Genomics

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Patient-derived xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management


ABSTRACT: Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for the development of dedicated drug development programs, and this disease is too rare and heterogeneous to gather enough children into a clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas, 1 transitional liver cancer tumor, 1 hepatocellular carcinoma and two rhabdoid tumors. SNP array and mutational analysis of the parental tumors and the corresponding PLC-PDXs show high conservation of the molecular features of the parental tumors. The histology of PLC-PDXs is strikingly similar to that observed in primary tumors, and recapitulates well the heterogeneity of recurrent disease observed in the clinic. Tumor growth in the mouse is strongly associated with elevated circulating alpha-fetoprotein (AFP), low rate of necrosis/fibrosis after treatment and gain of chromosome 20, all indicators of resistance to chemotherapy and poor outcome. Accordingly, the ability of a tumor to generate PLC-PDX is predictive of poor prognosis. Exposure of PLC-PDXs to standards of care or therapeutic options already in use for other pediatric malignancies revealed unique response profiles in these models. Among these combinations, irinotecan/temozolomide induced strong tumor regression in the transitional liver cancer tumor model and on a model derived from AFP-negative relapsing HB. These results provide promising evidence that this preclinical platform can strongly contribute to accelerate the identification and diversification of anti-cancer treatment for aggressive subtypes of pediatric liver cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76100 | GEO | 2016/06/03

SECONDARY ACCESSION(S): PRJNA306228

REPOSITORIES: GEO

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