Treatment-driven selection of chemoresistant Ewing sarcoma tumors with limited drug distribution

Castillo‐Ecija, Helena; Monterrubio, Carles; Pascual‐Pasto, Guillem; Gómez-González, Soledad; García-Domínguez, Daniel J.; Hontecillas-Prieto, Lourdes; Resa-Pares, Claudia; Burgueño, Victor; Paco, Sonia; Olaciregui, Nagore G.; Vilà-Ubach, Mònica; Restrepo-Perdomo, Camilo A.; Cuadrado‐Vilanova, Maria; Balaguer-Lluna, Leire; Perez-Jaume, Sara; Castañeda, Alicia; Santa‐María, Vicente; Roldán, Mónica; Suñol, Mariona; Álava, Enrique de; Mora, Jaume; Lavarino, Cinzia; Carcaboso, Ángel M.

doi:10.1016/j.jconrel.2020.05.032

Cited by 8 publications

(12 citation statements)

References 40 publications

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“…We selected one Ewing sarcoma tumor with low CNAs and one rhabdomyosarcoma with highly aberrant chromosomic profile for CNA analyses. Karyotype alterations of Ewing sarcoma (HSJD-ES-012) were equivalent for patient tumor and PDX models at F2 and F5 [10]. Ewing sarcoma CNA included a copy-neutral loss of heterogeneity in chromosomes 3p and 20q as previously reported [10] (see supplementary material, Figure S4).…”

Section: Cna In Patient Biopsies and Corresponding Pdxsmentioning

confidence: 57%

“…We compared the CNA profiles of tumor biopsies and PDX tissue at generations F2 and F5. We performed whole-genome analysis using the high-density array CytoScan ® HD platform (Affymetrix, Thermo Fisher Scientific, Waltham, MA, USA) as previously described [10]. Total DNA from frozen samples was digested, ligated, PCR-amplified and purified, fragmented, biotin-labeled, and hybridized according to manufacturer's instructions.…”

Section: Analysis Of Cnasmentioning

confidence: 99%

“…We used 20 of the new PDX models to evaluate the activity of irinotecan, as a model drug with established activity against pediatric solid tumors including sarcomas [10,28,29]. We reasoned that if the PDXs were truly representative of the patients' diseases, they would likely respond to this drug and such response should remain stable over successive PDX generations.…”

Section: Irinotecan Activity In Vivomentioning

confidence: 99%

“…Control groups received saline using the same regimen as treated groups. Tumor volume was measured three times a week, until day 14, in which response to treatment was evaluated as previously described [10]. We defined complete response (CR) as tumor mass <50 mm 3 and >50% reduction at the end of treatment (day 14); partial response (PR) as tumor volume regression ≥50% at day 14 but tumor volume ≥50 mm 3 ; stable disease (SD) as <50% regression and ≤25% increase in initial volume at day 14; and progressive disease as <50% regression from initial volume and >25% increase in initial volume at day 14.…”

Section: Irinotecan Activity In Vivomentioning

confidence: 99%

“…Unfortunately, intensive and multimodal treatments currently used in pediatric sarcomas have topped their efficacy [1,8,9]. A substantial proportion of patients relapse and do not respond consistently to rescue chemotherapies because of tumor evolution into a chemoresistant phenotype [10].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic value of patient‐derived xenograft engraftment in pediatric sarcomas

Castillo‐Ecija

Pascual‐Pasto

Perez-Jaume

et al. 2021

The Journal of Pathology CR

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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.

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Section: Cna In Patient Biopsies and Corresponding Pdxsmentioning

confidence: 57%

Section: Analysis Of Cnasmentioning

confidence: 99%

Section: Irinotecan Activity In Vivomentioning

confidence: 99%

Section: Irinotecan Activity In Vivomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic value of patient‐derived xenograft engraftment in pediatric sarcomas

Castillo‐Ecija

Pascual‐Pasto

Perez-Jaume

et al. 2021

The Journal of Pathology CR

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Prognostic value of xenograft engraftment in patients with metastatic high‐risk neuroblastoma

Aschero

Castillo‐Ecija

Baulenas-Farres

et al. 2023

Pediatric Blood & Cancer

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Background Successful engraftment of human cancer biopsies in immunodeficient mice correlates with the poor prognosis of patients. This was reported 30 years ago for children with neuroblastoma, but the standard of care treatment evolved significantly during the last 15 years, leading to improved survival of these patients. Here, we evaluated the association of patient‐derived xenograft (PDX) engraftment and prognosis in patients receiving up‐to‐date treatments for cancers classified as metastatic (stage M) high‐risk neuroblastoma (HR‐NB) by the International Neuroblastoma Risk Group Staging System (INRGSS). Methods We obtained biopsies from patients with stage M HR‐NB. We inoculated biopsy fragments subcutaneously in mice. We studied the association of PDX engraftment with event‐free survival (EFS) and overall survival (OS) of patients. Results Since 2009, we established 17 PDX from 97 samples of 66 patients with stage M HR‐NB, with a follow‐up of at least two years. Factors associated with higher probability of engraftment were the death as outcome (p = .0006) and the amplification of the gene MYCN in tumors (p = .0271). Patients whose biopsies established a PDX had significantly shorter EFS and OS (p = .0039 and .0002, respectively) than patients whose samples did not engraft. The association of PDX engraftment and OS was significant in patients without MYCN amplification (p = .0041), but not in patients with MYCN amplification (p = .2707). Conclusion Positive PDX engraftment is a factor related to poor prognosis and fatal outcome in patients with stage M HR‐NB treated with up‐to‐date therapies.

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