Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment
Ravi Chakra Turaga, Malvika Sharma, Falguni Mishra, Alyssa M. Krasinskas, Yi Yuan, Jenny J. Yang, Shiyuan Wang, Chun‐Feng Liu, Li Sun, Zhi‐Ren Liu
Abstract
BACKGROUND & AIMS: , we aimed to analyze the effects of ProAgio in PDAC tumor. METHODS: ; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. RESULTS: ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse-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 an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. CONCLUSIONS: Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors.