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Targeted Therapy of Hepatocellular Carcinoma: Present and Future

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A special issue of Diseases (ISSN 2079-9721). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (20 August 2015) | Viewed by 84715

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Special Issue Editor

Dr. Stephen L. Chan

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Guest Editor

Department of Clinical Oncology, Prince of Wales Hospital, Shatin, HKSAR, China
Interests: hepatocellular carcinoma; pancreatic cancer; biliary tract cancer; biomarker; inflammation; targeted therapy

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Drug development for HCC used to be slow due to the relative chemo-refractoriness of the tumor and underlying co-morbid cirrhosis in most patients. Since 2008, clinical trial results on sorafenib have led to development of molecular targeted agents for HCC. For the past 5 years, a number of tyrosine kinase inhibitors have completed phase III testing but all of them have turned out to be negative. These studies persistently reported a median overall survival of 9 to 10 months, indicating that the benefit of an existing panel of targeted agents may have reached a plateau for advanced HCC. To overcome this deadlock, novel agents and concepts are needed from researchers of the HCC research world.

This Special Issue provides an Open Access opportunity to publish research and review articles on targeted therapy for HCC. The focus will be put on a comprehensive review of the current literatures as well as insights into the improvement of success rate of clinical trials on novel agents for the aggressive tumor.

Dr. Stephen L. Chan
Guest Editor

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Keywords

hepatocellular carcinoma
sorafenib
clinical trial
targeted agent
cirrhosis
hepatitis

Published Papers (13 papers)

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Research

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776 KiB

Open AccessArticle

Factors Associated with Post-Progression Survival in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib

by Taiga Otsuka, Shunya Nakashita, Kimihiko Yanagita, Keisuke Ario, Hiroaki Kawasoe, Seiji Kawazoe, Yuichiro Eguchi and Toshihiko Mizuta

Diseases 2015, 3(2), 68-77; https://doi.org/10.3390/diseases3020068 - 15 May 2015

Cited by 3 | Viewed by 4937

Abstract

Sorafenib exerts modest antitumor activity in patients with advanced hepatocellular carcinoma (HCC), and radiological progressive disease (rPD) does not always correspond to so-called clinical progressive disease (cPD). We evaluated 101 patients who initiated sorafenib treatment for HCC and assessed post-progression survival (PPS) using the Cox proportional hazards model. PPS was calculated from the date of the first rPD until the date of death or the last follow-up. Using Cox model analysis of the 76 patients who experienced first rPD, we identified the Child-Pugh class, Eastern Cooperative Oncology Group performance status, the best antitumor response during treatment (using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1) and α-fetoprotein levels as independent factors affecting PPS. When these factors were used to define scores ranging from zero to five with a cutoff value of two, PPS of patients who received best supportive care (BSC) after rPD was not statistically significantly different from that of patients who received post-rPD therapy with scores ≥2 (p = 0.220). In contrast, the PPS for the post-rPD therapy group was significantly longer compared with the BSC patients with scores <2 (p < 0.001). Patients who scored ≥2 at their first rPD were judged cPD and as candidates for BSC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Review

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523 KiB

Open AccessReview

Targeted Therapy of Hepatitis B Virus-Related Hepatocellular Carcinoma: Present and Future

by Sarene Koh, Anthony Tanoto Tan, Lietao Li and Antonio Bertoletti

Diseases 2016, 4(1), 10; https://doi.org/10.3390/diseases4010010 - 15 Feb 2016

Cited by 8 | Viewed by 6590

Abstract

Cancer immunotherapy using a patient’s own T cells redirected to recognize and kill tumor cells has achieved promising results in metastatic melanoma and leukemia. This technique involves harnessing a patient’s T cells and then delivering a gene that encodes a new T cell receptor (TCR) or a chimeric antigen receptor (CAR) that allow the cells to recognize specific cancer antigens. The prospect of using engineered T cell therapy for persistent viral infections like hepatitis B virus (HBV) and their associated malignancies is promising. We recently tested in a first-in-man clinical trial, the ability of HBV-specific TCR-redirected T cells to target HBsAg-productive hepatocellular carcinoma (HCC) and demonstrated that these redirected T cells recognized HCC cells with HBV–DNA integration [1] We discuss here the possibility to use HBV-specific TCR-redirected T cells targeting hepatitis B viral antigens as a tumor specific antigen in patients with HBV-related HCC, and the potential challenges facing the development of this new immunotherapeutic strategy. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Hepatocellular Carcinoma: Past and Future of Molecular Target Therapy

