Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis

Gao, Wei; Tang, Zhewei; Zhang, Yifan; Feng, Mingqian; Qian, Min; Dimitrov, Dimiter S.; Ho, Mitchell

doi:10.1038/ncomms7536

Cited by 120 publications

(150 citation statements)

References 49 publications

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“…Interestingly, single-domain antibodies have the ability to bind in protein clefts or hidden substrate pockets not accessible to conventional antibodies (46,47). We previously identified a human single-domain antibody that recognizes a cryptic functional site on GPC3 and inhibits Wnt signaling in liver cancer (48). In the present study, we isolated a group of seven representative binders specific for GPC2, and all of these single-domain antibodies significantly inhibited Wnt/β-catenin signaling in neuroblastoma cells.…”

Section: Discussionmentioning

confidence: 74%

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

Hewitt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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107

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Neuroblastoma is a childhood cancer that is fatal in almost half of patients despite intense multimodality treatment. This cancer is derived from neuroendocrine tissue located in the sympathetic nervous system. Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite outgrowth. In this study, we find that GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression. We demonstrate that silencing of GPC2 by CRISPR-Cas9 or siRNA results in the inhibition of neuroblastoma tumor cell growth. GPC2 silencing inactivates Wnt/ β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. We have isolated human single-domain antibodies specific for GPC2 by phage display technology and found that the single-domain antibodies can inhibit active β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a. To explore GPC2 as a potential target in neuroblastoma, we have developed two forms of antibody therapeutics, immunotoxins and chimeric antigen receptor (CAR) T cells. Immunotoxin treatment was demonstrated to inhibit neuroblastoma growth in mice. CAR T cells targeting GPC2 eliminated tumors in a disseminated neuroblastoma mouse model where tumor metastasis had spread to multiple clinically relevant sites, including spine, skull, legs, and pelvis. This study suggests GPC2 as a promising therapeutic target in neuroblastoma.glypican | neuroblastoma | single-domain antibody | chimeric antigen receptor T-cell therapy | immunotoxin

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Section: Discussionmentioning

confidence: 74%

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

Hewitt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

107

124

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“…Apart from activating mutations several additional mechanisms exist for Wnt pathway activation in HCC, including TGFβ pathway activation, Wnt3a upregulation and overexpression of frizzled receptors. Hence inhibiting the Wnt pathway is an area of active interest and promising results have been reported recently using antibodies directed against GPC3, which inhibit the Wnt pathway (79). Mutations in p53 are also very common in HCC, but so far this has molecule has not proven to be a suitable target for drug development (78).…”

Section: Treatment Of Hcc – Focus On Molecular Targeted Therapiesmentioning

confidence: 99%

Clinical implications of basic research in hepatocellular carcinoma

Dhanasekaran

Venkatesh

Torbenson

et al. 2016

Journal of Hepatology

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Clinical Vignette A 58-year old Caucasian female has compensated hepatitis C related cirrhosis. Her surveillance ultrasound showed hypodense liver nodules and subsequent triple phase CT scan showed five tumor nodules with diameters ranging from 3-5 cms involving both hepatic lobes. The nodules showed characteristic radiologic findings on the CT scan and she was diagnosed with hepatocellular carcinoma (HCC) based on non-invasive criteria. There was also associated right portal vein tumor thrombosis. Her functional capacity at diagnosis was slightly limited, but she was capable of performing all activities of daily living and self-care. Her laboratory tests at diagnosis were as follows: Na 129, K 3.6, BUN 22, creatinine 1.0, albumin 2.9, bilirubin 1.8, ALT 87, AST 68, Alk Phos 139, WBC 3.5, Hgb 10.4, Plt 73,000, INR 1.9 and AFP 5200 ng/ml. An upper endoscopy was negative for esophageal or gastric varices. Based on the tumor burden, presence of macrovascular invasion, ECOG performance status of 1 and Child Pugh class A she was classified to have BCLC stage C HCC. She was started on sorafenib therapy at 400 mg oral twice daily but unfortunately this had to be discontinued since she experienced severe diarrhea and skin rash. She now returns for follow up and requests information on the available therapeutic options. This particular case scenario is not uncommon and does raise several clinically relevant questions: Should her liver lesions have been biopsied for diagnosis?Are there any serum or tissue biomarkers that could have helped in prognostication?Was sorafenib the best first option for her and were there any biomarkers that could have predicted the adverse reactions she experienced?What other potential therapies will be available for her in the near future? This review provides a comprehensive overview of the current state of HCC management and also examines the clinical implications of recent basic research in HCC.

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“…Immunohistochemical analysis indicated that downregulation of GPC-3 with miRNA significantly (p < 0.01) decreases expression of β-catenin, p-GSK3β, and cyclin D1. β-catenin and GSK3β are known to play an important role in regulating metabolism, transcription, embryonic development, and other processes and to also play a key role in the Wnt/β-catenin-induced phosphorylation of GSK3β, which results in the dissolution of the complex responsible for β-catenin degradation (62,63). A therapeutic intervention targeting GPC-3 is a promising approach for the clinical management of HCC.…”

Section: Studies In Vivomentioning

confidence: 99%

Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma

Yao

Wang

Miao

et al. 2016

BST

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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis

Cited by 120 publications

References 49 publications

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

Clinical implications of basic research in hepatocellular carcinoma

Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma

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