Use of patient derived orthotopic xenograft models for real-time therapy guidance in a pediatric sporadic malignant peripheral nerve sheath tumor

Fernández Rodríguez, Juana; Morales la Madrid, Andrés; Gel, Bernat; Castañeda Heredia, Alicia; Salvador, Héctor; Martínez Iniesta, María; Moutinho, Catia; Morata, Jordi; Heyn, Holger; Blanco, Ignacio; Creus Bachiller, Edgar; Capellá, Gabriel; Farré, Lourdes; Vidal, August; Soldado, Francisco; Krauel, Lucas; Suñol, Mariona; Serra, Eduard; Villanueva, Alberto; Lázaro García, Conxi

Use of patient derived orthotopic xenograft models for real-time therapy guidance in a pediatric sporadic malignant peripheral nerve sheath tumor

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dc.contributor.author Fernández Rodríguez, Juana
dc.contributor.author Morales la Madrid, Andrés
dc.contributor.author Gel, Bernat
dc.contributor.author Castañeda Heredia, Alicia
dc.contributor.author Salvador, Héctor
dc.contributor.author Martínez Iniesta, María
dc.contributor.author Moutinho, Catia
dc.contributor.author Morata, Jordi
dc.contributor.author Heyn, Holger
dc.contributor.author Blanco, Ignacio
dc.contributor.author Creus Bachiller, Edgar
dc.contributor.author Capellá, Gabriel
dc.contributor.author Farré, Lourdes
dc.contributor.author Vidal, August
dc.contributor.author Soldado, Francisco
dc.contributor.author Krauel, Lucas
dc.contributor.author Suñol, Mariona
dc.contributor.author Serra, Eduard
dc.contributor.author Villanueva, Alberto
dc.contributor.author Lázaro García, Conxi
dc.date.accessioned 2020-10-22T06:15:55Z
dc.date.available 2020-10-22T06:15:55Z
dc.date.issued 2020
dc.description.abstract Background: The aim of this study was to test the feasibility and utility of developing patient-derived orthotopic xenograft (PDOX) models for patients with malignant peripheral nerve sheath tumors (MPNSTs) to aid therapeutic interventions in real time. Patient & methods: A sporadic relapsed MPNST developed in a 14-year-old boy was engrafted in mice, generating a PDOX model for use in co-clinical trials after informed consent. SNP-array and exome sequencing was performed on the relapsed tumor. Genomics, drug availability, and published literature guided PDOX treatments. Results: A MPNST PDOX model was generated and expanded. Analysis of the patient's relapsed tumor revealed mutations in the MAPK1, EED, and CDK2NA/B genes. First, the PDOX model was treated with the same therapeutic regimen as received by the patient (everolimus and trametinib); after observing partial response, tumors were left to regrow. Regrown tumors were treated based on mutations (palbociclib and JQ1), drug availability, and published literature (nab-paclitaxel; bevacizumab; sorafenib plus doxorubicin; and gemcitabine plus docetaxel). The patient had a lung metastatic relapse and was treated according to PDOX results, first with nab-paclitaxel, second with sorafenib plus doxorubicin after progression, although a complete response was not achieved and multiple metastasectomies were performed. The patient is currently disease free 46 months after first relapse. Conclusion: Our results indicate the feasibility of generating MPNST-PDOX and genomic characterization to guide treatment in real time. Although the treatment responses observed in our model did not fully recapitulate the patient's response, this pilot study identify key aspects to improve our co-clinical testing approach in real time.
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dc.identifier.citation Fernández-Rodríguez J, Morales La Madrid A, Gel B, Castañeda Heredia A, Salvador H, Martínez-Iniesta M, Moutinho C, Morata J, Heyn H, Blanco I, Creus-Bachiller E, Capella G, Farré L, Vidal A, Soldado F, Krauel L, Suñol M, Serra E, Villanueva A, Lázaro C. Use of patient derived orthotopic xenograft models for real-time therapy guidance in a pediatric sporadic malignant peripheral nerve sheath tumor. Ther Adv Med Oncol. 2020; 12:1758835920929579. DOI: 10.1177/1758835920929579
dc.identifier.doi http://dx.doi.org/10.1177/1758835920929579
dc.identifier.issn 1758-8340
dc.identifier.uri http://hdl.handle.net/10230/45552
dc.language.iso eng
dc.publisher SAGE Publications
dc.relation.ispartof Ther Adv Med Oncol. 2020; 12:1758835920929579
dc.rights © The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
dc.subject.keyword MPNST
dc.subject.keyword PDOX model
dc.subject.keyword SNP-array
dc.subject.keyword Exome sequencing
dc.subject.keyword Personalized medicine
dc.subject.keyword Targeted drug treatment
dc.title Use of patient derived orthotopic xenograft models for real-time therapy guidance in a pediatric sporadic malignant peripheral nerve sheath tumor
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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