B-S.B.25: Multi-omics data analysis unveils treatment opportunities in Brain Metastases
Authors
Laura Serrano-Ron
Spanish National Cancer Research Centre
Neibla Priego
Spanish National Cancer Research Centre
Dido Carrero
Spanish National Cancer Research Centre
Carmen Ortega-Sabater
Spanish National Cancer Research Centre
Juan Vázquez-Cantó
Spanish National Cancer Research Centre
Ana de Pablos-Aragoneses
Spanish National Cancer Research Centre
Santiago García-Martín
Spanish National Cancer Research Centre
Óscar Lapuente-Santana
Spanish National Cancer Research Centre
Andrea Rojas
Spanish National Cancer Research Centre
Beatriz Ocaña-Tienda
Spanish National Cancer Research Centre
Ariane Steindl
Medical University of Viena
Daniel Cerdán-Vélez
Spanish National Cancer Research Centre
María González-Bermejo
Spanish National Cancer Research Centre
José Córdoba-Caballero
Spanish National Cancer Research Centre
Pilar Gallego-García
Spanish National Cancer Research Centre
Leticia Cuarental
Spanish National Cancer Research Centre
Violeta Fernández
Spanish National Cancer Research Centre
Diana Retana
Spanish National Cancer Research Centre
Catalina Vela
Spanish National Cancer Research Centre
Carolina Hernández-Oliver
Spanish National Cancer Research Centre
Patricia Baena
Spanish National Cancer Research Centre
Lucía Zhu
Spanish National Cancer Research Centre
Ana Cayuela
Spanish National Cancer Research Centre
Antonia Stammberger
TUD Dresden University of Technology
Isabel Peset
Spanish National Cancer Research Centre
Tomás Di Domenico
Spanish National Cancer Research Centre
Gonzalo Gómez-López
Spanish National Cancer Research Centre
Marc Schmitz
TUD Dresden University of Technology
Marcos Díaz-Gay
Spanish National Cancer Research Centre
Alicia González-Martínez
Spanish National Cancer Research Centre
Eva Ortega-Paino
Spanish National Cancer Research Centre
Víctor M Pérez-García
University of Castilla-La-Mancha
María Jesús Artiga
Spanish National Cancer Research Centre
RENACER
Red Nacional de Metástasis Cerebral
Fátima Al-Shahrour
Spanish National Cancer Research Centre
Manuel Valiente
Spanish National Cancer Research Centre
Keywords
Brain metastasis, transcriptomics, genomics, WES, RNA-Seq
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Brain metastases represent a critical clinical challenge, affecting approximately 20% of cancer patients and conferring a median survival of less than one year. Current treatment strategies, largely dictated by the primary tumor of origin, fail to account for brain metastasis specific vulnerabilities, resulting in limited intracranial control and frequent therapeutic failure. Here, we present a comprehensive multi-omics characterization of 381 brain metastases from 360 patients across 19 primary tumor types, integrating RNA sequencing, whole-exome sequencing, and magnetic resonance imaging data. Clustering based on inferred drug sensitivity profiles revealed three distinct Therapeutic Clusters (TCs), notably independent of primary tumor origin. TC1 is characterized by high proliferation, replicative stress, and sensitivity to cell-cycle and DNA damage response inhibitors; TC2 is driven by PI3K-AKT-mTOR signaling and high metabolic activity, and shows sensitivity to MAPK/RTK pathway inhibitors; and TC3 exhibits an invasive phenotype characterized by EMT, angiogenesis, and sensitivity to SRC/VEGFR blockade. These clusters display distinct genomic features, tumor microenvironment compositions, and transcriptional subtypes, with key functional traits validated by immunohistochemistry and multiplex tissue microarrays. To facilitate clinical translation, we developed a drug prioritization pipeline that identified 40 candidate compounds, currently under ex vivo validation in patient-derived organotypic cultures. Additionally, a machine learning classifier based on a minimal four-gene qPCR signature achieved 76% cross-validated accuracy in TC prediction. Together, these findings provide a framework for stratifying patients with brain metastases and identify novel candidate therapies, paving the way toward more precise and effective treatment strategies.
Co-authors: Patricia Baena, Marcos Díaz Gay, Isabel Peset, Carolina Hernández Oliver, Catalina Vela, Violeta Fernández, Leticia Cuarental, Jose Córdoba Caballero, Manuel Valiente, Fátima Al-Shahrour, RENACER Consortium, Gonzalo Gómez López, Tomás Di Domenico, Ariane Steindl, Neibla Priego, Diana Retana, Pilar Gallego García, MarÃa González Bermejo, Daniel Cerdán Vélez, MarÃa Jesús Artiga, Carmen Ortega Sabater, Juan Vázquez Cantó, Andrea Rojas Rojas, Ana de Pablos Aragoneses, Óscar Lapuente Santanta, Beatriz Ocaña Tienda, Santiago GarcÃa MartÃn, Dido Carrero Muñiz
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