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Sorafenib in HCC

Jing-De Wu, Ying-Jie Cui, Yi-Gang Zhou, Long-Qian Tang, Cheng-Mei Zhang, Zhao-Peng Liu
Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog...
March 18, 2019: Investigational New Drugs
Jeong-Ju Yoo, Su Jong Yu, Juri Na, Kyungmin Kim, Young Youn Cho, Yun Bin Lee, Eun Ju Cho, Jeong-Hoon Lee, Yoon Jun Kim, Hyewon Youn, Jung-Hwan Yoon
This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor to target HK-II. The human HCC cell line was tested as both subcutaneous and orthotopic tumor xenograft models in BALB/c nu/nu mice. The prognostic role of HK-II was evaluated in data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patients treated with sorafenib...
March 14, 2019: International Journal of Molecular Sciences
Pietro Gatti, Antonio Giorgio, Emanuela Ciracì, Italia Roberto, Alessandro Anglani, Spano Sergio, Fernando Rizzello, Valentina Giorgio, Stefano Semeraro
PURPOSE: Hepatocellular carcinoma (HCC) is the most common form of liver cancer. In advanced cancer stages (metastatic disease and/or vascular invasion), the generally accepted standard of care is systemic therapy using sorafenib as first-line treatment and, recently, regorafenib and nivolumab as second-line treatment, but the quality of life and the prognosis of patients remain very poor. Our paper reports a case of US-guided radiofrequency ablation (RFA) of both intraparenchymal HCC and inferior vena cava tumor thrombus...
March 12, 2019: Journal of Ultrasound
Hong Zhu, Chunyan Zhang, Xi Yang, Cheng Yi
RATIONALE: Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death worldwide. Its poor prognosis is due to the high invasiveness of the disease and limited efficacy of available treatments. PATIENT CONCERNS: We reported an HCC patient who developed lung metastases 1 year after HCC resection. Sorafenib was then initiated; however, disease progression was noted 3 months later. Sorafenib therapy was initially maintained due to lack of effective alternatives, but disease progression continued...
March 2019: Medicine (Baltimore)
Baosheng Ren, Wansheng Wang, Jian Shen, Wanci Li, Caifang Ni, Xiaoli Zhu
Objective : To compare the outcomes of transarterial chemoembolization (TACE) combined with sorafenib versus TACE alone for treating patients with unresectable hepatocellular carcinoma (HCC). Methods : This retrospective analysis included all patients receiving either TACE plus sorafenib therapy or TACE alone for unresectable HCC between February 2008 and August 2015 at the First Affiliated Hospital of Soochow University, China. Propensity score matching (PSM) was carried out to reduce bias due to confounding variables...
2019: Journal of Cancer
Davide Ippolito, Anna Pecorelli, Giulia Querques, Silvia Girolama Drago, Cesare Maino, Cammillo Talei Franzesi, Adam Hatzidakis, Sandro Sironi
Early diagnosis of HCC is of paramount importance in order to enable the application of curative treatments. Among these, radiofrequency ablation (RFA) is actually considered the most effective ablative therapy for early stage hepatocellular carcinoma (HCC) not suitable for surgery. On the other hand, transarterial chemoembolization (TACE) represents the standard of care for intermediate stage HCC and compensated liver function. Finally, sorafenib, an oral antiangiogenic targeted drug, is the only approved systemic therapy for advanced HCC with vascular invasion, extrahepatic spread, and well-preserved liver function...
March 6, 2019: Academic Radiology
Zhongyi Fan, Jingjing Duan, Lingxiong Wang, Saisong Xiao, Lingling Li, Xiang Yan, Wei Yao, Liangliang Wu, Sujie Zhang, Yong Zhang, Ye Li, Xiang Zhu, Yi Hu, Dong Zhang, Shunchang Jiao, Xiaojie Xu
Emerging evidence indicates that cancer stem cells (CSCs) are involved in tumorigenesis, tumor recurrence, and therapeutic resistance in hepatocellular carcinoma (HCC). However, the mechanisms underlying HCC CSC regulation remain largely unknown. Here we report our analysis of 97 paraffin-embedded HCC tumor specimens. We found that protein tyrosine kinase 2 (PTK2) expression correlated with liver CSC marker expression, overall survival, and recurrence-free survival in HCC patients. Our results further showed that PTK2 activated Wnt/β-catenin signaling by promoting nuclear accumulation of β-catenin in HCC cells...
March 5, 2019: Cancer Letters
Jihye Kim, Dong-Hyun Sinn, Moon Seok Choi, Wonseok Kang, Geum-Youn Gwak, Yong-Han Paik, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik
BACKGROUND AND AIM: Currently, sorafenib is indicated for hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM), and many other systemic agents are becoming available. However, a few HCC patients with EHM still undergo transarterial chemoembolization (TACE) for intrahepatic tumor control. We aimed to investigate whether TACE is appropriate for patients with EHM, and if so, which subgroup may benefit from TACE. METHODS: A total of 186 consecutive HCC patients (median: 55 years, male: 86...
2019: PloS One
Rong-Zheng Ran, Jun Chen, Long-Jiu Cui, Xiao-Lu Lin, Ming-Ming Fan, Zhuang-Zhi Cong, Hai Zhang, Wei-Feng Tan, Qing-Guo Zhang, Yong-Jie Zhang
Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver CSCs remains unclear. Herein, we observed low expression of miR-194 in chemoresistant HCC cells. A remarkable decrease of miR-194 was detected in EpCAM or CD133-positive liver CSCs and CSC-enriched hepatoma spheres. Interference miR-194 facilitated liver CSCs expansion by enhancing the self-renewal of liver CSCs...
