Prognostic value of patient‐derived xenograft engraftment in pediatric sarcomas

Abstract

The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.

EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism

“…Evaluation of tumor volume during 21 days after the beginning of the treatment showed a higher response of EwS compared to non-EwS models (Fig. 1C), which is concordant with the potent activity of irinotecan in Ewing sarcoma PDXs 28 . When calculating tumor growth inhibition compared to tumor volume at the end of treatment (day 14), we found that growth inhibition was significantly higher in EwS PDX models (92.83%) compared to OS (33.67%) and UPS (-17.02%) (Fig.…”

Establishment of 6 pediatric rhabdomyosarcoma patient’s derived xenograft models closely recapitulating patients’ tumor characteristics

“…The analysis of clinico-pathological characteristics indicated a strong correlation between PDX establishment and patients OS, as already reported in another pediatric sarcomas platform. 23 Indeed, grafted PDXs were derived mainly from patients with very aggressive tumors. We observed a higher take rate for fusion-positive ARMS compared to ERMS, further suggesting that a more aggressive RMS histology is more likely to successfully grow in mice.…”

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

“…for peritoneal sarcomatosis (127,128)]. Although certainly technically challenging to establish, both heterotopic and orthotopic PDX models should be regarded as reference mouse RMS models due to their potential to maintain human tumor architecture, intratumoral and interpatient heterogeneity, and tumor microenvironment components, enabling their multipurpose use across various application areas (113,(129)(130)(131)(132). Figure 6 illustrates the process of selecting the preclinical mouse model based on specific utilization areas.…”