A blood test. That is enough to identify patients resistant to radiotherapy with brain metastases, according to research led by Spanish scientists who have also identified the mechanism that causes this resistance and found a drug that could be used to reverse the situation.
The description of the findings is published this Monday in the journal “Nature Medicine”, in an article led by researchers from the Spanish National Cancer Research Center (CNIO) and in which the authors propose a new strategy so that patients with metastases in the brain that would not respond to radiotherapy can benefit from it.
“We are very happy because we have, in a way, a triple result”, explains Manuel Valiente, head of the Brain Metastasis Group at the CNIO: with this work “we are beginning to understand the molecular mechanisms of resistance to radiotherapy; we stratify to patients, so that we can personalize therapy, and we find a drug that eliminates resistance.
A quarter of people with cancer are at risk of brain metastases, a type of lesion that is difficult to treat with drugs because the blood-brain barrier acts as an obstacle for drugs to enter the brain. Radiotherapy is one of the most used tools to treat metastasis, which mostly develops from primary lung, breast and melanoma tumors.
However, the secondary effects of the treatment can be important and the reappearance of the tumors is also frequent.
Therefore, Valiente’s team set out to study this resistance. He did it in animal models and in three-dimensional cell cultures of brain metastases from patients, which simulate tumor tissue. In addition, he analyzed numerous data from cohorts of people with lung, breast, and skin cancer with brain metastases.
The researchers managed to identify a molecular pathway involved in the appearance of resistance and, in particular, a protein -S100A9- that functions as an indicator of sensitivity to radiotherapy: the greater the presence of this protein, the more resistance.
The surprise was to verify that this protein can be detected in blood: a blood test is enough to identify patients resistant to the aforementioned treatment.
One of the hopeful things, indicates the CNIO, is that an inhibitor drug of the molecule to which S100A9 binds to activate resistance is already known; in clinical trials with humans in phase III (the last) against Alzheimer’s, its safety has been demonstrated.
Likewise, Valiente explains to Efe, it has been found that the drug is capable of crossing the blood-brain barrier and reaching the brain: “this creates a unique opportunity, as the drug is being tested with another pathology, there is already a long way to go.”
But before reaching a clinical trial for brain metastases, other steps must be taken. In this work, the researchers demonstrate in animal models and in cultures made from patient samples that the drug could be used to get resistant people to respond to radiotherapy.
They have done the latter thanks to METPlatform, a system that allows research with patient samples in a real context, in which metastatic cells grow in the tumor microenvironment that surrounds them, in this case the brain.
Once samples of fresh or “live” affected brain tissue are received from hospitals, they are processed using a simple methodology that allows them to be cultured for a few days. The METPlatform screening technique is applied to these cultures, which analyzes the behavior of hundreds of compounds simultaneously.
In this case, the team chose the drug being tested for Alzheimer’s. In samples of brain tissue from seven patients, they applied radiotherapy and, seeing that they did not respond, they combined it with the aforementioned drug: all were sensitive.
Now the researchers are designing the next step, an observational clinical trial with about 200 patients to verify that the S100A9 protein serves as a biomarker to establish resistance to radiotherapy and that a blood test detects it.
The last step will be a trial to test the drug that is now being tested for Alzheimer’s in people with brain metastases.
According to the CNIO, these S100A9 receptor inhibitors could also serve to reduce the dose of radiation needed to kill tumor cells, minimizing the effects of radiation on normal brain tissue and increasing the benefits.
“This study is an example of how with research that begins in the laboratory we are able to generate an opportunity that can change how radiotherapy is being given in brain metastases”, Valiente concludes.
–
