A tumor vessel-targeting fusion protein elicits a chemotherapeutic bystander effect in pancreatic ductal adenocarcinoma

Chun Te Chen, Yi Chun Chen, Yi Du, Zhenbo Han, Haoqiang Ying, Richard R. Bouchard, Jennifer L. Hsu, Jung Mao Hsu, Trevor M. Mitcham, Mei Kuang Chen, Hui Lung Sun, Shih Shin Chang, Donghui Li, Ping Chang, Ronald A. DePinho, Mien Chie Hung

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by a prominent desmoplastic stroma that may constrain tumor progression but also limit the access of therapeutic drugs. In this study, we explored a tumor-targeting strategy that enlists an engineered anti-angiogenic protein consisting of endostatin and cytosine deaminase linked to uracil phosphoribosyltransferase (EndoCD). This protein selectively binds to tumor vessels to compromise tumor angiogenesis and converts the non-toxic 5-fluorocytosine (5-FC) to the cytotoxic 5-fluorouracil to produce a chemotherapeutic bystander effect at the pancreatic tumor site. We found that resveratrol increased the protein stability of EndoCD through suppression of chymotrypsin-like proteinase activity and synergistically enhances EndoCD-mediated 5-FC-induced cell killing. In various PDAC mouse models, the EndoCD/5-FC/resveratrol regimen decreased intratumoral vascular density and stroma formation and enhances apoptosis in tumors cells as well as in surrounding endothelial, pancreatic stellate, and immune cells, leading to reduced tumor growth and extended survival. Thus, the EndoCD/5-FC/resveratrol combination may be an effective treatment option for PDAC.

Original languageEnglish (US)
Pages (from-to)657-672
Number of pages16
JournalAmerican Journal of Cancer Research
Volume7
Issue number3
StatePublished - Jan 1 2017
Externally publishedYes

Keywords

  • EndoCD
  • MRI
  • PDAC
  • Resveratrol
  • Two photon
  • Ultrasound

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'A tumor vessel-targeting fusion protein elicits a chemotherapeutic bystander effect in pancreatic ductal adenocarcinoma'. Together they form a unique fingerprint.

Cite this