by Khanh Nguyen, Kerri Jack and Weijing Sun

Diseases 2016, 4(1), 1; https://doi.org/10.3390/diseases4010001 - 25 Dec 2015

Cited by 11 | Viewed by 4877

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer related mortality worldwide. The incidence of HCC has been increasing annually. Viral infection, alcohol usage, and other causes of cirrhosis have been identified as major risk factors for HCC development. The underlying pathogenesis has not been as well defined. There have been multiple hypotheses to the specific mechanisms of hepatocarcinogenesis and they share the common theme of chronic inflammation, increase oxidative stress, and genomic alteration. Therapeutic options of HCC have been primarily local and/or regional including transplantation, resection, and radial frequency ablation, chemoembolization or radio-embolization. For unresectable or metastatic disease, the options are limited. Conventional chemotherapeutic options have been noted to have limited benefit. Sorafenib has been the one and only systemic therapy which has demonstrated modest overall survival benefit. This has led to more extensive research with focus on targeted therapy. Numerous pre-clinical and early phase clinical studies have been noted but failed to show efficacy in later phase clinical trials. In an effort to identify new potential therapeutic options, new understanding of underlying pathways to hepatocarcinogenesis should be one of the main focuses. This leads to development of more molecularly targeted agents to specific pathways, and immunotherapy. This article provides a review of major studies of molecular targeted agents which attempts to target these specific pathways in HCC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future

by Masafumi Ikeda, Shuichi Mitsunaga, Izumi Ohno, Yusuke Hashimoto, Hideaki Takahashi, Kazuo Watanabe, Kumiko Umemoto and Takuji Okusaka

Diseases 2015, 3(4), 360-381; https://doi.org/10.3390/diseases3040360 - 01 Dec 2015

Cited by 35 | Viewed by 5199

Abstract

Systemic chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). Before the introduction of sorafenib, cytotoxic agents, hormonal therapies, or many combinations of these were the mainly used modalities for systemic chemotherapy of advanced HCC. However, such regimens were of only limited value in clinical practice, because some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. In two pivotal phase III placebo-controlled studies, the SHARP trial and the Asia-Pacific trial, sorafenib was demonstrated to significantly delay the time to progression and the overall survival time in patients with advanced HCC. Therefore, sorafenib therapy has come to be acknowledged as a standard therapy for advanced HCC worldwide. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line chemotherapy and of various molecular-targeted agents vs. placebo as second-line chemotherapy have been conducted to determine if any of these agents could offer a survival benefit, however, none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo. Recently, favorable treatment efficacies have been reported in some clinical trials of molecular-targeted agents in the biomarker-enriched population. Development of individualized cancer treatments using molecular-targeted agents based on the results of genome-sequencing is aggressively ongoing. Furthermore, immune-oncologic agents, such as anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody, have been reported to provide promising outcomes. Thus, various novel systemic chemotherapeutic agents are currently under development, and further improvements in the treatment outcomes are expected. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

New Tools for Molecular Therapy of Hepatocellular Carcinoma

by Alessandra Marchetti, Francesca Bisceglia, Angela M. Cozzolino and Marco Tripodi

Diseases 2015, 3(4), 325-340; https://doi.org/10.3390/diseases3040325 - 30 Oct 2015

