Published February 17, 2022 | Version v1
Publication Open

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

  • 1. ROR icon Spanish National Cancer Research Centre


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.

Technical info

We want to thank all members from the Brain Metastasis Group, F.X. Real, M. Malumbres, and M. Barbacid for critical discussion of the manuscript, the CNIO Core Facilities for their excellent assistance, Antonio Cebriá and Javier Klett for their excellent assistance in drug‐screening, Sonsoles Rodríguez‐Arístegui for her excellent work with preparation of different compounds and Alexandra de Francisco, Yolanda Sierra, and María de la Jara Felipe for their excellent work with animal preparation and imaging protocols. We also thank J. Massagué (MSKCC) for some of the BrM cell lines. This work was supported by MINECO (SAF2017‐89643‐R, SAF2014‐57243‐R, SAF2015‐62547‐ERC) (M.V.), Fundación FERO (IX FERO Grant for Research in Oncology) (M.V.), Fundació La Marató de TV3 (141) (M.V.), Melanoma Research Alliance (Bristol‐Myers Squibb‐Melanoma Research Alliance Young Investigator Award 2017 ( (M.V.), Beug Foundation (Prize for Metastasis Research 2017) (M.V.), Fundación Ramón Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19‐0177) (M.V.), H2020‐FETOPEN (828972) (M.V.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545)) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), ERC CoG (864759) (M.V.), Sophien‐Stiftung zur Förderung der klinischen Krebsforschung (T.W.), Promedica Stiftung (T.W.), Stiftung für angewandte Krebsforschung (T.W.), Forschungskredit of the University of Zurich (FK‐18‐054) (T.W.), Betty and David Koetser Foundation for Brain Research (T.W.), Foundation for Applied Cancer Research in Zurich (T.W., M.W.), Comunidad de Madrid (S2017/BMD‐3867 RENIM‐CM and Y2018/NMT‐4949 NanoLiver‐CM) and European structural and investment funds (M.D.), ISCIII (PT20/00044) co‐funded by FEDER “A way of making Europe” (M.D.), Ministero dell'Istruzione, dell'Università e della Ricerca‐MIUR, “Dipartimenti di Eccellenza 2018‐2022”, (D15D18000410001) (L.B. and P.C.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award/ with the generous support of Walk the Walk (2019AugSF1310) (D.V.), La Caixa‐Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.), La Caixa International PhD Program Fellowship‐Marie Sklodowska‐Curie (LCF/BQ/DI17/11620028) (P.G‐G), MINECO‐Severo Ochoa PhD Fellowship (BES‐2017‐081995) (L.A‐E.), AECC Postdoctoral Fellowship (POSTD19016PRIE) (N.P.), Boehringer Ingelheim Fonds MD fellowship (L.M.). The contribution of the Experimental Therapeutics Programme was supported by core funding from the Spanish National Cancer Research Center (CNIO). CNIO is supported by the ISCIII, the Ministerio de Ciencia e Innovación, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0510). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). M.V. was named Ramón y Cajal Investigator (RYC‐2013‐13365) and is member of EMBO YIP (4053).



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NanoBRIGHT – BRInGing nano-pHoTonics into the brain 828972
European Commission