Multikinase Treatment of Glioblastoma : Evaluating the Rationale for Regorafenib
Muñoz-Mármol, Ana Maria (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Meléndez, Bárbara (Complejo Hospitalario de Toledo)
Hernández, Ainhoa (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Sanz, Carolina (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Domènech, Marta (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Arpí-Llucia, Oriol (Institut Hospital del Mar d'Investigacions Mèdiques)
Gut, Marta (Universitat de Barcelona)
Esteve, Anna (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Esteve-Codina, Anna (Universitat de Barcelona)
Parra, Genis (Universitat de Barcelona)
Carrato, Cristina (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Aldecoa, Iban (Universitat de Barcelona)
Mallo, Maria del Mar (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Pineda, Estela (Hospital Clínic i Provincial de Barcelona)
Alameda, Francesc (Institut Hospital del Mar d'Investigacions Mèdiques)
de la Iglesia, Nuria (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Martínez Balibrea, Eva (Institut Germans Trias i Pujol)
Martínez Cardús, Anna (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Estival, Anna (Hospital Universitario Insular de Gran Canaria)
Balañá, Carmen (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Date:	2025
Abstract:	For a targeted drug to be effective, the target must be present. To determine if this condition was met for regorafenib in glioblastoma, we analyzed 46 genes encoding protein kinases (PKs) inhibited by regorafenib in preclinical studies. We further focused on a subset of 18 genes encoding PKs inhibited by regorafenib at clinically achievable concentrations, which-together with the anti-angiogenetic activity of regorafenib-constituted the rationale for the REGOMA and AGILE trials. Oncogenic/likely oncogenic mutations, gene amplification, fusions, and/or gene overexpression indicated a potential regorafenib target. Thirty-four (33%) and twenty-six (25. 2%) patients harbored at least one such alteration in the 46- and 18-gene sets, respectively. However, these results may overestimate the effectiveness of regorafenib due to its difficulty in penetrating the blood-brain barrier to reach the target. Future use of multi-target drugs should be guided by a thorough understanding of target presence and the drug's ability to reach the target. We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib's binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs.
Grants:	Fundació la Marató de TV3 665/C/2013 Instituto de Salud Carlos III PI18/01062
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Glioblastoma ; Multikinase treatment ; Regorafenib ; Molecular target
Published in:	Cancers, Vol. 17 (january 2025) , ISSN 2072-6694

DOI: 10.3390/cancers17030375
PMID: 39941744

17 p, 1.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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