March 4, 2019: Experimental Cell Research
Brian I Carr
Recent clinical trials and new agents have permitted greater clarity in the choice of effective agents for that majority of patients with hepatocellular carcinoma who have advanced disease at diagnosis and thus cannot be offered potentially curative resection, ablation or liver transplantation. The main treatment for these patients remains chemoembolization, although evidence for selective internal radiation therapy (SIRT) with SIR-Spheres or Theraphere, is beginning to suggest that the results with this may be comparable with less toxicity...
2019: Hepatoma Research
Karim Fekir, Hélène Dubois-Pot-Schneider, Romain Désert, Yoann Daniel, Denise Glaise, Claudine Rauch, Fabrice Morel, Bernard Fromenty, Orlando Musso, Florian Cabillic, Anne Corlu
Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies...
March 5, 2019: Cancer Research
Xiufeng Liu, Shukui Qin
Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival...
February 2019: Oncologist
Jeongshim Lee, Won Sup Yoon, Woong Sub Koom, Chai Hong Rim
Purpose: Sorafenib is recommended as the standard treatment for hepatocellular carcinoma (HCC) of Barcelona Clinic of Liver Cancer stage C (BCLC C). However, local treatment including radiation therapy (LRT) is also widely administered in practice. The aim of our study was to define the role of LRT among BCLC C patients. Patients and methods: Of the patients with HCC enrolled the Korean Central Cancer Registry from 2008 to 2014, the Korean Liver Cancer Study Group randomly extracted 10,580 patient data from ~50 hospitals nationwide...
2019: Cancer Management and Research
Masatoshi Kudo
Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction...
February 21, 2019: World Journal of Gastroenterology: WJG
Jens U Marquardt, Anna Saborowski, Carolin Czauderna, Arndt Vogel
Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide with a rising incidence in the Western world. HCCs are characterized by high resistance to systemic therapies induced by phenotypic and molecular heterogeneity. For almost 10 years, the tyrosine kinase inhibitor sorafenib was the only approved treatment for advanced HCCs in patients with preserved liver function, and until 2016, no new compounds tested in large phase III studies have led to a survival benefit. The tyrosine kinase inhibitor regorafenib, a fluorinated sorafenib analog, was the first substance that showed a significant improvement in overall survival after failure of sorafenib treatment, which subsequently led to its regulatory approval in a second-line setting in 2017...
February 25, 2019: Targeted Oncology
Paola Todesca, Luca Marzi, Rosina Maria Critelli, Biagio Cuffari, Cristian Caporali, Laura Turco, Giovanni Pinelli, Filippo Schepis, Lucia Carulli, Nicola de Maria, Federico Casari, Riccardo Scaglioni, Erica Villa
Despite surveillance, hepatocellular carcinoma (HCC) often presents at such an advanced stage that only systemic therapy with sorafenib is feasible. However, aggressive HCCs bearing the neoangiogenic transcriptomic signature (TS)(1) are scarcely sensitive to sorafenib, which has no activity against the leading gene of the signature Angiopoietin-2 (Ang-2). The recently approved HCC drug regorafenib could instead possess some pharmacologic activity against it (2,3). We report a case of massive aggressive TS-positive HCC had a striking response to regorafenib...
February 25, 2019: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Shi-Bing Wang, Ying-Yu Ma, Xiao-Yi Chen, Yuan-Yuan Zhao, Xiao-Zhou Mou
Despite substantial efforts to develop novel therapeutic strategies for treating hepatocellular carcinoma (HCC), the effectiveness and specificity of available drugs still require further improvement. Previous work has shown that exogenous ceramide can play a key role in inducing the apoptotic death of cancer cells, however, the poor water-solubility of this compound has hampered its use for cancer treatment. In the present study, we used polyethylene glycol (PEG) and polyethylenimine (PEI) co-conjugated ultra-small nano-GO (NGO-PEG-PEI) loaded with C6-ceramide (NGO-PEG-PEI/Cer) as a strategy for HCC treatment...
2019: Frontiers in Pharmacology
Junfeng Ye, Ruoyan Zhang, Wengang Chai, Xiaohong Du
Combinational therapy is usually considered as a preferable approach for effective cancer therapy. Especially, combinational chemotherapies targeting different molecular targets are of particular interest due to its high flexibility as well as efficiency. In our study, the surface of silica nanoparticles (SLN) was modified with low-density lipoprotein (LDL) to construct platform (LDL-SLN) capable of specifically targeting low-density lipoprotein receptors (LDLRs) that overexpressing in hepatocellular carcinoma (HCC)...
November 2018: Drug Delivery
Pyeong Hwa Kim, Sang Hyun Choi, Jin Hyoung Kim, Seong Ho Park
OBJECTIVE: To compare the safety and efficacy of radioembolization with that of sorafenib for the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: MEDLINE, EMBASE, and Cochrane databases were searched for studies reporting outcomes in patients with HCC and PVTT treated with radioembolization or sorafenib. Meta-analyses of cumulative overall survival (OS) and Kaplan-Meier survival rates according to the time to progression (TTP) and incidence of adverse events (AEs) were performed...
March 2019: Korean Journal of Radiology: Official Journal of the Korean Radiological Society
Lilia Turcios, Eduardo Chacon, Catherine Garcia, Pedro Eman, Virgilius Cornea, Jieyun Jiang, Brett Spear, Chunming Liu, David S Watt, Francesc Marti, Roberto Gedaly
Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells...
2019: PloS One
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