Glypican-3 antibodies: a new therapeutic target for liver cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Feng M
PROVIDER: S-EPMC3947105 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
Publications
Glypican-3 antibodies: a new therapeutic target for liver cancer.
FEBS letters 20131015 2
Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation. He ...[more]
Similar Datasets
Project description:Glypican-3 (GPC3) is an oncogene, frequently upregulated in liver malignancies such as hepatocellular carcinoma (HCC) and hepatoblastoma and constitutes a potential molecular target for therapy in liver cancer. Using a functional screening system, we identified 10 new microRNAs controlling GPC3 expression in malignant liver cells, five of them e.g. miR-4510, miR-203a-3p, miR-548aa, miR-376b-3p and miR-548v reduce GPC3 expression. These 5 microRNAs were significantly downregulated in tumoral compared to non-tumoral liver and inhibited tumor cell proliferation. Interestingly, miR-4510 inversely correlated with GPC3 mRNA and protein in HCC samples. This microRNA also induced apoptosis of hepatoma cells and blocked tumor growth in vivo in the chick chorioallantoic membrane model. We further show that the tumor suppressive effect of miR-4510 is mediated through direct targeting of GPC3 mRNA and inactivation of Wnt/?-catenin transcriptional activity and signaling pathway. Moreover, miR-4510 up-regulated the expression of several tumor suppressor genes while reducing the expression of other pro-oncogenes. In summary, we uncovered several new microRNAs targeting the oncogenic functions of GPC3. We provided strong molecular, cellular and in vivo evidences for the tumor suppressive activities of miR-4510 bringing to the fore the potential value of this microRNA in HCC therapy.
| S-EPMC5522324 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide. There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches. Herein, we review the structure, function and biology of glypican-3 (GPC3) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. GPC3 is a cell-surface protein that is over-expressed in HCC. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog (Hh) signalling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC.
| S-EPMC3031711 | biostudies-other
Project description:Osteosarcoma (OS) is the most common bone malignancy without a reliable therapeutic target. Glypican-3 (GPC3) mutation and upregulation have been detected in multidrug resistant OS, and anti-GPC3 immunotherapy can effectively suppress the growth of organoids. Further profiling of GPC3 mutations and expression patterns in OS is of clinical significance. To address these issues, fresh OS specimens were collected from 24 patients for cancer-targeted next-generation sequencing (NGS) and three-dimensional patient-derived organoid (PDO) culture. A tumor microarray was prepared using 37 archived OS specimens. Immunohistochemical (IHC) staining was performed on OS specimens and microarrays to profile GPC3 and CD133 expression as well as intratumoral distribution patterns. RT-PCR was conducted to semiquantify GPC3 and CD133 expression levels in the OS tissues. Anti-GPC3 immunotherapy was performed on OS organoids with or without GPC3 expression and its efficacy was analyzed using multiple experimental approaches. No OS cases with GPC3 mutations were found, except for the positive control (OS-08). IHC staining revealed GPC3 expression in 73.77% (45/61) of OSs in weak (+; 29/45), moderate (++; 8/45), and strong (+++; 8/45) immunolabeling densities. The intratumoral distribution of GPC3-positive cells was variable in the focal (+; 10%-30%; 8/45), partial (++; 31%-70%; 22/45), and the most positive patterns (+++; >71%; 15/45), which coincided with CD133 immunolabeling (P = 9.89 × 10-10 ). The anti-GPC3 antibody efficiently inhibits Wnt/β-catenin signaling and induces apoptosis in GPC3-positive PDOs and PDXs, as opposed to GPC3-negative PDOs and PDXs. The high frequency of GPC3 and CD133 co-expression and the effectiveness of anti-wild-type GPC3-Ab therapy in GPC3-positive OS models suggest that GPC3 is a novel prognostic parameter and a promising therapeutic target for osteosarcoma.
| S-EPMC9530858 | biostudies-literature
Project description:Transmembrane-4 L-six family member-1 (TM4SF1) is a small plasma membrane glycoprotein that regulates cell motility and proliferation. TM4SF1 is an attractive cancer target because of its high expression in both tumor cells and on the vascular endothelial cells lining tumor blood vessels. We generated mouse monoclonal antibodies against human TM4SF1 in order to evaluate their therapeutic potential; 13 of the antibodies we generated reacted with extracellular loop-2 (EL2), TM4SF1's larger extracellular, lumen-facing domain. However, none of these antibodies reacted with mouse TM4SF1, likely because the EL2 of mouse TM4SF1 differs significantly from that of its human counterpart. Therefore, to test our antibodies in vivo, we employed an established model of engineered human vessels in which human endothelial colony-forming cells (ECFC) and human mesenchymal stem cells (MSC) are incorporated into Matrigel plugs that are implanted subcutaneously in immunodeficient nude mice. We modified the original protocol by (1) preculturing human ECFC on laminin, fibronectin, and collagen-coated plates, and (2) increasing the ECFC/MSC ratio. These modifications significantly increased the human vascular network in Matrigel implants. Two injections of one of our anti-TM4SF1 EL2 monoclonal antibodies, 8G4, effectively eliminated the human vascular component present in these plugs; they also abrogated human PC3 prostate cancer cells that were incorporated into the ECFC/MSC Matrigel mix. Together, these studies provide a mouse model for assessing tumor xenografts that are supplied by a human vascular network and demonstrate that anti-TM4SF1 antibodies such as 8G4 hold promise for cancer therapy.
