Abstract
Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone. It is characterized by a complex genotype, mainly due to the high frequency of chromothripsis, which leads to multiple somatic copy number alterations and structural rearrangements. Any effort to design genome-driven therapies must therefore consider such high inter- and intra-tumor heterogeneity. Therefore, many laboratories and international networks are developing and sharing OS patient-derived xenografts (OS PDX) to broaden the availability of models that reproduce OS complex clinical heterogeneity. OS PDXs, and new cell lines derived from PDXs, faithfully preserve tumor heterogeneity, genetic, and epigenetic features and are thus valuable tools for predicting drug responses. Here, we review recent achievements concerning OS PDXs, summarizing the methods used to obtain ectopic and orthotopic xenografts and to fully characterize these models. The availability of OS PDXs across the many international PDX platforms and their possible use in PDX clinical trials are also described. We recommend the coupling of next-generation sequencing (NGS) data analysis with functional studies in OS PDXs, as well as the setup of OS PDX clinical trials and co-clinical trials, to enhance the predictive power of experimental evidence and to accelerate the clinical translation of effective genome-guided therapies for this aggressive disease.
Highlights
Osteosarcoma (OS) is a highly aggressive bone tumor
This Review describes recent advancements in OS patient-derived xenografts (OS patient-derived xenograft (PDX)), summarizes the methods for ectopic or orthotopic engraftment in immunodeficient mice, the available models, and the international repositories, and illustrates the utility of PDXs in clinical decision-making, such as the categorization of genetic-driven drug responses, to accelerate the translation of new targeted drugs into the clinics
3D systems using OS PDX-derived cell lines faithfully recapitulating the behavior of human tumors represent dynamic models that may help scientists to assess the efficacy of therapeutic treatments in an appropriate cellular context
Summary
Osteosarcoma (OS) is a highly aggressive bone tumor. Representing no more than 0.2% of all malignant tumors, it is classified as a rare tumor, but its social impact is relevant because the primary peak of tumor onset is in childhood and adolescence [1,2,3]. OS PDXs and new cell lines derived from PDXs have been shown to closely maintain the phenotypic and genotypic properties of the tumor of origin [12,13,14], including genetic and epigenetic features, inter-and intra-tumor heterogeneity, and drug sensitivity [15]. This Review describes recent advancements in OS PDXs, summarizes the methods for ectopic or orthotopic engraftment in immunodeficient mice, the available models, and the international repositories, and illustrates the utility of PDXs in clinical decision-making, such as the categorization of genetic-driven drug responses, to accelerate the translation of new targeted drugs into the clinics. The setup of mouse clinical trials enrolling different OS PDX models can better reproduce the clinical heterogeneity and ensure high predictive value
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