Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models.

Area of Science:

• Pediatric Oncology
• Cancer Genomics
• Drug Discovery

Background:

• Childhood relapsed tumors exhibit poor survival due to heterogeneity and drug resistance.
• Current precision oncology, like the INFORM study, shows molecular profiling benefits only a subset of patients.
• Functional drug testing is needed to complement molecular profiling in pediatric precision oncology.

Purpose of the Study:

• To compare drug screening results from patient-derived spheroid cultures, mouse PDX, organoid-like cultures, and zebrafish PDX (zPDX) models.
• To evaluate the utility of different patient-derived models for selecting anti-cancer drugs and combinations.
• To assess the potential of in vivo zPDX drug screening as part of precision medicine platforms.

Main Methods:

• Utilized molecularly characterized tumor samples from the INFORM study.
• Established and compared four patient-derived models: spheroid cultures, mouse PDX, organoid-like cultures, and zPDX.
• Performed functional drug screening assays on all established models.

Main Results:

• Each tested model (spheroids, mouse PDX, organoids, zPDX) demonstrated unique advantages.
• The models complemented each other in identifying effective drug hits and combinations.
• In vivo zebrafish PDX drug screening showed promise as an add-on to existing functional screening methods.

Conclusions:

• Patient-derived spheroid cultures, mouse PDX, organoids, and zPDX models each offer distinct benefits for drug screening.
• Combining data from multiple functional assays enhances drug hit and combination selection for pediatric precision oncology.
• In vivo zebrafish PDX models represent a valuable and promising tool for enhancing personalized cancer therapy in children.