Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

Abstract

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers

“…Written informed consent was signed by the patient or parents/legal representative and assent of the minor child according to local laws for the main study and for ancillary research studies. The establishment and molecular characterization of PDX models have been described elsewhere (79). Sequencing data and clinical annotations from patients and PDXs have been deposited in the European Genome-phenome Archive (Accession No.…”

“…Sequencing data and clinical annotations from patients and PDXs have been deposited in the European Genome-phenome Archive (Accession No. EGAS00001005935 and EGAS00001007327) (61,79).…”

“…The data presented in the study have been deposited in the European Genome-phenome Archive, accession numbers EGAS00001005935 and EGAS00001007327 (61,79).…”

“…To better understand the HLA class I status in pediatric solid cancers, we further characterized the HLA class I genotypes, antigen expression and transcriptional levels in 44 PDX models established in the context of an ancillary study of MAPPYACTS (79) and -C genes identified in the corresponding patient tumors in two out of eight osteosarcoma (GR-OS-11 and GR-OS-17) and one out of four HGG PDXs (GR-HGG-4, GBM) (Figure 11; Supplementary Table S13).…”