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

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

PROVIDER: PRJNA929912 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23283958_1.fastq.gz	Fastqsanger.gz
	SRR23283958_2.fastq.gz	Fastqsanger.gz
	SRR23283959_1.fastq.gz	Fastqsanger.gz
	SRR23283959_2.fastq.gz	Fastqsanger.gz
	SRR23283960_1.fastq.gz	Fastqsanger.gz

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

Project description:Tumor vasculature are structurally chaotic and functionally inefficient. Restoring aberrant tumor blood vessels, or “normalize” the tumor vasculature can alleviate hypoxia and enhance intra-tumoral drug delivery. However, identifying tumor vascular normalizing drugs are currently hampered by an absence of efficient screening platform. We aimed to develop a robust method to visualize, digitalize and evaluate the structural and functional changes of tumor vasculature in batch: zebrafish functional xenograft vasculature platform (zFXVP). As proof of principle, we applied zFXVP to a small compound library which has been implicated in affecting the morphology of tumor vasculature. zFXVP identified PF-502 as a durable tumor vascular normalization agent. Further molecular analysis using RNA-Seq, pharmaceutical inhibition and gene knockout indicate PF-502 can induce endothelial cell cycle arrest and simplify redundant tumor vasculature by blocking PI3K/mTOR signaling and stabilize the vessel lumen and stimulate the blood function by activating Notch1 signaling with mediating S3 cleavage. Last, in mouse tumor xenograft model, PF-502 reproduced a potent vascular normalizing effect at a sub MTD (maximum tolerated dose) and showed its ability to improve intra-tumoral drug delivery and synergize chemotherapy, which confirms the reliability of zFXVP and implicates the potential application of PF-502 in clinical practice as an adjuvant vascular normalization drug.

2023-09-13 | GSE224106 | GEO

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

Project description: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.

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