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Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels.
Haaker, MW, Vaandrager, AB, Helms, JB
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2020;(6):158674
Abstract
Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs.
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2.
Alcohol and hepatocarcinogenesis.
Taniai, M
Clinical and molecular hepatology. 2020;(4):736-741
Abstract
An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, cirrhosis, and lead to hepatocellular carcinoma (HCC). The aim of this review is to clarify the present condition and the mechanisms of alcohol-related hepatocarcinogenesis and clinical risk factors for alcohol-related HCC. There are several possible mechanisms through which alcohol may induce hepatocarcinogenesis, including the mutagenic effects of acetaldehyde toxicity through the formation of protein and DNA adducts and the production of reactive oxygen species due to the excessive hepatic deposition of iron, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. Furthermore, it has been reported that alcohol accelerates liver carcinogenesis through several signaling pathways including gut-liver axis. From a clinical perspective, it is well known that alcohol interacts with other factors, such as age, gender, viral hepatitis, obesity, and diabetes leading to an increased risk of HCC.
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3.
Tyrosine Kinase Inhibitors and Hepatocellular Carcinoma.
da Fonseca, LG, Reig, M, Bruix, J
Clinics in liver disease. 2020;(4):719-737
Abstract
Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.
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4.
Molecular therapies for HCC: Looking outside the box.
Faivre, S, Rimassa, L, Finn, RS
Journal of hepatology. 2020;(2):342-352
Abstract
Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.
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5.
Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy. Trends and perspectives.
Mazzolini, GD, Malvicini, M
Medicina. 2018;(1):29-32
Abstract
Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.
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6.
New chemical treatment options in second-line hepatocellular carcinoma: what to do when sorafenib fails?
Woo, HY, Yoo, SY, Heo, J
Expert opinion on pharmacotherapy. 2017;(1):35-44
Abstract
There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors. Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC. The reported data were obtained from abstracts of international conferences and journal articles published up to August 2016 and found in a PubMed search. Expert opinion: Based on favorable data from preclinical and clinical trials, regorafenib, c-Met inhibitor, and checkpoint inhibitors are promising agents for HCC after sorafenib failure. However, further efforts to maximize the survival benefit and minimize adverse events of these drugs in the treatment of HCC are still necessary. Additionally, searching for predictors of good responders could allow these new drugs to be applied in personalized treatments of HCC.