scholarly journals Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 526 ◽  
Author(s):  
Alqahtani ◽  
Khan ◽  
Alloghbi ◽  
Said Ahmed ◽  
Ashraf ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Advanced Hcc ◽  
Complex Process ◽  
Clinical Benefits ◽  
Approved Drugs

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of balance between activation and inactivation of protooncogenes and tumor suppressor genes, respectively. Since HCC most often occurs in the setting of a diseased or cirrhotic liver and most of the patients are diagnosed at the late stage of disease, prognosis is generally poor. At present, limited treatment options with marginal clinical benefits are available. Systemic therapy, particularly in the form of conventional cytotoxic drugs, are generally ineffective. In recent years, molecular-targeted therapies have been clinically used to treat various cancers, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules that are involved in carcinogenesis, which makes it more selective and specific than cytotoxic chemotherapy. Many clinical trials have been carried out while using molecular targeted drugs in advanced HCC with many more in progress. The clinical trials in HCC to date have evaluated a single-targeted therapy alone, or two or more targeted therapies in parallel. The aim of this review is to provide insight of various molecular mechanisms, leading to HCC development and progression, and also the range of experimental therapeutics for patients with advanced HCC. The review will summarize different clinical trials data the successes and failures of these treatments, as well as the most effective and approved drugs designed against HCC.

scholarly journals Emerging agents and regimens for hepatocellular carcinoma

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiao-Dong Zhu ◽  
Hui-Chuan Sun
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Treatment Options ◽  
Intermediate Stage ◽  
Line Treatment ◽  
Advanced Hcc ◽  
Treatment Practices ◽  
Improve Patient Survival ◽  
Phase Ii Clinical Trials ◽  
Early Phase Clinical Trials

Abstract Liver cancer, mostly hepatocellular carcinoma (HCC), is the second leading cause of cancer mortality globally. Most patients need at least one systemic therapy at different phases of their treatment for HCC. Sorafenib was the first agent shown to improve the survival of patients with advanced HCC. A decade after the approval of sorafenib, most agents failed to improve patient survival more than sorafenib. In recent years, treatment practices have changed, with lenvatinib as another first-line treatment choice and regorafenib, ramucirumab, and cabozantinib as second-line treatment options. Anti-PD-1 antibodies, including nivolumab, pembrolizumab, and camrelizumab, have demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials. The combination of an anti-PD-1 antibody and an anti-angiogenesis agent has shown more potent anti-tumor effects in early phase clinical trials and is now the hotspot in clinical studies. Furthermore, these agents are investigated in combination treatment with surgery or other loco-regional therapies in patients with early or intermediate-stage HCC.

scholarly journals Hepatocellular Carcinoma: Novel Molecular Targets in Carcinogenesis for Future Therapies

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Gaetano Bertino ◽  
Shirin Demma ◽  
Annalisa Ardiri ◽  
Maria Proiti ◽  
Giulia Malaguarnera ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Therapy ◽  
Web Of Science ◽  
Malignant Tumors ◽  
Tumor Staging ◽  
Treatment Options ◽  
Advanced Hcc ◽  
The Past ◽  
Dismal Prognosis ◽  
Keywords Hepatocellular Carcinoma

Background. Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Materials and Methods. A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: “hepatocellular carcinoma,” “molecular hepatocarcinogenesis,” “targeted therapy,” and “immunotherapy.” Discussion and Conclusion. Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.

scholarly journals Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5232
Author(s):  
Jun Gong ◽  
Jeremy Chuang ◽  
May Cho ◽  
Kyra Toomey ◽  
Andrew Hendifar ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Cancer Mortality ◽  
Molecular Targets ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Therapeutic Implications ◽  
The Past ◽  
Selection Of

Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.

scholarly journals Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 555
Author(s):  
Soyoung Hur ◽  
Eungyeong Jang ◽  
Jang-Hoon Lee
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Perennial Plant

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

GCSF As a Potential Molecular Target for Overall Survival of Hepatocellular Carcinoma

2021 ◽  
Vol 24 ◽  
Author(s):  
Heng Cao ◽  
Peng Guo ◽  
Xiaohui Wu ◽  
Jiankun Li ◽  
Chenlong Ge ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Survival Analysis ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Basic Research ◽  
Clinical Samples ◽  
Tumor Diameter ◽  
Overall Survival Analysis

