Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas

Programa de Doctorat en Biomedicina / Tesi realitzada a l'Hospital Sant Joan de Déu

Detalles Bibliográficos
Autor: Castillo Écija, Helena
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/674596
Acceso en línea:http://hdl.handle.net/10803/674596
Access Level:acceso abierto
Palabra clave:Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Osteosarcoma
Sarcoma d'Ewing
Sarcoma de Ewing
Ewing's sarcoma
Medicaments antineoplàstics
Medicamentos antineoplásicos
Antineoplastic agents
Ciències de la Salut
616
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
title Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
spellingShingle Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
Castillo Écija, Helena
Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Osteosarcoma
Sarcoma d'Ewing
Sarcoma de Ewing
Ewing's sarcoma
Medicaments antineoplàstics
Medicamentos antineoplásicos
Antineoplastic agents
Ciències de la Salut
616
title_short Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
title_full Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
title_fullStr Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
title_full_unstemmed Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
title_sort Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
dc.creator.none.fl_str_mv Castillo Écija, Helena
author Castillo Écija, Helena
author_facet Castillo Écija, Helena
author_role author
dc.contributor.none.fl_str_mv Montero Carcaboso, Ángel
Ribalta Farrés, Teresa Maria
Universitat de Barcelona. Facultat de Medicina
dc.subject.none.fl_str_mv Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Osteosarcoma
Sarcoma d'Ewing
Sarcoma de Ewing
Ewing's sarcoma
Medicaments antineoplàstics
Medicamentos antineoplásicos
Antineoplastic agents
Ciències de la Salut
616
topic Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Osteosarcoma
Sarcoma d'Ewing
Sarcoma de Ewing
Ewing's sarcoma
Medicaments antineoplàstics
Medicamentos antineoplásicos
Antineoplastic agents
Ciències de la Salut
616
description Programa de Doctorat en Biomedicina / Tesi realitzada a l'Hospital Sant Joan de Déu
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/674596
url http://hdl.handle.net/10803/674596
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 175 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869411243063771136
spelling Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomasCastillo Écija, HelenaOncologia pediàtricaOncología pediátricaTumors in childrenOsteosarcomaSarcoma d'EwingSarcoma de EwingEwing's sarcomaMedicaments antineoplàsticsMedicamentos antineoplásicosAntineoplastic agentsCiències de la Salut616Programa de Doctorat en Biomedicina / Tesi realitzada a l'Hospital Sant Joan de DéuTherapy development in cancer involves several consecutive steps including (1) the identification of the unmet medical need (disease or clinical question), (2) the establishment of clinically relevant resources or models to address such need, (3) the evaluation of therapies or experimental questions in the established models, and (4) the design and execution of clinical trials or protocols. The ambition of my PhD work was to follow the mentioned steps to build a body of results with potential clinical impact in the pediatric oncology field. Research at our institution, SJD, focuses on several types of cancers with bad prognosis, such as pediatric sarcomas. These cancers belong to a rare and heterogeneous group of skeletal and soft tissue malignancies accounting for approximately 12% of all childhood solid tumors. The most frequently occurring ones are Ewing sarcoma, osteosarcoma and rhabdomyosarcoma. With the up-to-date treatment modalities, based on surgery, radiation and chemotherapy, the 5-year survival rates of these patients have improved up to 70-80% in the last decades. However, a substantial proportion of patients relapse and do not respond consistently to rescue therapy. Whether the lack of response to therapy of these patients is due to drug delivery issues in resistant tumor cells is not completely understood. The main question I wanted to address in my work was whether patients whose tumors stop responding to anticancer medicines show diminished intratumoral drug distribution. Because this experimental question was challenging to address in the clinical setting, we needed to generate the adequate laboratory models. Thus, we established PDX models in immunodeficient mice. There is compelling evidence suggesting that PDX, at least at initial passages, reproduce the clonal heterogeneity, genetics and histology of several types of cancer. Whether this holds true for pediatric sarcomas was not sufficiently clear. Thus, we embraced an ambitious project to address (1) the identification of clinical and technical factors involved in pediatric sarcoma PDX engraftment, (2) the characterization of the stability of the PDX during initial passages, and (3) the relationship between successful PDX and patient prognosis. The main hypotheses of my work were: (1) PDX models faithfully represent pediatric sarcoma tumors established from patients at different disease stages. PDX conserve the main histology, molecular and functional properties of human tumors over successive passages in mice. (2) PDX engraftment correlates with patient prognosis. Successful establishment of PDX models helps identify patients with higher risk of recurrence and disease progression. (3) Intratumoral distribution of anticancer drugs becomes restricted due to the evolution of patient disease. Cancer cells in relapsed tumors displace chemotherapeutics from the intracellular to the extracellular tumor compartment. (4) The expression of multidrug resistance efflux transporters explains, at least partially, the shift of the intratumoral drug distribution towards the extracellular compartment upon tumor evolution in relapsed patients. To address my hypotheses, the main objectives of my thesis were: (1) To establish and characterize PDX models from biopsies and necropsies of pediatric patients diagnosed with Ewing sarcoma, osteosarcoma and rhabdomyosarcoma. To address this goal, we implanted patient samples obtained at Hospital Sant Joan de Déu in immunodeficient mice. Upon successful engraftment as PDX, we characterized the histology, genomics and response to model therapy (irinotecan) of the established tumor models over time in successive passages in mice. (2) To identify factors favoring PDX engraftment and to study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma and rhabdomyosarcoma. To address this goal, we collected clinical and technical data from the patients and the PDX, and we studied the relationship between PDX engraftment and several patient and sample factors, including disease stage (diagnosis or relapse) and patient outcome (event free survival and overall survival). (3) To detect and characterize changes in anticancer drug activity and intratumoral drug distribution during the evolution of Ewing sarcoma. To address this goal, we established pairs of PDX models from patients at diagnosis and late disease stages. In such paired PDX, we studied the activity and distribution of the model drug irinotecan and its active metabolite, SN-38. We applied the intratumoral microdialysis – tumor homogenate technique to obtain samples of PDX engrafted in mice receiving irinotecan infusions, and we calculated the unbound volume of distribution of SN-38 in the established PDX. We analyzed the expression and function of multidrug resistance efflux transporters, such as P-glycoprotein, as likely cause of the limited drug distribution and acquisition of resistance in relapsed tumors.Universitat de BarcelonaMontero Carcaboso, ÁngelRibalta Farrés, Teresa MariaUniversitat de Barcelona. Facultat de Medicina202220222022info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion175 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/674596TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6745962026-06-14T12:46:07Z
score 15,300719

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