1. A clinically compatible drug‐screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis
- Author
-
Lucía Zhu, Diana Retana, Pedro García‐Gómez, Laura Álvaro‐Espinosa, Neibla Priego, Mariam Masmudi‐Martín, Natalia Yebra, Lauritz Miarka, Elena Hernández‐Encinas, Carmen Blanco‐Aparicio, Sonia Martínez, Cecilia Sobrino, Nuria Ajenjo, Maria‐Jesus Artiga, Eva Ortega‐Paino, Raúl Torres‐Ruiz, Sandra Rodríguez‐Perales, RENACER, Riccardo Soffietti, Luca Bertero, Paola Cassoni, Tobias Weiss, Javier Muñoz, Juan Manuel Sepúlveda, Pedro González‐León, Luis Jiménez‐Roldán, Luis Miguel Moreno, Olga Esteban, Ángel Pérez‐Núñez, Aurelio Hernández‐Laín, Oscar Toldos, Yolanda Ruano, Lucía Alcázar, Guillermo Blasco, José Fernández‐Alén, Eduardo Caleiras, Miguel Lafarga, Diego Megías, Osvaldo Graña‐Castro, Carolina Nör, Michael D Taylor, Leonie S Young, Damir Varešlija, Nicola Cosgrove, Fergus J Couch, Lorena Cussó, Manuel Desco, Silvana Mouron, Miguel Quintela‐Fandino, Michael Weller, Joaquín Pastor, Manuel Valiente, Adolfo de la Lama‐Zaragoza, Lourdes Calero‐Felix, Concepcion Fiaño‐Valverde, Pedro David Delgado‐López, Antonio Montalvo‐Afonso, Mar Pascual‐Llorente, Ángela Díaz‐Piqueras, SH Nam‐Cha, Cristina Barrena López, Gerard Plans Ahicart, Elena Martínez‐Saez, Santiago Ramón y Cajal, and Pilar Nicolás
- Subjects
drug‐screen ,metastasis ,organotypic cultures ,patient‐derived ,resistance ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
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.
- Published
- 2022
- Full Text
- View/download PDF