Cargando…

Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus

Goals of investigation: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develo...

Descripción completa

Detalles Bibliográficos
Autores principales: Moore, Kate M., Desai, Ami, Delgado, Bea de Luxán, Trabulo, Sara Maria David, Reader, Claire, Brown, Nicholas F., Murray, Elizabeth R., Brentnall, Adam, Howard, Philip, Masterson, Luke, Zammarchi, Francesca, Hartley, John A., van Berkel, Patrick H., Marshall, John F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053198/
https://www.ncbi.nlm.nih.gov/pubmed/32194845
http://dx.doi.org/10.7150/thno.38702
_version_ 1783502994817417216
author Moore, Kate M.
Desai, Ami
Delgado, Bea de Luxán
Trabulo, Sara Maria David
Reader, Claire
Brown, Nicholas F.
Murray, Elizabeth R.
Brentnall, Adam
Howard, Philip
Masterson, Luke
Zammarchi, Francesca
Hartley, John A.
van Berkel, Patrick H.
Marshall, John F.
author_facet Moore, Kate M.
Desai, Ami
Delgado, Bea de Luxán
Trabulo, Sara Maria David
Reader, Claire
Brown, Nicholas F.
Murray, Elizabeth R.
Brentnall, Adam
Howard, Philip
Masterson, Luke
Zammarchi, Francesca
Hartley, John A.
van Berkel, Patrick H.
Marshall, John F.
author_sort Moore, Kate M.
collection PubMed
description Goals of investigation: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511). PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC. Immunohistochemical analyses were performed to establish therapeutic mechanism. Results: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better). Moreover, SG3299 eliminated established (100mm(3)) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005). Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.
format Online
Article
Text
id pubmed-7053198
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-70531982020-03-19 Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus Moore, Kate M. Desai, Ami Delgado, Bea de Luxán Trabulo, Sara Maria David Reader, Claire Brown, Nicholas F. Murray, Elizabeth R. Brentnall, Adam Howard, Philip Masterson, Luke Zammarchi, Francesca Hartley, John A. van Berkel, Patrick H. Marshall, John F. Theranostics Research Paper Goals of investigation: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511). PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC. Immunohistochemical analyses were performed to establish therapeutic mechanism. Results: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better). Moreover, SG3299 eliminated established (100mm(3)) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005). Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer. Ivyspring International Publisher 2020-02-12 /pmc/articles/PMC7053198/ /pubmed/32194845 http://dx.doi.org/10.7150/thno.38702 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Moore, Kate M.
Desai, Ami
Delgado, Bea de Luxán
Trabulo, Sara Maria David
Reader, Claire
Brown, Nicholas F.
Murray, Elizabeth R.
Brentnall, Adam
Howard, Philip
Masterson, Luke
Zammarchi, Francesca
Hartley, John A.
van Berkel, Patrick H.
Marshall, John F.
Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
title Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
title_full Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
title_fullStr Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
title_full_unstemmed Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
title_short Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
title_sort integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053198/
https://www.ncbi.nlm.nih.gov/pubmed/32194845
http://dx.doi.org/10.7150/thno.38702
work_keys_str_mv AT moorekatem integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT desaiami integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT delgadobeadeluxan integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT trabulosaramariadavid integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT readerclaire integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT brownnicholasf integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT murrayelizabethr integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT brentnalladam integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT howardphilip integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT mastersonluke integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT zammarchifrancesca integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT hartleyjohna integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT vanberkelpatrickh integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus
AT marshalljohnf integrinavb6specifictherapyforpancreaticcancerdevelopedfromfootandmouthdiseasevirus