Non-toxic fragment of botulinum neurotoxin type A and monomethyl auristatin E conjugate for targeted therapy for neuroendocrine tumors.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
14
11
2019
accepted:
20
01
2020
revised:
27
11
2019
pubmed:
8
2
2020
medline:
22
12
2021
entrez:
8
2
2020
Statut:
ppublish
Résumé
Surgical resection is the only cure for neuroendocrine tumors (NETs). However, widespread metastases have already occured by the time of initial diagnosis in many cases making complete surgical removal impossible. We developed a recombinant heavy-chain receptor binding domain (rHCR) of botulinum neurotoxin type A that can specifically target synaptic vesicle 2 (SV2), a surface receptor abundantly expressed in multiple neuroendocrine tumors. Expression of neuroendocrine differentiation markers chromogranin A (CgA) and achaete-scute complex 1 (ASCL1) were signficantly reduced when treated with rHCR. rHCR conjugated to the antimitotic agent monomethyl auristatin E (MMAE) significantly suppressed proliferation of pancreatic carcinoid (BON) and medullary thyroid cancer cells (MZ) at concentrations of 500 and 300 nM respectively, while no growth suppression was observed in pulmonary fibroblasts and cortical neuron control cell lines. In vivo, rHCR-MMAE significantly reduced tumor volume in mouse xenografts with no observed adverse effects. These data suggest recombinant HCR (rHCR) of BoNT/A preferentially targets neuroendocrine cancer without the neurotoxicity of the full BoNT/A and that SV2 is a specific and promising target for delivering drugs to neuroendocrine tumors.
Identifiants
pubmed: 32029905
doi: 10.1038/s41417-020-0167-x
pii: 10.1038/s41417-020-0167-x
doi:
Substances chimiques
Neuromuscular Agents
0
Oligopeptides
0
Botulinum Toxins, Type A
EC 3.4.24.69
monomethyl auristatin E
V7I58RC5EJ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
898-909Références
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