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| Status |
Public on Apr 15, 2015 |
| Title |
Effective sorafenib treatment response in a panel of genomically-characterized malignant peripheral nerve sheath tumor orthoxenograft models |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Background: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available.
Methods: We generated five patient-derived MPNST orthoxenograft models (three NF1-related and two sporadic) and performed an exhaustive histological and molecular characterization of primary MPNSTs and their corresponding orthoxenografts. Finally, orthoxenografts models were used as an in vivo pre-clinical platform to test several treatment strategies.
Results: MPNST orthoxenografts recapitulate the histopathological properties and preserve the genomic and transcriptomic status of their parental primary tumors. Additionally, they mimic distal dissemination properties in mice. Compatible with an origin in a catastrophic event and subsequent stabilization, MPNSTs contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Although preliminary, the results presented here point to clear differences between NF1-associated and sporadic MPNSTs. In accordance, mutation frequency in sporadic MPNSTs was an order of magnitude higher than in NF1-associated MPNSTs and unsupervised cluster analysis and principal component analysis (PCA) using a MPNST signature perfectly divided the samples between NF1 and sporadic MPNST. Finally, different therapeutic approaches tested in the validated orthoxenograft MPNST models, reveal that sorafenib, or in combination with doxorubicin or rapamycin caused a great tumor reduction in all models.
Conclusion: The development of a well-characterized and standardized preclinical model for MPNSTs has laid the foundations for evaluating novel therapeutic strategies in the clinical setting. Moreover, results obtained strongly support the clinical evaluation of Sorafenib in this subset of patients.
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| Overall design |
Primary MPNSTs were implanted in the sciatic nerve of nude mices to create orthoxenograft MPNST models. Several orthoxenograft passages were created. The primary tumor (when available) and passages 1 and 4 were selected for gene expression profiling to demonstrate that the orthoxenografts closely resemble their primary tumors and are stable along xenograft passages.
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| Contributor(s) |
Castellsagué J, Gel B, Fernández-Rodríguez J, Llatjós R, Blanco I, Benavente Y, Pérez-Sidelnikova D, García-del Muro J, MariaViñals J, Valdés-Mas R, Terribas E, López-Doriga A, Pujana MA, Capellá G, Puente XS, Serra E, Villanueva A, Lázaro C |
| Citation(s) |
25810463 |
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| Submission date |
Aug 04, 2014 |
| Last update date |
Jul 26, 2018 |
| Contact name |
Bernat Gel Moreno |
| E-mail(s) |
bgel@imppc.org
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| Phone |
+34935543068
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| Organization name |
Institut de Medicina Predictiva i Personalitzada del Càncer
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| Department |
Hereditary Cancer Program
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| Lab |
Genetic Variation and Cancer
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| Street address |
Ctra. de Can Ruti, camí de les escoles, s/n
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| City |
Badalona |
| State/province |
Barcelona |
| ZIP/Postal code |
08916 |
| Country |
Spain |
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| Platforms (1) |
| GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| GSM1464653 |
orthoxenograft passage 1, from NF1-associated MPNST number 1 |
| GSM1464654 |
orthoxenograft passage 4, from NF1-associated MPNST number 1 |
| GSM1464655 |
primary tumor, from NF1-associated MPNST number 2 |
| GSM1464656 |
orthoxenograft passage 1, from NF1-associated MPNST number 2 |
| GSM1464657 |
orthoxenograft passage 4, from NF1-associated MPNST number 2 |
| GSM1464658 |
primary tumor, from sporadic MPNST number 1 |
| GSM1464659 |
orthoxenograft passage 1, from sporadic MPNST number 1 |
| GSM1464660 |
primary tumor, from sporadic MPNST number 2 |
| GSM1464661 |
orthoxenograft passage 1, from sporadic MPNST number 2 |
| GSM1464662 |
orthoxenograft passage 4, from sporadic MPNST number 2 |
| GSM1464663 |
cell line, from NF1 associated MPNST cell line S462 |
| GSM1464664 |
orthoxenograft passage 1, from NF1 associated MPNST cell line S462 |
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| Relations |
| BioProject |
PRJNA257431 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE60082_RAW.tar |
52.9 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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