Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas

Programa de Doctorat en Medicina i Recerca Translacional / Tesi realitzada a l'Institut de Recerca Sant Joan de Déu

Bibliographic Details
Author: Balaguer Lluna, Leire
Format: doctoral thesis
Status:Published version
Publication Date:2024
Country:España
Institution:CBUC, CESCA
Repository:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/693862
Online Access:http://hdl.handle.net/10803/693862
Access Level:Open access
Keyword:Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Ciències de la Salut
616
id ES_6e26eea5879d7a452e4c8b04872cafda
oai_identifier_str oai:www.tdx.cat:10803/693862
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
title Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
spellingShingle Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
Balaguer Lluna, Leire
Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Ciències de la Salut
616
title_short Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
title_full Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
title_fullStr Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
title_full_unstemmed Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
title_sort Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomas
dc.creator.none.fl_str_mv Balaguer Lluna, Leire
author Balaguer Lluna, Leire
author_facet Balaguer Lluna, Leire
author_role author
dc.contributor.none.fl_str_mv Montero Carcaboso, Ángel
Ribalta Farrés, Teresa María
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Ciències de la Salut
616
topic Oncologia pediàtrica
Oncología pediátrica
Tumors in children
Ciències de la Salut
616
description Programa de Doctorat en Medicina i Recerca Translacional / Tesi realitzada a l'Institut de Recerca Sant Joan de Déu
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
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/10803/693862
url http://hdl.handle.net/10803/693862
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 152 p.
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_ 1869410404446240768
spelling Inhibition of the PI3K/Akt pathway as a therapeutic strategy for pediatric-type diffuse high-grade gliomasBalaguer Lluna, LeireOncologia pediàtricaOncología pediátricaTumors in childrenCiències de la Salut616Programa de Doctorat en Medicina i Recerca Translacional / Tesi realitzada a l'Institut de Recerca Sant Joan de Déu[eng] This thesis aims to contribute to the field of therapy development in pHGG. These deadly cancers infiltrate structures such as the brainstem, cerebellum, thalamus and spinal cord, rendering surgery unfeasible. All pharmacological approaches for patients with pHGG have failed in clinical trials, partly because the BBB remains intact, impeding CNS drug distribution, and partly because we have not evaluated the right medicines. The RTK-PI3K-MAPK axis is altered in more than 60% of the pHGG. Activating mutations and amplifications of the PI3K/Akt pathway are shared by 40% of DIPG. These tumorigenic alterations are likely actionable with novel small molecule medicines, provided that such medicines cross the BBB. In this thesis work, I hypothesized that the inhibition of the PI3K/Akt pathway is a therapeutic strategy for human pHGG xenografts in mice bearing mutations in the gene PIK3CA. To address my hypothesis, the main objectives of my thesis were: i. To establish preclinical pHGG models covering most of the subclasses of the disease, and to compare the methods of paraffin tissue analysis, liquid biopsy of CSF and mouse weight monitoring to assess tumor burden in mice with orthotopic pHGG xenografts. I will develop ddPCR methods to quantify allele frequencies of human genes H3F3A K27M, H3F3A G34R and ACVR1 R206H in mouse samples. I will use the developed methods to evaluate the preclinical activity of potential therapeutic candidates, including ACVR1 inhibitors, ONC201, trametinib and taselisib in DIPG xenografts. ii. To characterize the PI3K/Akt/mTOR pathway in preclinical pHGG models and in patients diagnosed with DIPG. In preclinical models, I will use next generation sequencing (NGS) technology to detect the alterations in the PI3K/Akt pathway. I will measure RNA and protein expression related to the activation of the pathway. In samples from patients diagnosed with pHGG, I will analyse markers of the pathway using immunoassays. iii. To test the efficacy and CNS drug distribution of the PI3K/Akt pathway inhibitors ipatasertib and inavolisib in pHGG xenografts. I will evaluate the pharmacodynamic profile of both candidate drugs in DIPG models in vitro. I will measure their preclinical efficacy, selectivity for the tumor and distribution in the blood, CSF and brain in mice bearing DIPG intracranial xenografts with conserved BBB.Universitat de BarcelonaMontero Carcaboso, ÁngelRibalta Farrés, Teresa MaríaUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut202520252024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion152 p.application/pdfhttp://hdl.handle.net/10803/693862TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6938622026-06-14T12:46:07Z
score 15,812429

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