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Abstract: We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.
Fuente: EMBO Mol Med . 2022 Mar 7;14(3):e14552
Publisher: Wiley-Blackwell
Year of publication: 2022
No. of pages: 29
Publication type: Article
DOI: 10.15252/emmm.202114552
ISSN: 1757-4676,1757-4684
Spanish project: SAF2017-89643-R
Publication Url: https://www.doi.org/10.15252/emmm.202114552
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ZHU, LUCÍA
RETANA, DIANA
GARCÍA-GÓMEZ, PEDRO
ÁLVARO-ESPINOSA, LAURA
PRIEGO, NEIBLA
MASMUDI-MARTÍN, MARIAM
YEBRA, NATALIA
MIARKA, LAURITZ
HERNÁNDEZ-ENCINAS, ELENA
BLANCO-APARICIO, CARMEN
MARTÍNEZ, SONIA
SOBRINO, CECILIA
AJENJO, NURIA
ARTIGA, MARIA-JESUS
ORTEGA-PAINO, EVA
TORRES-RUIZ, RAÚL
RODRÍGUEZ-PERALES, SANDRA
SOFFIETTI, RICCARDO
BERTERO, LUCA
MIGUEL ANGEL LAFARGA COSCOJUELA
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