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Researchers from the National Cancer Research Center, headed by Manuel Valiente, have found a new strategy for patients with Brain metastases that do not respond to radiation therapy can benefit from it.
The authors of the study, which is published in ‘Nature Medicine’, have discovered that a simple blood test can help detect patients with resistance to brain radiotherapy and at the same time have identified a drug that could reverse it. A multicenter clinical study is currently underway to validate the predictive potential of this biomarker through the National Brain Metastasis Network (RENACER).
“We are very happy because we have, in a way, a triple result: we are beginning to understand the molecular mechanisms of resistance to radiotherapy; we stratify patients, so that we can personalize therapy; and we found a drug that eliminates resistance”, says Valiente.
Between 20 and 40 percent of solid tumors develop brain metastases, mainly derived from the lung, breast and skin (melanoma). Since many drugs cannot cross the blood-brain barrier, systemic treatments are quite ineffective. Radiotherapy is therefore one of the most common tools to treat these metastases.
However, patients who undergo whole-brain radiation therapy, rarely experience significant impact on tumor progression, while they have a high risk of side effects due to the impact of the therapy on healthy tissue. According to the study authors, the ineffectiveness of radiotherapy on metastases indicates the “emergence of radiation resistance.”
Resistance to radiotherapy in brain metastases has not yet been thoroughly studied. The CNIO Brain Metastasis Group, led by Manuel Valiente, has investigated animal models and 3D cell culture models derived from patients that reproduce tumor tissue. In addition, data from large patient cohorts for lung cancer, breast cancer, and melanoma metastases to the brain were analyzed.
The study identified a pathway involved in the development of resistance to radiotherapy, specifically, elevated levels of S100A9 protein associated with limited sensitivity to this therapy. The greater the presence of S100A9, the more resistance to radiotherapy.
“Edogenous levels of S100A9 are associated with response to whole-brain radiotherapy in lung and breast adenocarcinoma and melanoma brain metastasis,” the study authors note.
To the surprise of the CNIO researchers, S100A9 can be easily found in the blood of patients. “I didn’t expect it to be so simple,” says Valiente, “but there is a correlation between the levels of S100A9 in the blood of patients and their resistance to radiotherapy.”
Another promising result is that an existing drug known to inhibit the receptor that binds to S100A9 reverse radioresistance. The drug has previously been tested in clinical trials for Alzheimer’s disease, where it was shown to be safe in patients and able to cross the blood-brain barrier and enter the brain.
With the help of the METPlatform tool, it was found that the drug could be used to transform radioresistant metastases from mice and patient-derived organotypic cultures into radiotherapy-responsive metastases.
In the article, the study authors report “a comprehensive approach that can be used to identify patients who might benefit from whole-brain radiation therapy, as well as to design combination therapies to overcome radiation resistance.”
“Our findings present a new approach to personalize radiation therapy», they add. The expression of S100A9 in blood would make it possible to “select patients who would benefit from radiotherapy, preventing neurocognitive impairment of patients with high resistance. Furthermore, the use of S100A9 receptor inhibitors could be used to reduce the radiation dose needed to eliminate tumor cells, thus minimizing the effects of irradiation on normal brain tissue and increasing the benefits for patients.”
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