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 alphavbeta6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an alphavbeta6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an alphavbeta6-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 alphavbeta6-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 alphavbeta6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for alphavbeta6-expressing versus alphavbeta6-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 gammaH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), beta6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed alphavbeta6-selectivity in vitro and in vivo and can specifically eliminate alphavbeta6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.