Hepatocellular carcinoma

Abstract

Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies - resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches.

Aberrant ketolysis fuels hepatocellular cancer progression

“…In response to all these microenvironmental challenges, HepG2 cells upregulated multiple enzymes involved in ketogenesis [6], including BDH1, HMGCL, HMGCS1 and HMGCS2, consistent with the prominent role played by the liver in the provision of ketone bodies to other tissues in response to starvation. Surprisingly, HepG2 cells subjected to serum (but not glucose or glutamine) deprivation also exhibited increased levels of 3-oxoacid CoA-transferase 1 (OXCT1), which catalyzes the rate-limiting reaction of ketolysis and is normally not expressed in the adult liver [7]. Similar results were obtained with other human HCC cell lines, including Hep3B and PLC cells, and OXCT1 upregulation driven by serum withdrawal was confirmed by immunoblotting [4].…”

Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions

“…In fact, liver cancer has become the second most deadly malignant disease worldwide (Llovet et al, 2016), in part due to the rise of metabolic disorders, including alcoholic and non-alcoholic fatty liver diseases, and viral hepatitis (Farazi and DePinho, 2006; Michelotti et al, 2013). Unfortunately, the rapid increase of this malignant disease has not been met by effective therapeutics in the clinic.…”

Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial

“…OS is generally used as the primary endpoint in Phase III studies of cancer treatments and is also recommended as an endpoint for TACE [17, 18]. However, the median OS in clinical trials of TACE is never shorter than 18 months, and can even be as long as 32 months, which is a very long time to conduct a clinical trial.…”