A novel drug screening platform to combat brain metastasis

Brain metastasis affects up to a quarter of cancer patients. Unfortunately, available treatments are not very effective and fail to improve the patient’s survival. A major issue is that scientists do not know enough about the therapeutic vulnerabilities, which – if properly exploited – could lead to better treatments.

To address this lack, researchers supported in part by the EU-funded ALTER-brain project have created an organotypic culture-based drug-screening system called METPlatform. The platform will help scientists to study the impact of different drugs on brain metastases, allowing them to identify relevant drug candidates rapidly and cost-effectively. The study was published in the journal ‘EMBO Molecular Medicine’.As reported in a news item posted on the website of ALTER-brain project host Spanish National Cancer Research Center (CNIO), the METPlatform screening system is “infinitely superior to others in use.” It is easy to use in the lab, requires no sophisticated technology, is much cheaper than other methods and offers an alternative to animal experimentation. It is also very fast, yielding results in seven days rather than the months needed to obtain results in mice.

With METPlatform, preclinical research can be conducted using patients’ own samples. Samples of fresh brain tissue affected by metastases are received from hospitals and processed using a simple method that makes it possible to culture them in the lab over a few days. The screening system is then applied to these cultures, analysing the behaviour of hundreds of compounds at the same time. “Cancer is not just a tumour, but the tumour and its context, and this system allows us to conduct investigations with patient samples in a real context in which metastatic cells grow in the microenvironment around the tumour, in this case the brain,” observes study senior author Dr Manuel Valiente of CNIO in the same news item.

In search of drugs – either approved or in clinical trials – that could be used to treat brain metastasis, the team used METPlatform to screen 114 such compounds. Among the anti-tumoural drugs identified are blood-brain barrier permeable inhibitors of heat shock protein 90 (HSP90) that had never been tested for brain metastasis. HSP90 is a highly abundant chaperone protein that plays a key role in many cellular processes: it helps other proteins fold correctly, stabilises proteins against heat stress and aids in protein degradation. Importantly, it also stabilises various proteins required for tumour growth, which is why it has become a major therapeutic target for cancer. The study suggests that HSP90 inhibitors could be useful given that their target protein increases in brain metastases.

Additionally, METPlatform has a potential value as a patient avatar. Dr Valiente concludes: “Looking to the future, our goal is to incorporate this platform into clinical trials, so that we can test the drug we intend to administer to the patient using the patient’s own biopsies, so we know as soon as possible if it will work, and better prepare ourselves for possible therapeutic resistance with a battery of drugs that we would test in parallel on these same biopsies.” ALTER-brain (Metastasis-associated altered molecular patterns in the brain) ends in 2025.

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ALTER-brain project