Patient Derived Xenografts for Genome-Driven Therapy of Osteosarcoma

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.

Keywords: PDX-derived cell lines; genome-driven therapy; mouse PDX clinical trial; osteosarcoma; patient-derived xenograft (PDX); personalized therapy..

Figure 1

Advantages and limits of the available osteosarcoma patient-derived xenografts (OS PDX) and PDX-derived experimental models. PDX models allow the amplification of patient-derived tumor samples by highly preserving genetic traits and show a higher success rate compared to primary patient-derived cell cultures. In addition, PDX models can be a source of material for the study of tumor-host immune interactions in the human immune system (HIS) reconstituted mice after gamma-irradiation and transplantation of CD34^pos human stem cells (HSC). The prompt generation of PDX-derived cell cultures can allow faster and cheaper high throughput drug screening and ex-vivo manipulation compared to PDX models. However, the setup of mouse clinical trials enrolling different OS PDX models can better reproduce the clinical heterogeneity and ensure high predictive value.

Figure 2

Development of genome-driven therapeutic approaches for OS: From PDX and preclinical in vitro and in vivo studies to molecular data and DNA/RNA-guided personalized medicine. Patient tumors, PDXs, and PDX-derived cell lines should undergo comprehensive molecular characterization, including sequencing and genetic analyses. Targeted therapies should be selected based on genomic analysis and assessed in mechanism-based preclinical studies. The results obtained can potentially guide the design of genome-driven, personalized approaches based on PDX models, including co-clinical trials and PDX clinical trials.