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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.

SUBMITTER: Zhu L 

PROVIDER: S-EPMC8899920 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

Zhu Lucía L   Retana Diana D   García-Gómez Pedro P   Álvaro-Espinosa Laura L   Priego Neibla N   Masmudi-Martín Mariam M   Yebra Natalia N   Miarka Lauritz L   Hernández-Encinas Elena E   Blanco-Aparicio Carmen C   Martínez Sonia S   Sobrino Cecilia C   Ajenjo Nuria N   Artiga Maria-Jesus MJ   Ortega-Paino Eva E   Torres-Ruiz Raúl R   Rodríguez-Perales Sandra S   Soffietti Riccardo R   Bertero Luca L   Cassoni Paola P   Weiss Tobias T   Muñoz Javier J   Sepúlveda Juan Manuel JM   González-León Pedro P   Jiménez-Roldán Luis L   Moreno Luis Miguel LM   Esteban Olga O   Pérez-Núñez Ángel Á   Hernández-Laín Aurelio A   Toldos Oscar O   Ruano Yolanda Y   Alcázar Lucía L   Blasco Guillermo G   Fernández-Alén José J   Caleiras Eduardo E   Lafarga Miguel M   Megías Diego D   Graña-Castro Osvaldo O   Nör Carolina C   Taylor Michael D MD   Young Leonie S LS   Varešlija Damir D   Cosgrove Nicola N   Couch Fergus J FJ   Cussó Lorena L   Desco Manuel M   Mouron Silvana S   Quintela-Fandino Miguel M   Weller Michael M   Pastor Joaquín J   Valiente Manuel M  

EMBO molecular medicine 20220217 3


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 neur  ...[more]

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