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Pharmaceuticals
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New Therapies for Hepatocellular Carcinoma
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New Therapies for Hepatocellular Carcinoma

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 October 2020) | Viewed by 22391

Special Issue Editors

Dr. Francesco Tovoli

E-Mail Website
Guest Editor
Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
Interests: hepatocellular carcinoma; cholangiocellular carcinoma; liver cancer; autoimmune hepatitis; celiac disease
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro Granito

E-Mail Website1 Website2
Guest Editor
1. Associate Professor, Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
2. Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
Interests: hepatocellular carcinoma; liver cancer; autoimmune hepatitis; primary biliary cholangitis; primary sclerosing cholangitis; celiac disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The last few years have brought tremendous progress in the therapy of hepatocellular carcinoma, with immune oncology drugs (IOs) becoming pivotal players. Their success is not limited to the atezolizumab plus bevacizumab combination, as favorable results are coming from Phase 2 trials of dual immune checkpoint blockade and combination of IOs plus oral tirosine kinase inhibitors.

While this news is widely appreciated, new questions appear at the horizon. With no head-to-head trials, which frontline combination will be the most effective? Will we ever benefit from biomarkers to guide our choices? Which sequential treatments will grant the maximum benefit? What will be the role of tyrosine kinase inhibitors?   

Additionally, the possible success of these combinations in the adjuvant and neo-adjuvant setting might revolutionize the whole therapeutic algorithm of hepatocellular carcinoma.

Finally, in a time in which the COVID-19 pandemic is putting a strain on most National Health Systems, cost-effectiveness data of these new combinations are urgently needed.

Therefore, we invite researchers to submit up-to-date original research articles, short communications, and review articles in this Special Issue of Pharmaceuticals.

Dr. Francesco Tovoli
Dr. Alessandro Granito
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hepatocellular carcinoma
  • sorafenib
  • regorafenib
  • lenvatinib
  • cabozantinib
  • atezolizumab
  • nivolumab
  • outcome

Related Special Issues

Published Papers (6 papers)

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Research

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18 pages, 11692 KiB  
Article
The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells
by Maria Narożna, Violetta Krajka-Kuźniak, Barbara Bednarczyk-Cwynar, Robert Kleszcz and Wanda Baer-Dubowska
Pharmaceuticals 2021, 14(1), 32; https://doi.org/10.3390/ph14010032 - 31 Dec 2020
Cited by 12 | Viewed by 3270
Abstract
Nrf2 and NF-κB play a key role in inflammation-driven cancers. Conjugation of anti-inflammatory drugs with oleanolic acid oxime (OAO) may enhance their therapeutic potential as a result of downregulation of these pathways. Novel OAO derivatives conjugated with indomethacin (IND) were synthesized, and their [...] Read more.
Nrf2 and NF-κB play a key role in inflammation-driven cancers. Conjugation of anti-inflammatory drugs with oleanolic acid oxime (OAO) may enhance their therapeutic potential as a result of downregulation of these pathways. Novel OAO derivatives conjugated with indomethacin (IND) were synthesized, and their effect on the activation and expression of Nrf2 and NF-κB in HepG2 hepatoma cells and THLE-2 immortalized normal hepatocytes was evaluated in relation to cell cycle arrest and apoptosis. Treatment with OAO–IND conjugates reduced the activation of Nrf2 and NF-κB and the expression of their active forms in HepG2 cells, while in normal hepatocytes, the activation of Nrf2 was increased and NF-κB diminished. Compounds 3d, 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide, and 3c, 3-indomethacinoxyiminoolean-12-en-28-oic acid benzyl ester, were the most efficient. In THLE-2 cells, as opposed to HepG2 cells, the expressions of SOD-1 and NQO1 were significantly enhanced after treatment with these compounds. The COX-2 expression was diminished in both cell lines. OAO–IND derivatives affected the cell cycle arrest at G2/M, leading to increased apoptosis and increased number of resting HepG2 cells. Therefore, the conjugation of IND with OAO derivatives may preserve cancer cells against chemoresistance through the inhibition of the Nrf2-ARE pathway and NF-κB and, at the same time, exert a chemopreventive effect in normal hepatocytes. Full article
(This article belongs to the Special Issue New Therapies for Hepatocellular Carcinoma)
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Review

