Integrin αvß6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus.
Theranostics
; 10(7): 2930-2942, 2020.
Article
em En
| MEDLINE
| ID: mdl-32194845
ABSTRACT
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 αvß6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvß6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology:
We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvß6-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 αvß6-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 αvß6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvß6-expressing versus αvß6-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 (100mm3) 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), ß6 expression and PDAC tumour growth.Conclusions:
The FMDV-peptide drug conjugate SG3299 showed αvß6-selectivity in vitro and in vivo and can specifically eliminate αvß6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.Palavras-chave
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Bases de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Dano ao DNA
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Integrinas
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Apoptose
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Carcinoma Ductal Pancreático
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Proteínas do Capsídeo
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Theranostics
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido