations in HCC and introduce the current progress with some of the representative molecular targeting inhibitors, listing some of the approved drugs for the targets of HCC. The structure–activity relationship of molecules (e.g. thalidomide, bortezomil) used for HCC is also discussed.

Expert opinion: Effective therapeutic targets and effective drugs for HCC treatment are an urgent unmet need. Better understanding and characterization of genetic and epigenetic alterations, which are important to hepatocarcinogenesis, may help to understand the molecular pathogenesis of HCC, as well as provide novel therapeutic lead compounds for HCC treatment.

KEYWORDS:

• Epigenetic
• genetic
• hepatocellular carcinoma
• histone modification
• receptor-tyrosine-kinase inhibitors
• DNA methyltransferases

Article highlights

• The global incidence of hepatocellular carcinoma (HCC) will not decline significantly over the next 30 years.

• Sorafenib was the first approved by FDA for the treatment of HCC. In the past 3 years, lenvatinib in the frontline, regorafenib, cabozantinib, and ramucirumab in the second line were approved by FDA. In addition, immunotherapy drugs, nivolumab, and pembrolizumab, which are monoclonal antibodies have been granted accelerated approval by FDA. By contrast, several kinase inhibitors (e.g. sunitinib, bevacizumab, and erlotinib) failed to improve survival in patients with unresectable HCC.

• Proof-of-concept and biomarker-based trials of molecularly targeted agents should be focus on signaling pathways of genetic and epigenetic alterations in HCC.

• Based on the urgent needs on clinical, the future research direction of liver cancer treatment is not only focused on the new drugs research, but also the multidisciplinary comprehensive treatment mode. Combined therapy including chemotherapy, targeted therapy, and immunotherapy would maximize the benefit of patients with HCC.

• All effective drugs in phase III trials of HCC were multi-kinase inhibitors with no known predictive biomarkers and the therapeutic effect of immune-checkpoint inhibitors also have no diagnostic tools. So, it is difficult to make sure the driving gene of HCC.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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Funding

This manuscript was not funded