A drug screening platform compatible with biopsies from cancer patients

It is estimated that approximately a quarter of cancer patients are at risk of brain metastases, a rate that increases especially in those who suffer relapses after undergoing various cancer treatments. This, in addition to the fact that there are no specific curative treatments for this type of metastasis, makes this disease a serious and growing public health problem.

To deal with this situation, the team led by Manuel Valiente, head of the Brain Metastasis Group at the National Cancer Research Center (CNIO), designed MET platform, which will allow researchers to test drugs for possible use in brain metastases. Thanks to a first screening process conducted using METPlatform, researchers have already confirmed the ability of this platform to identify new therapeutic targets, as well as poor prognosis biomarkers that identify more aggressive forms of brain metastases. In the next phase, they will seek to extend this tool to patient “avatars”, where they can test potential treatments to apply the most effective for each patient.

The study is published this week in the journal EMBO Molecular medicine.

“Cancer is not just a tumour, but the tumor and its context”

One of the major limitations of treating brain metastases is that these patients have traditionally been excluded from clinical trials, so there are no specific cures for this disease. “Thus, exploring therapeutic vulnerabilities and corresponding CNS-potent pharmacological agents in preclinical models is crucial to promote urgent prospective clinical trials that include patients with brain metastases,” the authors write in the article. .

New MET platform will allow research to be carried out using patients’ own samples in the preclinical phases. “Cancer is not just a tumor, but the tumor and its context, and this system allows us to conduct investigations with patient samples in a real-world setting where metastatic cells are growing in the microenvironment around the tumor. , in this case the brain,” says Valiente. In addition, this tool offers an alternative to experimentation on animals.

The strategy starts from so-called organotypic cultures, which already existed. In this study, Valiente and his team have shown that they can also be used directly with patient samples: once samples of fresh brain tissue affected by metastases are received from hospitals, they are processed using a simple methodology that allows them to be grown in the lab for a few days. The METPlatform screening platform is applied to these cultures, simultaneously analyzing the behavior of hundreds of compounds.

This screening method is “infinitely superior to others in use” because it is very simple and easy to deploy in the laboratory, does not require sophisticated technology, is much cheaper and is very fast (results can be obtained in 7 days , versus the months needed to see results in mice).

New compounds that could block metastasis in the brain

In order to find drugs already approved or in clinical trials that could be used to treat brain metastases, the researchers carried out, through METP Platform, a initial screening with a library of 114 of these compoundsof the CNIO’s Experimental Therapeutic Program.

Among the drugs identified are HSP90 inhibitors, which have already been tested for different types of tumors, but never in brain metastases.

This study suggests that these inhibitors could be useful since their target, HSP90, increases brain metastases. The use of the HSP90 inhibitor in animal models and in organotypic cultures of brain metastases obtained from 19 patients with different types of cancer showed strong anti-tumor activity.

Valiente is cautious about these results, as these molecules have shown side effects and toxicities in clinical trials with cancer patients, and he notes that a safe therapeutic window must be sought or their use in combination with other medications should be explored.

Patient “avatars” to advance in personalized medicine

With this new biomarker platform, the authors of this article also seek to identify patients with poor prognosis of the disease, for which they found a molecular signature of four genes linked to HSP90. “We speculate that this signature of poor prognosis could identify patients with greater sensitivity to the HSP90 inhibitor,” explains the researcher. If validated, these results could be decisive for better clinical management of brain metastases.

But the study is even more ambitious, and Valiente hopes that MET platform could position itself as an “avatar” of the patients themselves: “As far as the future is concerned, our goal is to integrate this platform into clinical trials, in order to be able to test the drug that we intend to administer to the patient using his own biopsies, so that we know as quickly as possible if it will work, and we are better prepared for possible therapeutic resistance with a battery of drugs that we would test in parallel on these same biopsies.

A first proof of concept shows that the predictive value of MET platform could be real, reproducing in organotypic cultures the responses of 14 glioblastoma patients treated with standard therapy. In a next phase, thanks to RENACER, the Valiente team, in collaboration with the CNIO Biobank and the 12 hospitals associated with the network, will study whether this possibility can be validated on a large scale.

Reference: Zhu L, et al. A clinically compatible drug screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastases. EMBO Mol. Medium. 2022;e14552. doi: 10.15252/emmm.202114552

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