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Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus.
- Source :
-
Theranostics [Theranostics] 2020 Feb 12; Vol. 10 (7), pp. 2930-2942. Date of Electronic Publication: 2020 Feb 12 (Print Publication: 2020). - Publication Year :
- 2020
-
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 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 <superscript>3</superscript> ) 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.<br />Competing Interests: Competing Interests: Philip Howard, Francesca Zammarchi, Patrick H. van Berkel and John A. Hartley are employees and/or shareholders of ADC Therapeutics. All other authors declare no conflicts of interest.<br /> (© The author(s).)
- Subjects :
- Animals
Antigens, Neoplasm
Benzodiazepines therapeutic use
Cell Line, Tumor
Female
Humans
Mice
Mice, Knockout
Peptides therapeutic use
Pyrroles therapeutic use
Apoptosis drug effects
Capsid Proteins therapeutic use
Carcinoma, Pancreatic Ductal drug therapy
DNA Damage drug effects
Integrins antagonists & inhibitors
Pancreatic Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 32194845
- Full Text :
- https://doi.org/10.7150/thno.38702