Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.

BACKGROUND & AIMS: Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability of these tumors. METHODS: Here we established an orthotopic engraftment technique to model a series of patient-derived tumor xenograft (PDTX) from pediatric liver cancers of all major histologic subtypes: hepatoblastoma, hepatocellular cancer and hepatocellular malignant neoplasm. We utilized standard (immuno) staining methods for histological characterization, RNA sequencing for gene expression profiling and genome sequencing for identification of druggable targets. We also adapted stem cell culturing techniques to derive two new pediatric cancer cell lines from the xenografted mice. RESULTS: The patient-derived tumor xenografts recapitulated the histologic, genetic, and biological characteristics-including the metastatic behavior-of the corresponding primary tumors. Furthermore, the gene expression profiles of the two new liver cancer cell lines closely resemble those of the primary tumors. Targeted therapy of PDTX from an aggressive hepatocellular malignant neoplasm with the MEK1 inhibitor trametinib and pan-class I PI3 kinase inhibitor NVP-BKM120 resulted in significant growth inhibition, thus confirming this PDTX model as a valuable tool to study tumor biology and patient-specific therapeutic responses. CONCLUSIONS: The novel metastatic xenograft model and the isogenic xenograft-derived cell lines described in this study provide reliable tools for developing mutation- and patient-specific therapies for pediatric liver cancer. LAY SUMMARY: Pediatric liver cancer is a rare but serious disease and no experimental animal model currently captures the complexity and metastatic capability of these tumors. We have established a novel animal model using human tumor tissue that recapitulates the genetic and biological characteristics of this cancer. We demonstrate that our patient-derived animal model, as well as two new cell lines, are useful tools for experimental therapies.

Drug-induced liver injury in children.

PURPOSE OF REVIEW: Drug-induced liver injury (DILI) is an underrecognized cause of pediatric liver disease, accounts for almost 20% of pediatric acute liver failure cases, and is a major reason for liver transplantation in the USA. This article reviews the pathogenesis of DILI, approach to diagnosis and management, and highlights recent pediatric DILI case series. RECENT FINDINGS: Select individuals have an increased propensity to develop DILI. Known genetic polymorphisms of enzymes and host factors play an important role in medication management and influence the clinical outcome in 20-25% of all drug therapies. Children are more likely to have mitochondrial dysfunction from drugs, increasing their susceptibility to severe liver injury or acute liver failure. Antibiotics and central nervous system agents account for the majority of pediatric DILI in the West, although herbals are becoming more common. SUMMARY: Clinical features of DILI vary and overlap so exclusion of other conditions, identification of latency period and risk factors, and use of a searchable database can aid evaluation. Treatment consists of cessation of the offending agent and supportive care. Areas needing further research include elucidating mechanisms, identifying at risk individuals, and therapeutic interventions.