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

• Published in: EMBO molecular medicine Vol. 14; no. 3; pp. e14552 - n/a
• Main Authors: 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, Cassoni, Paola, Weiss, Tobias, Muñoz, Javier, Sepúlveda, Juan Manuel, González‐León, Pedro, Jiménez‐Roldán, Luis, Moreno, Luis Miguel, Esteban, Olga, Pérez‐Núñez, Ángel, Hernández‐Laín, Aurelio, Toldos, Oscar, Ruano, Yolanda, Alcázar, Lucía, Blasco, Guillermo, Fernández‐Alén, José, Caleiras, Eduardo, Lafarga, Miguel, Megías, Diego, Graña‐Castro, Osvaldo, Nör, Carolina, Taylor, Michael D, Young, Leonie S, Varešlija, Damir, Cosgrove, Nicola, Couch, Fergus J, Cussó, Lorena, Desco, Manuel, Mouron, Silvana, Quintela‐Fandino, Miguel, Weller, Michael, Pastor, Joaquín, Valiente, Manuel, de la Lama‐Zaragoza, Adolfo, Calero‐Felix, Lourdes, Fiaño‐Valverde, Concepcion, Delgado‐López, Pedro David, Montalvo‐Afonso, Antonio, Pascual‐Llorente, Mar, Díaz‐Piqueras, Ángela, Nam‐Cha, SH, Barrena López, Cristina, Plans Ahicart, Gerard, Martínez‐Saez, Elena, Ramón y Cajal, Santiago, Nicolás, Pilar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-03-2022; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Bioluminescence; Blood-Brain Barrier; Brain cancer; Brain Neoplasms - drug therapy; Brain research; Breast cancer; Clinical trials; drug‐screen; EMBO03; EMBO08; Hsp90 protein; Medical prognosis; Medical research; Metastases; Metastasis; Mice; Neoplasm Recurrence, Local; Neurosurgery; organotypic cultures; patient‐derived; Proteomics; resistance; organotypic cultures; patient‐derived; metastasis; resistance; drug‐screen; drug-screen; patient-derived
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202114552

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.
Synopsis
A novel drug‐screening platform compatible with patient‐derived samples identifies effective therapies to prevent brain metastasis.
METPlatform is a novel drug‐screening strategy to identify vulnerabilities of metastasis while colonizing organs
ex vivo
.
METPlatform identified hits that were confirmed
in vivo
as effective against brain metastasis.
METPlatform allows to dissect the molecular mechanisms downstream of target inhibition using omic approaches.
METPlatform has a potential value as a patient "avatar".
Graphical Abstract
A novel drug‐screening platform compatible with patient‐derived samples identifies effective therapies to prevent brain metastasis.