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21 pages, 1330 KiB  
Review
How to Treat Hepatocellular Carcinoma in Elderly Patients
by Piera Federico, Emilio Francesco Giunta, Annalisa Pappalardo, Andrea Tufo, Gianpaolo Marte, Laura Attademo, Antonietta Fabbrocini, Angelica Petrillo and Bruno Daniele
Pharmaceuticals 2021, 14(3), 233; https://doi.org/10.3390/ph14030233 - 08 Mar 2021
Cited by 10 | Viewed by 2280
Abstract
Hepatocellular carcinoma (HCC) is the primary tumour of the liver with the greatest incidence, particularly in the elderly. Additionally, improvements in the treatments for chronic liver diseases have increased the number of elderly patients who might be affected by HCC. Little evidence exists [...] Read more.
Hepatocellular carcinoma (HCC) is the primary tumour of the liver with the greatest incidence, particularly in the elderly. Additionally, improvements in the treatments for chronic liver diseases have increased the number of elderly patients who might be affected by HCC. Little evidence exists regarding HCC in old patients, and the elderly are still underrepresented and undertreated in clinical trials. In fact, this population represents a complex subgroup of patients who are hard to manage, especially due to the presence of multiple comorbidities. Therefore, the choice of treatment is mainly decided by the physician in the clinical practice, who often tend not to treat elderly patients in order to avoid the possibility of adverse events, which may alter their unstable equilibrium. In this context, the clarification of the optimal treatment strategy for elderly patients affected by HCC has become an urgent necessity. The aim of this review is to provide an overview of the available data regarding the treatment of HCC in elderly patients, starting from the definition of “elderly” and the geriatric assessment and scales. We explain the possible treatment choices according to the Barcelona Clinic Liver Cancer (BCLC) scale and their feasibility in the elderly population. Full article
(This article belongs to the Special Issue New Therapies for Hepatocellular Carcinoma)
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17 pages, 1004 KiB  
Review
The Growing Skyline of Advanced Hepatocellular Carcinoma Treatment: A Review
by Francesca Matilde Schipilliti, Ingrid Garajová, Giulia Rovesti, Rita Balsano, Federico Piacentini, Massimo Dominici and Fabio Gelsomino
Pharmaceuticals 2021, 14(1), 43; https://doi.org/10.3390/ph14010043 - 08 Jan 2021
Cited by 10 | Viewed by 2865
Abstract
Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, [...] Read more.
Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated. Full article
(This article belongs to the Special Issue New Therapies for Hepatocellular Carcinoma)
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20 pages, 1213 KiB  
Review
Lenvatinib for Hepatocellular Carcinoma: A Literature Review
by Takeshi Hatanaka, Atsushi Naganuma and Satoru Kakizaki
Pharmaceuticals 2021, 14(1), 36; https://doi.org/10.3390/ph14010036 - 06 Jan 2021
Cited by 35 | Viewed by 7305
Abstract
Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic [...] Read more.
Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC. Full article
(This article belongs to the Special Issue New Therapies for Hepatocellular Carcinoma)
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21 pages, 307 KiB  
Review
Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives
by Daniel M. Girardi, Jana Priscila M. Pacífico, Fernanda P. L. Guedes de Amorim, Gustavo dos Santos Fernandes, Marcela C. Teixeira and Allan A. L. Pereira
Pharmaceuticals 2021, 14(1), 28; https://doi.org/10.3390/ph14010028 - 31 Dec 2020
Cited by 16 | Viewed by 2804
Abstract
Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, [...] Read more.
Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies. Full article
(This article belongs to the Special Issue New Therapies for Hepatocellular Carcinoma)
23 pages, 646 KiB  
Review
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: An Overview
by Diederick J. van Doorn, Robert Bart Takkenberg and Heinz-Josef Klümpen
Pharmaceuticals 2021, 14(1), 3; https://doi.org/10.3390/ph14010003 - 22 Dec 2020
Cited by 16 | Viewed by 3117
Abstract
Patients with hepatocellular carcinoma (HCC) face a common type of cancer, which is amongst the most deadly types of cancer worldwide. The therapeutic options range from curative resection or ablation to loco regional therapies in palliative setting and last but not least, systemic [...] Read more.
Patients with hepatocellular carcinoma (HCC) face a common type of cancer, which is amongst the most deadly types of cancer worldwide. The therapeutic options range from curative resection or ablation to loco regional therapies in palliative setting and last but not least, systemic treatment. The latter group underwent major changes in the last decade and a half. Since the introduction of sorafenib in 2007, many other systemic treatments have been investigated. Most without success. It took more than ten years before lenvatinib could be added as alternative first-line treatment option. Just recently a new form of systemic treatment, immunotherapy, entered the field of therapeutic options in patients with HCC. Immune checkpoint inhibitors are becoming the new standard of care in patients with HCC. Several reviews reported on the latest phase 1/2 studies and discussed the higher response rates and better tolerability when compared to current standard of care therapies. This review will focus on elaborating the working mechanism of these checkpoint inhibitors, give an elaborate update of the therapeutic agents that are currently available or under research, and will give an overview of the latest trials, as well as ongoing and upcoming trials. Full article
(This article belongs to the Special Issue New Therapies for Hepatocellular Carcinoma)
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