Advances of Targeted Therapy for Hepatocellular Carcinoma
TL;DR: In this article, the authors presented all approved targeted agents for advanced HCC with an emphasis on their clinical efficacy, summarized the advances of multi-target drugs in research for HCC and potential therapeutic targets for drug development, and discussed the exciting results of the combination between targeted therapy and ICI.
Abstract: Hepatocellular carcinoma (HCC) is one of the common and fatal malignancies, which is a significant global health problem. The clinical applicability of traditional surgery and other locoregional therapies is limited, and these therapeutic strategies are far from satisfactory in improving the outcomes of advanced HCC. In the past decade, targeted therapy had made a ground-breaking progress in advanced HCC. Those targeted therapies exert antitumor effects through specific signals, including anti-angiogenesis or cell cycle progression. As a standard systemic therapy option, it tremendously improves the survival of this devastating disease. Moreover, the combination of targeted therapy with immune checkpoint inhibitor (ICI) has demonstrated more potent anticancer effects and becomes the hot topic in clinical studies. The combining medications bring about a paradigm shift in the treatment of advanced HCC. In this review, we presented all approved targeted agents for advanced HCC with an emphasis on their clinical efficacy, summarized the advances of multi-target drugs in research for HCC and potential therapeutic targets for drug development. We also discussed the exciting results of the combination between targeted therapy and ICI.
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TL;DR: SOR/SeNps are a promising combination for tumor suppression and overcoming sorafenib resistance in HCC by modulating apoptosis, AKT/mTOR and NF-κB pathways, as well as CD34 and lncRNA-AF085935/GPC3 axis as discussed by the authors .
Abstract: The first-line treatment for advanced hepatocellular carcinoma (HCC) is the multikinase inhibitor sorafenib (SOR). Sofafenib resistance is linked to protein kinase B/ mammalian target of rapamycin (AKT/mTOR) and nuclear factor kappa B (NF-κB) activation, apoptosis inhibition and oxidative stress. This study investigated selenium nanoparticles (SeNps) to overcome SOR resistance in thioacetamide (TAA) induced HCC in rats.TAA (200 mg/kg/twice weekly, i.p.) was administered for 16 weeks to induce HCC.s. Rats were treated with oral SOR (10 mg/Kg daily), selenium, and SeNps (5 mg/kg three times/week) alone or in combination, for two weeks. Apoptosis, proliferation, angiogenesis, metastasis and drug resistance were assessed. Cleaved caspase 3 (C. CASP3), mTOR, and NF-κB were determined by western blotting. Expression of p53 gene and long-noncoding RNA-AF085935 was determined by qRT-PCR. Expression of B- Cell Leukemia/Lymphoma 2 (Bcl2), Bcl associated X protein (Bax)and glypican 3 (GPC3) was determined by enzyme-linked immunosorbent assay. Liver functions, antioxidant capacity, histopathology and CD34 immunohistochemistry were performed.SOR/SeNps reversed TAA-induced HCC in rats, through reduction of oxidative stress, activation of p53, Bax and CASP3, and inhibition of Bcl2. SOR/SeNps ameliorated the HCC-induced effect on cell proliferation and drug resistance by targeting mTOR and NF-κB pathways. SOR/SeNps decreased CD34 immunostaining indicating a decrease in angiogenesis and metastasis. SOR/SeNps regulated HCC epigenetically through the lncRNA-AF085935/GPC3 axis.SOR/SeNps are a promising combination for tumor suppression and overcoming sorafenib resistance in HCC by modulating apoptosis, AKT/mTOR and NF-κB pathways, as well as CD34 and lncRNA-AF085935/GPC3 axis.
23 citations
TL;DR: In this article , the role of PI3K/Akt signaling in hepatocellular carcinoma (HCC) progression was investigated, and it was shown that PI3k/akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation.
Abstract: Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.
13 citations
TL;DR: These findings provide the first evidence that TAE226 combined with SOR efficiently reduce HCC growth in vitro and in vivo and highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising therapeutic approaches for HCC.
