Solid tumor therapy by selectively targeting stromal endothelial cells

Shihui Liu, Jie Liu, Qian Ma, Liu Cao, Rasem J. Fattah, Zuxi Yu, Thomas H. Bugge, Toren Finkel, Stephen H. Leppla

Research output: Contribution to journalArticlepeer-review

Abstract

Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.

Original languageEnglish (US)
Pages (from-to)E4079-E4087
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number28
DOIs
StatePublished - Jul 12 2016
Externally publishedYes

Keywords

  • Angiogenesis
  • Anthrax toxin
  • CMG2
  • TEM8
  • Tumor targeting

ASJC Scopus subject areas

  • General

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