Dataset Information

Integrin ?v?6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus.

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 ?v?6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an ?v?6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an ?v?6-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 ?v?6-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 ?v?6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for ?v?6-expressing versus ?v?6-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 ?H2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), ?6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed ?v?6-selectivity in vitro and in vivo and can specifically eliminate ?v?6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.

SUBMITTER: Moore KM

PROVIDER: S-EPMC7053198 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Moore Kate M KM Desai Ami A Delgado Bea de Luxán BL Trabulo Sara Maria David SMD Reader Claire C Brown Nicholas F NF Murray Elizabeth R ER Brentnall Adam A Howard Philip P Masterson Luke L Zammarchi Francesca F Hartley John A JA van Berkel Patrick H PH Marshall John F JF

Theranostics 20200212 7

<b>Goals of investigation</b>: 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. <b>Methodology</b>: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specif ...[more]

PMID: 32194845

Similar Datasets

Project description:BACKGROUND: Foot-and-mouth disease virus (FMDV) initiates infection via recognition of one of at least four cell-surface integrin molecules ?v?1, ?v?3, ?v?6, or ?v?8 by a highly conserved Arg-Gly-Asp (RGD) amino acid sequence motif located in the G-H loop of VP1. Within the animal host, the ?v?6 interaction is believed to be the most relevant. Sub-neutralizing levels of soluble secreted ?v?6 (ss?v?6) was used as a selective pressure during passages in vitro to explore the plasticity of that interaction. RESULTS: Genetically stable soluble integrin resistant (SIR) FMDV mutants derived from A24 Cruzeiro were selected after just 3 passages in cell culture in the presence of sub-neutralizing levels of ss?v?6. SIR mutants were characterized by: replication on selective cell lines, plaque morphology, relative sensitivity to ss?v?6 neutralization, relative ability to utilize ?v?6 for infection, as well as sequence and structural changes. All SIR mutants maintained an affinity for ?v?6. Some developed the ability to attach to cells expressing heparan sulfate (HS) proteoglycan, while others appear to have developed affinity for a still unknown third receptor. Two classes of SIR mutants were selected that were highly or moderately resistant to neutralization by ss?v?6. Highly resistant mutants displayed a G145D substitution (RGD to RDD), while moderately resistant viruses exhibited a L150P/R substitution at the conserved RGD + 4 position. VP1 G-H loop homology models for the A-type SIR mutants illustrated potential structural changes within the integrin-binding motif by these 2 groups of mutations. Treatment of O1 Campos with ss?v?6 resulted in 3 SIR mutants with a positively charged VP3 mutation allowing for HS binding. CONCLUSIONS: These findings illustrate how FMDV particles rapidly gain resistance to soluble receptor prophylactic measures in vitro. Two different serotypes developed distinct capsid mutations to circumvent the presence of sub-neutralizing levels of the soluble cognate receptor, all of which resulted in a modified receptor tropism that expanded the cell types susceptible to FMDV. The identification of some of these adaptive mutations in known FMDV isolates suggests these findings have implications beyond the cell culture system explored in these studies.

Dataset Information

Integrin ?v?6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets