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A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

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

Authorship

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