Cited by 6 | Viewed by 6275

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, arising from neoplastic transformation of hepatocytes or liver precursor/stem cells. HCC is often associated with pre-existing chronic liver pathologies of different origin (mainly subsequent to HBV and HCV infections), such as fibrosis or cirrhosis. Current therapies are essentially still ineffective, due both to the tumor heterogeneity and the frequent late diagnosis, making necessary the creation of new therapeutic strategies to inhibit tumor onset and progression and improve the survival of patients. A promising strategy for treatment of HCC is the targeted molecular therapy based on the restoration of tumor suppressor proteins lost during neoplastic transformation. In particular, the delivery of master genes of epithelial/hepatocyte differentiation, able to trigger an extensive reprogramming of gene expression, could allow the induction of an efficient antitumor response through the simultaneous adjustment of multiple genetic/epigenetic alterations contributing to tumor development. Here, we report recent literature data supporting the use of members of the liver enriched transcription factor (LETF) family, in particular HNF4α, as tools for gene therapy of HCC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Clinical Development of c-MET Inhibition in Hepatocellular Carcinoma

by Joycelyn J. X. Lee, Jack J. Chan and Su Pin Choo

Diseases 2015, 3(4), 306-324; https://doi.org/10.3390/diseases3040306 - 28 Oct 2015

Cited by 8 | Viewed by 5337

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. In patients with advanced or unresectable HCC, there are few treatment options. Conventional chemotherapy has limited benefits. Sorafenib, a multi-kinase inhibitor, improves survival, but options for patients intolerant of or progressing on sorafenib are limited. There has been much interest in recent years in molecular therapeutic targets and drug development for HCC. One of the more promising molecular targets in HCC is the cellular-mesenchymal-epithelial transition (c-MET) factor receptor. Encouraging phase II data on two c-MET inhibitors, tivantinib and cabozantinib, has led to phase III trials. This review describes the c-MET/hepatocyte growth factor (HGF) signalling pathway and its relevance to HCC, and discusses the preclinical and clinical trial data for inhibitors of this pathway in HCC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma

by Dimitra Repana and Paul Ross

Diseases 2015, 3(4), 294-305; https://doi.org/10.3390/diseases3040294 - 28 Oct 2015

Cited by 56 | Viewed by 9984

Abstract

Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to in vivo models. This review aims to describe the role of the FGF19/FGFR4 pathway in hepatocellular carcinoma and its role as a potential predictive biomarker for novel targeted agents against FGF19/FGFR4 signalling. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Synergistic Anticancer Activities of Natural Substances in Human Hepatocellular Carcinoma

by Akiko Kojima-Yuasa, Xuedan Huang and Isao Matsui-Yuasa

Diseases 2015, 3(4), 260-281; https://doi.org/10.3390/diseases3040260 - 22 Oct 2015

Cited by 16 | Viewed by 5648

Abstract

Hepatocellular carcinoma (HCC) is highly resistant to currently available chemotherapeutic agents. The clinical outcome of HCC treatment remains unsatisfactory. Therefore, new effective and well-tolerated therapy strategies are needed. Natural products are excellent sources for the development of new medications for disease treatment. Recently, we and other researchers have suggested that the combined effect of natural products may improve the effect of chemotherapy treatments against the proliferation of cancer cells. In addition, many combination treatments with natural products augmented intracellular reactive oxygen species (ROS). In this review we will demonstrate the synergistic anticancer effects of a combination of natural products with chemotherapeutic agents or natural products against human HCC and provide new insight into the development of novel combination therapies against HCC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma

by Claire Faltermeier, Ronald W. Busuttil and Ali Zarrinpar

Diseases 2015, 3(4), 221-252; https://doi.org/10.3390/diseases3040221 - 29 Sep 2015

Cited by 2 | Viewed by 10169

Abstract

Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%–30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Menahydroquinone-4 Prodrug: A Promising Candidate Anti-Hepatocellular Carcinoma Agent

by Munechika Enjoji, Daisuke Watase, Kazuhisa Matsunaga, Mariko Kusuda, Nami Nagata-Akaho, Yoshiharu Karube and Jiro Takata

Diseases 2015, 3(3), 150-158; https://doi.org/10.3390/diseases3030150 - 22 Jul 2015

