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Updated: Oct 3, 2025
Quantifying the Brain Metastatic Tumor Micro-Environment using an Organ-On-A Chip 3D Model, Machine Learning, and Confocal Tomography
Published on: August 16, 2020
A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent
Lucía Zhu1, Diana Retana1, Pedro García-Gómez1
1Brain Metastasis Group, CNIO, Madrid, Spain.
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.
Insights
We developed a drug-screening platform for organotypic cultures to test brain metastasis inhibitors. A heat shock protein 90 (HSP90) inhibitor showed high potency, revealing new therapeutic targets and resistance mechanisms.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Brain metastases represent a significant unmet clinical need with limited treatment options.
- Developing effective therapies requires robust models to screen drug candidates and understand resistance mechanisms.
Purpose of the Study:
- To establish and validate a medium-throughput drug-screening platform (METPlatform) using organotypic cultures for evaluating inhibitors against brain metastases in situ.
- To identify novel therapeutic vulnerabilities and molecular programs in brain metastases.
Main Methods:
- Development of METPlatform based on organotypic cultures for drug screening.
- Application of METPlatform to screen for inhibitors of brain metastases, including a novel model of local relapse.
- In situ proteomic analysis of treated metastases to uncover molecular programs.
Main Results:
- Identification of a blood-brain barrier permeable heat shock protein 90 (HSP90) inhibitor with high potency against mouse and human brain metastases.
- Discovery of a novel molecular program in brain metastases, including poor prognosis biomarkers and actionable resistance mechanisms.
- Validation of METPlatform as a resource compatible with human samples for drug screening and omics analysis.
Conclusions:
- METPlatform is a validated resource for metastasis research, integrating drug screening and omics approaches.
- The identified HSP90 inhibitor and molecular program offer potential for personalized management of brain metastases.
- This strategy aims to improve the clinical management of metastatic disease in the brain and other organs.
