GPC1-Targeted Immunotoxins Inhibit Pancreatic Tumor Growth in Mice via Depletion of Short-lived GPC1 and Downregulation of Wnt Signaling.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
01 06 2022
01 06 2022
Historique:
received:
21
09
2021
revised:
01
02
2022
accepted:
08
03
2022
pubmed:
22
3
2022
medline:
3
6
2022
entrez:
21
3
2022
Statut:
ppublish
Résumé
Glypican-1 (GPC1) is a cell surface proteoglycan that is upregulated in multiple types of human cancers including pancreatic cancer. Here, we investigated whether GPC1 could be a target of antibody-toxin fusion proteins (i.e., immunotoxins) for treating pancreatic cancer. We constructed a panel of GPC1-targeted immunotoxins derived from a functional domain of Pseudomonas exotoxin A. An albumin-binding domain was also introduced into the anti-GPC1 immunotoxin to improve serum half-life. Small-molecule screening was performed to identify irinotecan that shows synergistic efficacy with the immunotoxin. We showed that GPC1 was internalized upon antibody binding. Anti-GPC1 immunotoxins alone inhibited tumor growth in a pancreatic cancer xenograft model. The immunotoxin treatment reduced active β-catenin expression in tumor cells. Furthermore, immunotoxins containing an albumin-binding domain in combination with irinotecan caused pancreatic tumor regression. GPC1 expression was reduced by the immunotoxin treatment due to the degradation of the internalized GPC1 and its short cellular turnover rate. Our data indicate that the GPC1-targeted immunotoxin inhibits pancreatic tumor growth via degradation of internalized GPC1, downregulation of Wnt signaling, and inhibition of protein synthesis. The anti-GPC1 immunotoxin in combination with irinotecan thus provides a potential new treatment strategy for patients with pancreatic tumors.
Identifiants
pubmed: 35312769
pii: 682321
doi: 10.1158/1535-7163.MCT-21-0778
pmc: PMC9167738
mid: NIHMS1792647
doi:
Substances chimiques
Albumins
0
Glypicans
0
Immunotoxins
0
Irinotecan
7673326042
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
960-973Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC010891
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010891
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC BC011891
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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