Cited by 2 | Viewed by 5071

Abstract

Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo. The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

by Hiroyasu Sakai, Masahito Shimizu and Hisataka Moriwaki

Diseases 2014, 2(3), 226-242; https://doi.org/10.3390/diseases2030226 - 07 Jul 2014

Cited by 2 | Viewed by 7827

Abstract

Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis due to its high rate of recurrence after the initial curative treatment. Therefore, development of effective therapeutic strategies that can prevent recurrence and secondary tumor formation is required to improve the clinical outcomes of HCC patients. Malfunctioning of the retinoid X receptor-s (RXRs) of HCC patient by activation of the Ras- mitogen-activated protein kinase (MAPK) signaling pathway is strongly associated with hepatocarcinogenesis. Acyclic retinoid (ACR), a synthetic retinoid, prevents HCC recurrence by inhibiting Ras-MAPK activation and the subsequent RXRα phosphorylation, thereby improving patient prognosis. Here, we have reviewed the detailed effects of ACR on the prevention of HCC development, with particular references to the results of our previous basic and clinical research. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessReview

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

by Xiangbing Meng, Eric J. Devor, Shujie Yang, Brandon M. Schickling and Kimberly K. Leslie

Diseases 2014, 2(3), 209-225; https://doi.org/10.3390/diseases2030209 - 01 Jul 2014

Cited by 2 | Viewed by 7312

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance. Vaccination and improved treatment for hepatitis are the most effective means to reduce the burden of liver cancer worldwide. Expression of biomarkers such as AFP (alpha-fetoprotein), DDK1 (Dickkopf WNT Signaling Pathway Inhibitor 1) and microRNAs in blood are being tested for early screening of liver cancer. Since 2008, sorafenib has been used as the standard molecular targeting agent for HCC. However, overall outcomes for sorafenib alone or in combination with other tyrosine kinase inhibitors are unsatisfactory. Whether simultaneously or sequentially, addiction switches and compensatory pathway activation in HCC, induced by sorafenib treatment, may induce acquired resistance. Forkhead box M1 (FOXM1) and metadherin (MTDH) have been shown to be master regulators of different aspects of tumorigenesis, including angiogenesis, invasion, metastasis and drug resistance. Elevated expression of both FOXM1 and MTDH is known to be a consequence of both activating mutations in oncogenes such as PI3K, Ras, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN in various types of cancers including HCC. The role of FOXM1 and MTDH as potential prognostic markers as well as therapeutic targets in HCC will be discussed. In addition, microRNAs (miRNAs), endogenous small non-coding RNAs involved in the regulation of gene expression, are involved in HCC and interact with both FOXM1 and MTDH in several ways. Thus, altered expression of miRNAs in HCCs will also be discussed as potential tools for diagnosis, prognosis and therapy in HCC. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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Open AccessBrief Report

HBV Core Protein Enhances Cytokine Production

by Tatsuo Kanda, Shuang Wu, Reina Sasaki, Masato Nakamura, Yuki Haga, Xia Jiang, Shingo Nakamoto and Osamu Yokosuka

Diseases 2015, 3(3), 213-220; https://doi.org/10.3390/diseases3030213 - 17 Sep 2015

Cited by 9 | Viewed by 4613

Abstract

Hepatitis B virus (HBV) infection, a cause of hepatocellular carcinoma (HCC), remains a serious global health concern. HCC development and human hepatocarcinogenesis are associated with hepatic inflammation caused by host interferons and cytokines. This article focused on the association between the HBV core protein, which is one of the HBV-encoding proteins, and cytokine production. The HBV core protein induced the production of interferons and cytokines in human hepatoma cells and in a mouse model. These factors may be responsible for persistent HBV infection and hepatocarcinogenesis. Inhibitors of programmed death (PD)-1 and HBV core and therapeutic vaccines including HBV core might be useful for the treatment of patients with chronic HBV infection. Inhibitors of HBV core, which is important for hepatic inflammation, could be helpful in preventing the progression of liver diseases in HBV-infected patients. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

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