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.

The Immune Landscape of Osteosarcoma: Implications for Prognosis and Treatment Response

“…Furthermore, the technological progress has been paralleled, in the last two decades, by the creation of well-annotated tissue banks in different countries, including the U.S. and the U.K. and the European Union; considering the rarity of the disease, the set-up of tissue banks has greatly increased the availability of OS samples, thereby facilitating a large number of molecular analysis of pathways and genomic signatures. In the last few years, advances have also been made in OS preclinical models to test the activity of different therapeutic approaches, with the development of a large number of PDX (patient-derived xenograft) models [ 70 ]. Interestingly, the molecular alterations identified by molecular profiling of OS samples from patients were mostly recapitulated in the PDX models.…”

Functional Drug Screening in the Era of Precision Medicine

“…Shortcomings of this approach are expense, low transplantation success rate, the large number of tumor samples needed, and the time required for xenografts to grow. Transplantation success rates vary, ranging from 20 to 100% in osteosarcoma ( 40 ) and 11 to 100% in head and neck cancer, and depend on whether specimens were obtained from a primary or metastatic site ( 41 ). Likewise, in some cancer types, metastasis is not observed in vivo and some features of the tumor are not fully represented including the TME, tumor-host interactions, and local growth of PDX’s ( 40 ).…”

Chromothripsis—Explosion in Genetic Science

“…So in a recent study, it was found that chromothripsis was detected in 100% cases of malignant tumors of the peripheral nerve sheath, and in 71% cases of germ cell tumors [ 48 ]. Chromothripsis is regularly found in blood cancer, cancer of the central nervous system, in soft tissue tumors and carcinomas [ 49 , 50 ], in osteosarcoma and glioblastoma [ 8 , 51 , 52 , 53 , 54 , 55 ]. It was found that the incidence of chromothripsis in cancer is significantly higher in patients with hereditary genetic disorders associated with gene mutations in the cell cycle and DNA repair [ 56 , 57 ].…”