Evaluation of phospholipases A2 as novel therapeutic targets in hepatocellular carcinoma

Abstract

Liver cancer has variable incidence worldwide and high mortality. Histologically, the most common subtype of liver cancer is hepatocellular carcinoma (HCC). Approximately 30-40% of HCC patients are diagnosed at an advanced stage, and at present, there are limited treatment options for such patients. The current first-line therapy with tyrosine kinase inhibitors, sorafenib or lenvatinib, prolongs survival by a median of about 2.5-3 months after which the disease normally progresses. Additionally, many patients discontinue the use of tyrosine kinase inhibitors due to toxicity or may not be suitable candidates in the first place, due to comorbidity or frailty. It is, therefore, imperative to identify novel therapeutic targets for advanced HCC patients. Persistent injury to the liver as a result of insults such as hepatitis B or C viral (HBV or HCV) infections, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), results in chronic inflammation, which progresses to hepatic fibrosis and later, cirrhosis. These insults provide the conditions for initiation of HCC. One of the key pathways studied for its role in inflammation and carcinogenesis is the eicosanoid pathway. Various members of the eicosanoid pathway have been implicated in the development and progression of liver diseases, including HCC, however there is little information about the importance of intervention in this pathway as a means of treating HCC. Phospholipase A2 (PLA2) enzymes are the first enzyme of the eicosanoid pathway and have been classified into six subgroups, comprising more than 30 members. This PhD project focused on two members of the PLA2 enzymes viz. cytosolic phospholipase A2! (cPLA2!) and secreted phospholipase A2-group IIA (sPLA2-IIA) to investigate their roles in HCC and its premalignant conditions, such as NAFLD, hepatic fibrosis, and cirrhosis. The oncogenic role of these enzymes has been established by various studies, however, their role in HCC is not well defined. This project aimed to investigate (i) the role of these PLA2 enzymes in liver diseases, and (ii) whether targeting these enzymes could be a potential therapy for HCC. In summary, this study provides strong evidence of a role of cPLA2! and sPLA2-IIA in liver diseases. Genetic knockdown of cPLA2! and use of selective sPLA2-IIA inhibitor, c2 demonstrate that cPLA2! and sPLA2-IIA could be used as potential therapeutic targets in HCC.

Date of Award	2021
Original language	English