Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics due to dense fibrotic stroma orchestrated by Cancer Associated Pancreatic Stellate Cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein ProAgio that targets integrin αβ at a novel site and induces apoptosis in integrin αβ expressing cells. Since both CAPaSC and angiogenic endothelial cells express high levels of integrin αβ, we aim to analyze the effects of ProAgio in PDAC tumor.
Expression of integrin αβ was examined in both patient tissue and cultured cells. Effects of ProAgio on CAPaSC were analyzed by using apoptosis assay kit. Effects of ProAgio in PDAC tumor were studied in three murine tumor models, including s.c. xenograft, genetic engineered (Kras; p53; Pdx1-Cre, GEM-KPC) mice, and orthotopic KPC model.
ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of GEM-KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral IGF1 levels due to depletion of CAPaSC and consequently decreased cytidine deaminase (Cda), a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis.
Our study suggests that ProAgio is an effective PDAC treatment agent as it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhances drug delivery and Gem efficacy in PDAC tumors.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.