iScience (Sep 2023)

Zebrafish functional xenograft vasculature platform identifies PF-502 as a durable vasculature normalization drug

  • Jian Zhong,
  • Chaoxin Xiao,
  • Qin Chen,
  • Xiangyu Pan,
  • Tongtong Xu,
  • Yiyun Wang,
  • Wanting Hou,
  • Lu Liu,
  • Fujun Cao,
  • Yulin Wang,
  • Xiaoying Li,
  • Lin Zhou,
  • Hanshuo Yang,
  • Yu Yang,
  • Chengjian Zhao

Journal volume & issue
Vol. 26, no. 9
p. 107734

Abstract

Read online

Summary: Tumor vasculature often exhibits disorder and inefficiency. Vascular normalization offers potential for alleviating hypoxia and optimizing drug delivery in tumors. However, identifying effective agents is hindered by a lack of robust screening. We aimed to establish a comprehensive method using the zebrafish functional xenograft vasculature platform (zFXVP) to visualize and quantify tumor vasculature changes. Employing zFXVP, we systematically screened compounds, identifying PF-502 as a robust vascular normalization agent. Mechanistic studies showed PF-502 induces endothelial cell-cycle arrest, streamlines vasculature, and activates Notch1 signaling, enhancing stability and hemodynamics. In murine models, PF-502 exhibited pronounced vascular normalization and improved drug delivery at a sub-maximum tolerated dose. These findings highlight zFXVP’s utility and suggest PF-502 as a promising adjunctive for vascular normalization in clinical settings.

Keywords