A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis
- Zhu, Lucia
- Retana, Diana
- Garcia Gomez, Pedro
- Alvaro Espinosa, Laura
- Priego, Neibla
- Masmudi Martin, Mariam
- Yebra, Natalia
- Miarka, Lauritz
- Hernandez Encinas, Elena
- Blanco Aparicio, Carmen
- Martinez, Sonia
- Sobrino, Cecilia
- Ajenjo, Nuria
- Artiga, Maria Jesus
- Ortega Paino, Eva
- Torres Ruiz, Raul
- Rodriguez Perales, Sandra
- Soffietti, Riccardo
- Bertero, Luca
- Cassoni, Paola
- Weiss, Tobias
- Muñoz, Javier
- Sepulveda, Juan Manuel
- Gonzalez Leon, Pedro
- Jimenez Roldan, Luis
- Moreno, Luis Miguel Moreno
- Esteban, Olga
- Perez Nuñez, Angel
- Hernandez Lain, Aurelio
- Toldos, Oscar
- Ruano, Yolanda
- Alcazar, Lucia
- Blasco, Guillermo
- Fernandez Alen, Jose
- Caleiras, Eduardo
- Lafarga, Miguel
- Megías, Diego
- Graña Castro, Osvaldo
- Nör, Carolina
- Taylor, Michael D
- Young, Leonie S
- Vareslija, Damir
- Cosgrove, Nicola
- Couch, Fergus J
- Cusso Mula, Lorena
- Desco Menéndez, Manuel
- Mourón, Silvana
- Quintela Fandino, Miguel Quintela Fandino
- Weller, Michael
- Pastor, Joaquin
- Valiente, Manuel
DOIAbstract
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....
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