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of digestive tract in the world. Therefore, it is important to carry out studies on the molecular mechanisms of early diagnosis and treatment of HCC to reduce mortality. Methods: Bioinformatic analysis was performed to explore the significant role of GCSF on the occurrence and development of neoplasm. Differently expressed genes (DEGs) were screened, and the significant hub genes related with GCSF were identified by the multiple algorithms of Cytoscape. Functional annotation for DEGs, pathological stage and overall survival analysis were implemented. In addition, the verification for the role of GCSF on HCC was made via the clinical samples. A total of 70 participates diagnosed as HCC were recruited from November 2014 to November 2019. The immunohistochemistry assay, qRT-PCR, receiver operating characteristic (ROC) curves, and overall survival analysis were carried out. Results: GCSF was related with the tumor size, and the expression of GCSF was up-regulated in hepatocellular carcinoma tissues. The enrichment results of GO and KEGG analysis were mainly enriched in “Inflammatory response”, “Protein binding”, “Metabolic pathways”, and “Proteasome”. The tumor diameter (P < 0.001), and survival time (P < 0.001) were significantly associated with expression of GCSF via the verification of clinical data. The univariate and multivariate Cox proportional regression analysis manifested that high expression of GCSF in patients with HCC was related to poor OS. Conclusion: The expression level of GCSF is significantly associated with the prognostic survival of HCC, and it is expected to become a new prognostic marker of HCC, providing a novel idea for future basic research as well as targeted therapy.

scholarly journals New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

scholarly journals Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 21 (17) ◽  
pp. 6302
Author(s):  
Michela Guardascione ◽  
Giuseppe Toffoli
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Antiangiogenic Agents ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

scholarly journals Targeted Therapies in the Treatment of Advanced Hepatocellular Carcinoma

2013 ◽  
Vol 7 ◽  
pp. CMO.S7633 ◽  
Author(s):  
Zhengyu Wei ◽  
Cataldo Doria ◽  
Yuan Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Therapies ◽  
Recent Progress ◽  
Systemic Treatment ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
The Third ◽  
Promising Target ◽  
Targeted Treatments ◽  
Attractive Option

Hepatocellular carcinoma (HCC) is the most common liver cancer and the third leading cause of cancer death. It has been a major worldwide health problem with more new cases being diagnosed each year. The current available therapies for patients with advanced HCC are extremely limited. Therefore, it is of great clinical interests to develop more effective therapies for systemic treatment of advanced HCC. Several promising target-based drugs have been tested in a number of clinical trials. One breakthrough of these efforts is the approved clinical use of sorafenib in patients with advanced HCC. Targeted therapies are becoming an attractive option for the treatment of advanced HCC. In this review, we summarize the most recent progress in clinical targeted treatments of advanced HCC.

scholarly journals The Mechanism and Clinical Significance of Circular RNAs in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Ziyue Huang ◽  
Haoming Xia ◽  
Shuqiang Liu ◽  
Xudong Zhao ◽  
Risheng He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Early Diagnosis ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Clinical Symptoms ◽  
Malignant Tumors ◽  
Research Progress ◽  
Circular Rnas ◽  
Transcriptional Level ◽  
Specificity And Sensitivity

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. In view of the lack of early obvious clinical symptoms and related early diagnostic biomarkers with high specificity and sensitivity, most HCC patients are already at the advanced stages at the time of diagnosis, and most of them are accompanied by distant metastasis. Furthermore, the unsatisfactory effect of the follow-up palliative care contributes to the poor overall survival of HCC patients. Therefore, it is urgent to identify effective early diagnosis and prognostic biomarkers and to explore novel therapeutic approaches to improve the prognosis of HCC patients. Circular RNA (CircRNA), a class of plentiful, stable, and highly conserved ncRNA subgroup with the covalent closed loop, is dysregulated in HCC. Increasingly, emerging evidence have confirmed that dysregulated circRNAs can regulate gene expression at the transcriptional or post-transcriptional level, mediating various malignant biological behaviors of HCC cells, including proliferation, invasion, metastasis, immune escape, stemness, and drug resistance, etc.; meanwhile, they are regarded as potential biomarkers for early diagnosis and prognostic evaluation of HCC. This article reviews the research progress of circRNAs in HCC, expounding the potential molecular mechanisms of dysregulated circRNAs in the carcinogenesis and development of HCC, and discusses those application prospects in the diagnosis and prognosis of HCC.

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