Spanish researchers seek ways to increase the effectiveness of radiotherapy against brain metastases

Scientists at the National Center for Cancer Research (CNIO) have proposed a new strategy to help patients with brain metastases who do not respond to radiotherapy benefit from this.

The authors, led by Manuel Valiente, found that a blood test was sufficient to identify patients resistant to this treatment – before they underwent it – and they discovered a drug that could change the situation. They have already started a multicenter clinical trial to confirm the biomarker through the National Network of Brain Metastases (RENACER). The findings were published in the journal Today Natural medicine.

“We are very happy because, to some extent, we have threefold results: we are beginning to understand the molecular mechanisms of resistance to radiotherapy; We do stratify patients to be able to personalize it; “And we found a drug that diminishes resistance,” Valiente said.

Metastases of lung, breast and melanoma tumors

It has been estimated that 20 to 40% of patients with solid tumors develop brain metastases, a type of lesion that is difficult to treat with medication because the blood-brain barrier acts as a barrier to the entry of drugs into the body. Most of them come from primary tumors of the lung, breast and melanoma. Radiotherapy is one of the most commonly used means of treating them.

However, side effects can be significant and, in addition, re-emergence of tumors in the irradiated area is common after the use of whole cranial radiotherapy, so named because it is applied to all tissues of the brain. The latter suggests “the emergence of deep resistance to radiation,” the authors write.

However, this phenomenon is still little studied. The CNIO Brain Metastasis Group began research into animal models and patients using three-dimensional cell cultures of brain metastases that simulate tumor tissue. In addition, they analyzed numerous data from cohorts of lung, breast, and melanoma cancer with brain metastases.

Blood biomarker of resistance to radiotherapy

Thus, they were able to identify the molecular pathway involved in the detection of resistance, namely the protein, S100A9, which functions as an indicator of susceptibility to radiotherapy: the greater the presence of S100A9, the greater the resistance to this treatment.

“In patients, endogenous S100A9 levels correlate with response to radiotherapy in brain metastases from lung and breast adenocarcinoma and in brain metastases from melanoma,” the authors write.

The positive surprise for the researchers was the confirmation that this protein could be detected in the blood: “I did not expect it to be so simple, the amount of S100A9 in the blood correlated with resistance to radiotherapy,” says Valiente.

Therapy for patients’ “radiosensitivity”.

Another promising result is that the drug, which inhibits the protein binding to S100A9 to activate resistance, is already known and has been shown in clinical trials against Alzheimer to be safe and able to cross the blood-brain barrier and reach the brain.

Using the METP-platform, researchers are demonstrating cultures made from animal models and patient specimens that the drug could be used by resistant people to respond to this treatment.

“In summary, we outline a comprehensive strategy that not only identifies patients who can benefit from total cranial radiotherapy but also provides combination therapy to overcome radioresistance,” they write. Natural medicine.

“Our findings represent a new approach to personalizing radiotherapy,” they added. The expression of S100A9 in the blood will allow “patients selected to benefit from radiotherapy to be selected to prevent neurocognitive deterioration in patients with high resistance. In addition, the use of S100A9 receptor inhibitors can be used to reduce the radiation dose required to kill tumor cells, which reduces the effect of radiation on normal brain tissue and increases benefits for patients.