Abstract: Background & Aims
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR), the first-line systemic treatment against advanced HCC, causes resistance as unresolved question. Recent studies highlighted the ability of focal adhesion kinase (FAK) inhibitors (FAKi) in reducing HCC growth. Therefore, we investigated the antitumor effects of three different FAKi, alone or in combination with SOR, using in vitro and in vivo models of HCC.
Methods
The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. TAE226, emerging as the most effective FAKi, was then tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods.
Results
TAE226 emerged as the more effective FAKi to be combined with SOR against HCC. Combined TAE226 plus SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of the nuclear interactome of FAK. In particular, we characterize a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease of the nuclear amount of HDAC1/2 with consequent increase of histone H3 lysine 27 acetylation, counteracting its trimethylation.
Conclusions
Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduce HCC growth in vitro and in vivo. Our data also highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising therapeutic approaches for HCC.
12 citations
TL;DR: In this article , the authors comprehensively discussed the recent preclinical and clinical advances as well as significant challenges in immunotoxins targeting CSCs, which might reduce the burden of drug resistance conditions in cancer patients from bench to bedside.
7 citations
TL;DR: The aim of this review is to discuss the different types of transarterial therapies with regards to the pre-procedure, procedural, and post-procesural patient management, along with giving a review of evidence from the literature.
Abstract: Simple Summary Hepatocellular carcinoma is the most common liver cancer, leading to approximately 700,000 deaths worldwide and 30,000 deaths in the United States every year. Transarterial therapies play a crucial role in the management of these patients, with significant development in techniques over the last couple of decades. The aim of this review is to discuss the different types of transarterial therapies with regards to the pre-procedure, procedural, and post-procedural patient management, along with giving a review of evidence from the literature. Abstract Image-guided locoregional therapies play a crucial role in the management of patients with hepatocellular carcinoma (HCC). Transarterial therapies consist of a group of catheter-based treatments where embolic agents are delivered directly into the tumor via their supplying arteries. Some of the transarterial therapies available include bland embolization (TAE), transarterial chemoembolization (TACE), drug-eluting beads–transarterial chemoembolization (DEB–TACE), selective internal radioembolization therapy (SIRT), and hepatic artery infusion (HAI). This article provides a review of pre-procedural, intra-procedural, and post-procedural aspects of each therapy, along with a review of the literature. Newer embolotherapy options and future directions are also briefly discussed.
5 citations
References
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TL;DR: A status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions.
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society
58,675 citations
University of Barcelona1, University of Pisa2, University of Duisburg-Essen3, Auckland City Hospital4, University of São Paulo5, European University6, Icahn School of Medicine at Mount Sinai7, Goethe University Frankfurt8, University of Bologna9, Hannover Medical School10, University of Mainz11, Aix-Marseille University12, Université catholique de Louvain13, University of Düsseldorf14, Bayer15, Bayer Corporation16
TL;DR: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Abstract: Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
10,074 citations
TL;DR: The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.
7,851 citations
TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7,056 citations
National Taiwan University1, Anhui Medical University2, Korea University3, Fudan University4, Memorial Hospital of South Bend5, Academy of Military Medical Sciences6, Third Military Medical University7, Dalian Medical University8, Kyungpook National University Hospital9, Sir Run Run Shaw Hospital10, Bayer HealthCare Pharmaceuticals11, Bayer Corporation12, Sun Yat-sen University13
TL;DR: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated.
Abstract: Summary Background Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Methods Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. Findings 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6·5 months (95% CI 5·56–7·56) in patients treated with sorafenib, compared with 4·2 months (3·75–5·46) in those who received placebo (hazard ratio [HR] 0·68 [95% CI 0·50–0·93]; p=0·014). Median TTP was 2·8 months (2·63–3·58) in the sorafenib group compared with 1·4 months (1·35–1·55) in the placebo group (HR 0·57 [0·42–0·79]; p=0·0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10·7%]), diarrhoea (nine patients [6·0%]), and fatigue (five patients [3·4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11·4%]) and diarrhoea (11 patients [7·4%]); these adverse events rarely led to discontinuation. Interpretation Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.
4,890 citations