Overcoming Resistance to Radiotherapy for Brain Metastases

Roxanne Nelson, RN, BSN

April 21, 2022

Researchers have identified a new strategy that can help pinpoint which patients with brain metastasis may be resistant to whole brain radiation therapy (WBRT), and they have also identified a potential therapeutic option.

A Spanish team has found that activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases is a potential mediator of resistance. Secretion of S100A9 by metastatic cancer cells in the brain activated resistance to radiation therapy, suggesting that S100A9, which can be detected using a simple blood test, could be used as a potential biomarker to predict response to radiation therapy.

The team were also surprised that S100A9 could be easily measured in a blood sample. "I did not expect it to be that simple," said lead author Manuel Valiente, PhD, principal investigator, Brain Metastasis Group, Spanish National Cancer Research Center, Madrid, in a statement. "But there is a correlation between the levels of S100A9 in the blood of patients and their resistance to radiotherapy," he added.

"Because S100A9 expression correlates with poor response to radiotherapy, our findings present a novel approach to personalize radiotherapy," the authors comment. "Based on S100A9 expression on surgical specimens or circulating levels detected by liquid biopsy, patients who would benefit from radiotherapy could be selected while patients with high resistance could be spared, thereby avoiding neurocognitive decline."

The study was published online on April 11 in Nature Medicine.

Brain metastases develop in about 20%-40% of patients with solid tumors, spread primarily from lung cancer, breast cancer, or melanoma. Although treatment for brain metastases has recently shifted from WBRT towards more targeted stereotactic radiosurgery, WBRT remains an important treatment option, the researchers comment. They note, however, that the efficacy of WBRT is limited and patients rarely experience a significant impact on tumor progression but are at a high risk of side effects. There is also frequent recurrence of metastatic lesions within the irradiated field, and both of these observations suggest there is a resistance to radiation therapy.

To explore this issue, Valiente and colleagues studied resistance to radiation using mouse models, as well as brain metastasis organotypic cultures from patients who were radioresistant, and observations in cohorts of patients with melanoma, lung, or breast cancer with brain metastasis.

Study Details

Overall, there were three main study findings.

First, in patients with brain metastases, the brain metastatic cancer cells from different primary tumors are induced to highly express S100A9 within the brain microenvironment, which in turn, mediates resistance to radiotherapy.

Second, the findings suggest that S100A9 can be a clinically relevant biomarker for therapeutic response in brain metastasis.

The team analyzed blood samples from 71 patients with brain metastases (from any cancer type) who had received WBRT. The results showed that circulating S100A9 levels before or immediately after receiving WBRT correlated with survival from brain metastasis, but "of note," the authors point out, S100A9 levels showed no clinical correlation with survival in those patients with brain metastases who did not receive WBRT. 

None of the other possible variables, including age or Karnofsky Performance Status score, correlated with S100A9. However, to be conclusive about these additional variables, Valiente and colleagues caution that a larger prospective clinical study is required.

Third, the team showed that, experimentally at least, it is possible to restore sensitivity to radiation. Using experimental models of brain metastasis in mice and patient-derived organotypic cultures, the researchers showed the RAGE inhibitor FPS-ZM1 radiosensitized brain metastases. This product can cross the blood–brain barrier and so could be used together with WBRT, they comment.

They suggest the use of RAGE inhibitors could be used to "lower the radiation dose necessary for killing tumor cells, thereby minimizing effects of irradiation on normal brain tissue and increasing the survival benefit in these patients."

"We are really happy because we practically achieved a threefold result: we are beginning to understand the molecular mechanisms underlying radiotherapy resistance; we can stratify patients so as to enable personalized therapies; and we found a drug that reverses radioresistance," Valiente commented.

This work was funded by the Spanish Ministry of Science and Innovation, Portuguese Foundation for Science and Technology, Worldwide Cancer Research, and others. Valiente has reported no relevant financial relationships.

Nat Med. Published online on April 11, 2022. Full text

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