Advances in targeted therapies for hepatocellular carcinoma in the genomic era

Abstract

Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

“…Based on these results, a randomized phase III trial is currently comparing cabozantinib We agree that several reasons have potentially contributed to the failure of recent clinical trials [46]. In principle, even if the drug is active and effective, inadequate methodology and study design could be the reason for a negative result in a clinical trial.…”

Systemic therapy for advanced hepatocellular carcinoma: an update

“…In the process of liver cirrhosis, it is believed that chronic inflammation, continuous cycles of damage and regeneration, and the presence of etiology-specific carcinogens produce cumulative genetic derangements that are involved in the hepatocarcinogenic process. There are, on average, 30 to 40 mutations per liver tumor, and 5 to 8 of these are thought to be driver mutations (7). Several studies used deep genome sequencing to identify mutations in key genes thought to be involved in various pathways critical to normal cellular homeostasis, including telomerase reverse transcriptase (TERT) expression, chromatin remodeling, oxidative stress, cell cycle/TP53, Wnt/β-catenin, hepatic differentiation, growth factor/angiogenic receptor (EGF, IGF, c-MET, PDGF, FGF, VEGF), RAS/RAF/MAPK, PI3K/AKT/mTOR, and IL6/JAK/STAT (8)(9)(10)(11).…”

“…The non- proliferative subclass is correlated with better outcomes, lower AFP levels, and good-to-moderate differentiation. The proliferative subclass usually consists of HCC secondary to HBV, while the non-proliferative subclass consists of HCC secondary to HCV infection and alcoholic cirrhosis (7).…”

“…This, in turn, results in decreased cellular adhesion which then leads to tumor proliferation, metastasis, and consequently progression of HCC (7,16). The Wnt/β-catenin pathway can be activated not only by mutations in the pathway components, but also by soluble Wnt signaling antagonists that cause excessive signaling and activation of the pathway.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC. These pathways include CTNNB1/WNT‐β‐catenin, TPp53, ARID1/2s, HGF/c‐Met, and vascular endothelial growth factor/angiogenic signaling 5, 6, 7, 8, 9, 10, 11, 12. However, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models 13, 14, 15…”