A quarter of people with cancer are at risk of brain metastases, and finding treatments remains a challenge. Now, a Spanish scientific team has designed a platform capable of testing drugs on the patient’s own tumor tissue and identifying biomarkers of poor prognosis.
Magnetic resonance image of metastases in the cerebellum in a patient with a tumor of unknown origin. Photo: Ramón y Cajal Hospital.
Cancer is not just a tumor, but the tumor and its context and this new system, called METPlatform, allows research with patient samples in a real context, in which metastatic cells grow in the tumor microenvironment that surrounds them, in this case brain metastasis.
Its managers are scientists from the National Cancer Research Center (CNIO) and the results of the validation of this technique and its first experiments -in which inhibitors have been identified that could be useful in the future to treat brain metastasis- are published in the journal EMBO Molecular Medicine.
Between 10 and 30% of cancer patients develop brain metastases, mainly from breast, lung and skin tumors.
The fact that there are no specific curative strategies against this type of metastasis makes this disease a serious and growing public health problem, points out the CNIO, which recalls that one of the great limitations for treatment is that these patients have traditionally been excluded from clinical trials.
The objective, therefore, in addition to trying to understand why some tumor cells manage to overcome the strong defensive barriers of the brain, is to explore new therapeutic targets and biomarkers that identify the most aggressive brain metastases.
The platform from which the first results are now presented generates a new way of screening drugs and has as a novelty the use of the patients’ own tumor tissue, Manuel Valiente, head of the CNIO Brain Metastasis Group, explains to Efe.
The strategy is based on the so-called organotypic cultures, whose ultimate goal is the “ex vivo” use of tissues compatible with different experiments. In this work, Valiente and his team have shown that they can also be used directly with patient samples.
Once the samples of fresh or “living” brain tissue affected by metastases are received from the hospitals, they are processed using a simple methodology that allows them to be cultured in the laboratory for a few days.
The METPlatform screening technique is applied to these cultures, where the behavior of hundreds of compounds is analyzed simultaneously.
“The advantage is that for the first time we can use drug batteries to ask if they work by eliminating the metastasis that grows in the organ in which it develops in real life.”
This is important, adds Valiente, because “we know that metastasis needs cancer cells but also interaction with the environment” to progress.
This screening system is “infinitely superior to others”, since it is “very simple and easy to implement in the laboratory, it does not require sophisticated technology, it is much cheaper and faster”: results can be obtained in 7 days, compared to the months needed to obtain them in mice.
The tool favors the reduction of the use of experimental animals but does not replace them; There must always be a passage through animals, for example, to check the toxicity of the molecules.
In the first experiments with this technique, the team screened a library of 114 compounds already approved or in clinical trials; Among the drugs identified are HSP90 inhibitors, which have already been tested for different tumors, although never in brain metastases.
This study suggests that these inhibitors could be useful since their target, HSP90, is increased in brain metastasis. The use of the HSP90 inhibitor in animal models and in organotypic cultures of brain metastases obtained from 19 patients with different cancers showed potent anti-tumor activity.
However, Valiente is cautious, since these molecules have shown side effects and toxicities in clinical trials of cancer patients, and anticipates that a safe therapeutic window will have to be found or their use in combination with others will have to be explored.
Another objective of this platform is to search for biomarkers to identify those patients with a worse prognosis, for which the team found a molecular signature of four genes related to HSP90.
“We speculate that this signature of poor prognosis can identify those patients with greater sensitivity to the HSP90 inhibitor,” says the researcher: if validated, this could be decisive for better clinical management of brain metastasis.
The researchers now trust that METPlatform can position itself as an “avatar” of the patients themselves, that is, incorporate it into clinical trials to test the drug to be received on the patient’s own biopsy to find out if it works as soon as possible: in a proof of concept they saw that this technique is capable of predicting in almost 90% which patient would respond and which would not.
This research involved different hospitals that, through the National Brain Metastasis Network (Renacer), supplied living tissue from patients: 12 de Octubre and La Princesa University Hospitals (both in Madrid), Álvaro Cunqueiro Hospital (Vigo Hospital Complex ), Burgos University Hospital, Albacete University Hospital Complex and Research Unit and Bellvitge University Hospital.