| S-EPMC4177288 | biostudies-literature
Project description:Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.
| S-EPMC9456355 | biostudies-literature
Project description:Liver cancer is the sixth most common cancer and the fourth most fatal cancer in the world. Immunotherapy has already achieved modest results in the treatment of liver cancer. Meanwhile, the novel and optimal combinatorial strategies need further research. The complement system, which consists of mediators, receptors, cofactors and regulators, acts as the connection between innate and adaptive immunity. Recent studies demonstrate that complement system can influence tumor progression by regulating the tumor microenvironment, tumor cells, and cancer stem cells in liver cancer. Our review concentrates on the potential role of the complement system in cancer treatment, which is a promising strategy for killing tumor cells by the activation of complement components. Conclusions: Our review demonstrates that complement components and regulators might function as biomarkers and therapeutic targets for liver cancer diagnosis and treatment.
| S-EPMC9604633 | biostudies-literature
Project description:IntroductionHepatocellular carcinoma (HCC) is one of the most common and lethal cancers. Progress has been made in treatment of HCC; however, improved outcomes are much needed. The increased metabolic needs of cancer cells underscore the importance of metabolic pathways in cancer cell survival. Lipid metabolism has a role in HCC development; aberrant overexpression of several key enzymes is seen in many solid human tumors. Areas covered: We discuss aberrant lipid metabolism and the promise of multiple targets, in particular related to HCC treatment. We searched PubMed and clinicaltrials.gov for published and unpublished studies from 2000 to 2019. These terms were used: lipids, fatty acid metabolism, lipid metabolism, liver cancer, HCC, de novo fatty acid synthesis, ATP citrate lyase, stearoyl CoA denaturase, fatty acid synthase, acetyl coenzyme A carboxylase, CD147, KLF4, monoglyceride lipase, AMP activated protein kinase. Expert opinion: The importance of dysregulation of fatty acid synthesis in cancer is a growing area of research. HCC demonstrates significant alteration in lipid metabolism, representing great potential as a target for novel therapeutics. Various agents have demonstrated promising anti-neoplastic activity. This strategy deserves further development for improved outcomes.
| S-EPMC6594827 | biostudies-literature
Project description:Background: Increasing evidences have shown that abnormal alternative splicing (AS) events are closely related to the prognosis of various tumors. However, the role of AS in ovarian cancer (OV) is poorly understood. This study aims to explore the correlation between AS and the prognosis of OV and establish a prognostic model for OV. Methods: We downloaded the RNA-seq data of OV from The Cancer Genome Atlas databases and assessed cancer-specific AS through the SpliceSeq software. Then systemically investigated the overall survival (OS)-related AS and splicing factors (SFs) by bioinformatics analysis. The nomogram was established based on the clinical information, and the clinical practicability of the nomogram was verified through the calibration curve. Finally, a splicing correlation network was constructed to reveal the relationship between OS-related AS and SFs. Results: A total of 48,049 AS events were detected from 10,582 genes, of which 1523 were significantly associated with OS. The area under the curve of the final prediction model was 0.785, 0.681, and 0.781 in 1, 3, and 5 years, respectively. Moreover, the nomogram showed high calibration and discrimination in OV patients. Spearman correlation analysis was used to determine 8 SFs significantly related to survival, including major facilitator superfamily domain containing 11, synaptotagmin binding cytoplasmic RNA interacting protein, DEAH-box helicase 35, CWC15, integrator complex subunit 1, LUC7 like 2, cell cycle and apoptosis regulator 1, and heterogeneous nuclear ribonucleoprotein A2/B1. Conclusion: This study provides a prognostic model related to AS in OV, and constructs an AS-clinicopathological nomogram, which provides the possibility to predict the long-term prognosis of OV patients. We have explored the wealth of RNA splicing networks and regulation patterns related to the prognosis of OV, which provides a large number of biomarkers and potential targets for the treatment of OV. Put forward the potential possibility of interfering with the AS of OV in the comprehensive treatment of OV.
| S-EPMC8966091 | biostudies-literature
Project description:A critical step for maintenance of genetic stability is chromosome segregation, which requires a high coordination of cellular processes. Loss of mitotic regulation is a possible cause of aneuploidy in human epithelial malignancy and it is thought to create an abnormal nuclear morphology in cancer cells. Serine/threonine protein kinase Aurora B gene plays a regulatory role from G2 to cytokinesis, encompassing key cell cycle events such as centrosome duplication, chromosome bi-orientation, and segregation. The overexpression of Aurora B has been observed in several tumour types, and has been linked with a poor prognosis for cancer patients. Therapeutic inhibition of Aurora kinase showed great promise as a probable anticancer regime because of its important role during cell division.
| S-EPMC5982624 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies.
| S-EPMC5086635 | biostudies-literature