A Clinically Integrated Pediatric Patient-Derived Xenograft Program Enables Evaluation of Cohort and Patient-Specific Biology and Therapeutic Strategies.
UNLABELLED: Preclinical translational research has increasingly utilized patient-derived xenograft (PDX) models for mechanistic and experimental therapeutic studies, yet most existing models have been developed from adult cancer types. We describe the establishment of a PDX program to expand the availability of pediatric-specific PDXs for preclinical research and enable studies of pediatric cancer histologies, including ultrarare diseases. Processes for PDX generation were integrated into established clinical workflows to facilitate universal model generation. Methodologies for tissue procurement, processing, and cryopreservation were optimized to enable intra- and interinstitutional PDX model generation. Over a 6-year span, 388 PDX tumor models representing more than 40 diagnoses were generated, including ultrarare tumors and longitudinal models established from pretherapy, posttherapy, and relapse tumors from the same patient. Genomic characterization of these PDXs demonstrates excellent concordance and recapitulation of molecular alterations of the source tumor. Successful PDX generation was enhanced from relapsed samples, was higher in sarcomas compared with other solid tumor types, and was a negative prognosticator for clinical outcome. With a broad portfolio of molecularly annotated models, we demonstrate utility for validating cross-histology biomarker-driven therapeutic strategies by demonstrating antitumor activity of an MAT2A inhibitor in MTAP-deficient PDXs. Universal model creation also allows for experimental validation of therapeutic hypotheses on a patient-specific basis, as we describe the characterization of a novel RAF1 fusion (EPB41L2::RAF1) in an osteosarcoma PDX. Development of a diverse collection of pediatric PDX models enables hypothesis-driven and cross-histology studies that expand our understanding of cancer biology and aid ongoing drug prioritization efforts in rare tumors. SIGNIFICANCE: A clinically integrated, genomically annotated pediatric PDX portfolio supported by systematic benchmarking of model generation facilitates exploratory biomarker-driven and patient-specific translational studies.