Novel Molecular Targets for Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Cavalluzzo B
PROVIDER: S-EPMC8750630 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.
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Project description:Hepatocellular carcinoma (HCC) is a common and aggressive cancer with a high mortality rate. The incidence of HCC is increasing worldwide, and the lack of effective screening programs often results in delayed diagnosis, making it a challenging disease to manage. Immunotherapy has emerged as a promising treatment option for different kinds of cancers, with the potential to stimulate the immune system to target cancer cells. However, the current immunotherapeutic approaches for HCC have shown limited efficacy. Since HCC arises within a complex tumour microenvironment (TME) characterized by the presence of various immune and stromal cell types, the understanding of this interaction is crucial for the identification of effective therapy. In this review, we highlight recent advances in our understanding of the TME of HCC and the immune cells involved in anti-tumour responses, including the identification of new possible targets for immunotherapy. We illustrate a possible classification of HCC based on the tumour immune infiltration and give evidence about the role of SerpinB3, a serine protease inhibitor involved in the regulation of the immune response in different cancers.
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Project description: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.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."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.
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Project description:This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure-activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described.
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Project description:IntroductionUrothelial cancer (UC) remains a significant public health problem, with no new second-line agents FDA-approved in the US. Next-generation sequencing technologies are starting to generate a molecular landscape of UC thus revealing novel molecular targets.Areas coveredIn this review, the authors provide a detailed review of novel molecular targets in UC based on published genomic analyses of urothelial tumors. We provide an overview of each molecular target with a brief discussion of therapeutic strategies and clinical trials targeting each pathway.Expert opinionUC continues to be a lethal disease with no FDA-approved effective second-line therapies. Platinum resistance continues to be a daunting clinical problem. Next-generation sequencing methods have led to the elucidation of numerous molecular targets in UC, including PI3K, to the elucidation of numerous molecular targets in UC, including PI3K, ERBB2 and FGFR3, among many others. These molecular perturbations can be exploited therapeutically with targeted therapies in patient populations enriched for these molecular alterations, thus paving the way for precision medicine in UC management.
| S-EPMC4406627 | biostudies-literature
Project description: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.
| S-EPMC7432744 | biostudies-literature
Project description:BackgroundRadiation sensitive 52 (RAD52) is an important protein that mediates DNA repair in tumors. However, little is known about the impact of RAD52 on hepatocellular carcinoma (HCC). We investigated the expression of RAD52 and its values in HCC. Some proteins that might be coordinated with RAD52 in HCC were also analyzed.MethodsGlobal RAD52 mRNA levels in HCC were assessed using The Cancer Genome Atlas (TCGA) database. RAD52 expression was analyzed in 70 HCC tissues and adjacent tissues by quantitative real-time PCR (qRT-PCR), Western blotting and immunohistochemistry. The effect of over-expressed RAD52 in Huh7 HCC cells was investigated. The String database was then used to perform enrichment and functional analysis of RAD52 and its interactome. Cytoscape software was used to create a protein-protein interaction network. Molecular interaction studies with RAD52 and its interactome were performed using the molecular docking tools in Hex8.0.0. Finally, these DNA repair proteins, which interact with RAD52, were also analyzed using the TCGA dataset and were detected by qRT-PCR. Based on the TCGA database, algorithms combining ROC between RAD52 and RAD52 interactors were used to diagnose HCC by binary logistic regression.ResultsIn TCGA, upregulated RAD52 related to gender was obtained in HCC. The area under the receiver operating characteristic curve (AUC) of RAD52 was 0.704. The results of overall survival (OS) and recurrence-free survival (RFS) indicated no difference in the prognosis between patients with high and low RAD52 gene expression. We validated that RAD52 expression was increased at the mRNA and protein levels in Chinese HCC tissues compared with adjacent tissues. Higher RAD52 was associated with older age, without correlation with other clinicopathological factors. In vitro, over-expressed RAD52 significantly promoted the proliferation and migration of Huh7 cells. Furthermore, RAD52 interactors (radiation sensitive 51, RAD51; X-ray repair cross complementing 6, XRCC6; Cofilin, CFL1) were also increased in HCC and participated in some biological processes with RAD52. Protein structure analysis showed that RAD52-RAD51 had the firmest binding structure with the lowest E-total energy (- 1120.5 kcal/mol) among the RAD52-RAD51, RAD52-CFL1, and RAD52-XRCC6 complexes. An algorithm combining ROC between RAD52 and its interactome indicated a greater specificity and sensitivity for HCC screening.ConclusionsOverall, our study suggested that RAD52 plays a vital role in HCC pathogenesis and serves as a potential molecular target for HCC diagnosis and treatment. This study's findings regarding the multigene prediction and diagnosis of HCC are valuable.
| S-EPMC6836504 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third-leading cause of malignancy-associated mortality worldwide. HCC cells are highly resistant to chemotherapeutic agents. Therefore, there are currently only two US Food and Drug Administration-approved drugs available for the treatment of HCC. The objective of the present study was to analyze the results of previously published high-throughput drug screening, and in vitro genomic and transcriptomic data from HCC cell lines, and to integrate the obtained results to define the underlying molecular mechanisms of drug sensitivity and resistance in HCC cells. The results of treatment with 225 different small molecules on 14 different HCC cell lines were retrieved from the Genomics of Drug Sensitivity in Cancer database and analyzed. Cluster analysis using the treatment results determined that HCC cell lines consist of two groups, according to their drug response profiles. Continued analyses of these two groups with Gene Set Enrichment Analysis method revealed 6 treatment-sensitive molecular targets (epidermal growth factor receptor, mechanistic target of rapamycin, deoxyribonucleic acid-dependent protein kinase, the Aurora kinases, Bruton's tyrosine kinase and phosphoinositide 3-kinase; all P<0.05) and partially effective drugs. Genetic and genome-wide gene expression data analyses of the determined targets and their known biological partners revealed 2 somatically mutated and 13 differentially expressed genes, which differed between drug-resistant and drug-sensitive HCC cells. Integration of the obtained data into a short molecular pathway revealed a drug treatment-sensitive signaling axis in HCC cells. In conclusion, the results of the present study provide novel drug sensitivity-associated molecular targets for the development of novel personalized and targeted molecular therapies against HCC.
| S-EPMC6006500 | biostudies-literature
Project description:BackgroundGenetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood.ResultsHere, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 'mediators' that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC.ConclusionsThis study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.
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Project description:Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth, invasion, and metastasis, and enabled the development of molecular-targeted agents. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. In addition, the combination of sorafenib with standard treatment, such as resection, ablation, transarterial embolization, and hepatic arterial infusion chemotherapy are ongoing. This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways. Finally, the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed.
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