Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

TLDR

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity, evolving molecular mechanisms between diagnosis and relapse, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, the Pediatric Preclinical Testing Consortium develops patient‑derived xenografts from high‑risk childhood cancers that are often refractory to standard treatments. The consortium creates these xenograft models and employs expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We genomically characterized 261 PDX models from 37 pediatric cancers, demonstrating faithful recapitulation of histologies and subtypes, refining understanding of relapsed disease, and anticipate that these data will serve as a resource for drug development and guide rational clinical trial design.

Abstract

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.