Abstract
BackgroundPancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody–drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC.MethodsWe evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo.ResultsGPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice.ConclusionsGPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.
Highlights
Pancreatic cancer (PDAC) is the most lethal malignancy
We focused on the cell membrane protein and confirmed relatively low GPC-1 expression in normal tissues relative to ESCC.[19]
GPC-1 expression in ESCC is related to poor prognosis and chemoresistance, as previously reported.[19]
Summary
Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. CONCLUSIONS: GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patientderived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer. Surgical resection and adjuvant chemotherapy improve the prognosis of pancreatic cancer, and the overall median survival reaches 3–4 years after resection.[2,3,4] On the other hand, about 80% of all patients are unresectable when they were discovered. Several clinical trials have reported to improve the prognosis of metastatic PDAC, the clinical outcome for patients with metastatic PDAC remains poor.[6,7] There is, an urgent need for new, efficacious approaches for PDAC treatment The median survival for these patients with unresectable metastatic PDAC is < 1 year, and the 5-year overall survival rate is only 6%.5 several clinical trials have reported to improve the prognosis of metastatic PDAC, the clinical outcome for patients with metastatic PDAC remains poor.[6,7] There is, an urgent need for new, efficacious approaches for PDAC treatment
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