Aberrant lipid metabolism as a therapeutic target in liver cancer

ABSTRACT

Introduction: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers. Progress has been made in treatment of HCC; however, improved outcomes are much needed. The increased metabolic needs of cancer cells underscore the importance of metabolic pathways in cancer cell survival. Lipid metabolism has a role in HCC development; aberrant overexpression of several key enzymes is seen in many solid human tumors.

Areas covered: We discuss aberrant lipid metabolism and the promise of multiple targets, in particular related to HCC treatment. We searched PubMed and clinicaltrials.gov for published and unpublished studies from 2000 to 2019. These terms were used: lipids, fatty acid metabolism, lipid metabolism, liver cancer, HCC, de novo fatty acid synthesis, ATP citrate lyase, stearoyl CoA denaturase, fatty acid synthase, acetyl coenzyme A carboxylase, CD147, KLF4, monoglyceride lipase, AMP activated protein kinase.

Expert opinion: The importance of dysregulation of fatty acid synthesis in cancer is a growing area of research. HCC demonstrates significant alteration in lipid metabolism, representing great potential as a target for novel therapeutics. Various agents have demonstrated promising anti-neoplastic activity. This strategy deserves further development for improved outcomes.

KEYWORDS:

• Fatty acid
• hepatocellular carcinoma
• liver cancer
• lipids
• lipid metabolism
• stearoyl co-A desaturase
• SCD1

Article Highlights

• HCC is one of the leading causes of cancer deaths worldwide and has limited therapeutic options.

• Strategies targeting altered metabolic pathways that are so critical to cancer cell survival deserve increased attention and development.

• Recent studies implicate lipid biosynthesis and desaturation as a requirement for HCC survival.

• Multiple viable targets exist and a number of agents are poised for potential advancement into the clinic with continued support.

• There are fundamental challenges to the advancement of research in this area, including the use of rodents as preclinical models. There are significant discrepancies in genetic variation, tissue distribution, expression, and regulatory mechanisms governing lipid metabolism that may limit their translational relevance in humans

• There is a critical need for more effective therapeutic strategies.

This box summarizes key points contained in the article.

Declaration of interest

K Mody has received research support from Agios, Senwha Biosciences, Taiho, ArQule, Astra Zeneca, Genentech, Incyte, Tracon Pharmaceuticals, Medimmune, Puma Biotechnology and consulting fees from Astra Zeneca, Bayer, Celgene, Eisai, Exelixis, Merrimack and Vicus

JA Copland has filed a patent application for novel composition of matter for SCD1 inhibitors.

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. 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.

Additional information

Funding

This research was funded in part by the following grants: Mayo Clinic Liver SPORE (NCI/NIH P50 CA210964; KM, JAC), NCI STTR R42 grant (CA195946; JAC) and Florida Department of Health (8BC01; JAC).