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

doi:10.1016/j.isci.2023.107734

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

iScience. 2023 Aug 24;26(9):107734. doi: 10.1016/j.isci.2023.107734. eCollection 2023 Sep 15.

Authors

Jian Zhong¹, Chaoxin Xiao¹, Qin Chen¹, Xiangyu Pan¹, Tongtong Xu¹, Yiyun Wang¹, Wanting Hou², Lu Liu¹, Fujun Cao¹, Yulin Wang¹, Xiaoying Li², Lin Zhou³, Hanshuo Yang¹, Yu Yang², Chengjian Zhao¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
² Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, Sichuan 610041, China.
³ Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

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: Biological sciences; Cell biology; Molecular biology.