Spotlight on Bortezomib: potential in the treatment of hepatocellular carcinoma

ABSTRACT

Introduction: This study reviews the evidence for the use of Bortezomib (BZB), a first-in-class proteasome inhibitor in advanced Hepatocellular carcinoma (HCC). This review aims to delineate the role of BZB within the management of non-surgical and metastatic HCC, either as an alternative or as an adjunct to the current treatment paradigm.

Areas covered: In addition to BZB pharmacology and mechanism of action, safety and tolerance profiles of the drug obtained from clinical trials are explored. The utility of BZB as a therapeutic agent either alone or in combination with other therapies against HCC, including its application in both preclinical and clinical settings has been reviewed. In particular, we highlight the importance of preclinical evaluation of BZB as a combinatorial agent in synergism with other therapies for the use in the management of HCC.

Expert opinion: There has been much interest surrounding the use of BZB, a first-in-class proteasome inhibitor for HCC therapy. The discernment of outcomes of BZB clinical trials for HCC need to take into consideration the disease-specific factors that can affect survival outcomes including patient selection and aetiological differences. Further preclinical testing of BZB in combination with other therapeutic modalities can be important for eliciting enhanced anti-HCC effects.

KEYWORDS:

• Bortezomib
• hepatocellular carcinoma
• primary liver cancer
• combination therapy
• Sorafenib
• stemness
• EMT

Article highlights

• Despite the rising incidence of HCC and the emergence of novel approaches to its management, the 5-year survival from diagnosis remains below 12%. This highlights the urgent need for more efficacious approaches for the management of HCC

• BZB, a boronic acid dipeptide, has been repeatedly demonstrated to exert anti-proliferative and pro-apoptotic effects on HCC

• The mechanisms of action underlying BZB’s effectiveness in treating HCC are distinct to the mechanisms seen in haematological malignancies, and may be largely independent of proteasome inhibition

• A phase I study of BZB’s safety profile in a cohort of patients with dissimilar but advanced malignancies demonstrated no apparent dose relationship with toxicity and no difference in serious adverse effect frequency between different degrees of hepatic impairment

• HCC mounts an adaptive response to BZB. To overcome the inherent and acquired resistance to BZB monotherapy, attempts have been made to pair BZB with potentially synergistic agents for use in the management of HCC

Future research will focus on novel combinations of BZB with other synergistic agents that may enhance the activity of BZB

This box summarizes key points contained in the article.

Acknowledgments

We thank Gallipoli Medical Research Foundation for funding this study.

Declaration of interest

The authors have no other 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.

Reviewer Disclosures

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

Additional information

Funding

This paper was funded by the Gallipoli Medical Research Foundation.