Silibilin – a drug of hope against brain metastases

Researchersl National Center for Cancer Research (CNIO) found that Cancer perverts the type brain cellsastrocytes and causes them to produce a protein that acts to benefit the tumor; A medicine, silibinininhibits this protein and can be used to treat brain metastases using immunotherapy.

The work was published in the journal Cancer Discovery. American Association for Cancer Researchtherefore offers a new treatment for brain metastases that do not respond or respond poorly to immunotherapy and provides a biomarker to predict when to use it.

“Brain metastases are a serious clinical problem,” explains Manuel Valientehead of the brain metastasis group at the CNIO and leader of the study that is now publishing its results. “Patients with brain metastases, that is, those who are already experiencing symptoms of metastasis, respond poorly to immunotherapy. But it is also increasingly common for patients who have responded well to immunotherapy to relapse, as this is often due to new brain metastases,” adds Valiente, a grant recipient from European Research Council (ERC)

That is, immunotherapy with blocking antibodies does not appear to be an optimal system for brain metastases. A possible reason is the existence of the blood-brain barrier, a type of permeable membrane that filters blood entering the brain and protects it from toxins. But this vascular barrier also makes it difficult for antibodies used in immunotherapy to penetrate. Without antibodies, immunotherapy does not work.

The CNIO Group now offers very innovative hypothesis to combat this problem. “We discovered that a type of brain cell called astrocytes acts as immunomodulators, meaning they interact with the brain’s immune system, and in the case of brain metastases, they abuse this function because they are influenced by the tumor,” explains Neybla Priego. first signatory of the article.

Perverted by doggy style astrocytes they take the side of tumor cells during brain metastases. The interaction of astrocytes with the immune system, which should be a normal process of immunomodulation, becomes a mechanism that feeds cancer, as astrocytes impede the work of protective cells and prevent them from killing tumor cells.

The CNIO group identified key molecule in a process called TIMP1. “Pro-tumor astrocytes produce TIMP1, and this protein is involved in shutting down the protective cells that are supposed to kill cancer cells,” Priego says.

Once it was demonstrated that molecule, TIMP1affects the cells of the immune system and makes them less effective, – team CNIO proposes its use as a biomarker to detect brain metastases affected by this mechanism of immunosuppression. “TIMP1 is a good biomarker because in patients with brain metastases it is secreted into the cerebrospinal fluid in significantly higher quantities,” Priego says.

Manuel Valiente’s group offers therapeutic alternative Astrocyte-targeted: combined use of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule. “There is a drug called silibinin, which is already used for charitable purposes, which inhibits the production of the TIMP molecule. Clinical trials are already underway to test its therapeutic efficacy in brain metastases. We hope to have results in 2025. “, he notes. Brave.

The goal is to combine TIMP1 inhibition with itraditional immunotherapy“which will increase the effectiveness of the therapeutic strategy and facilitate its inclusion in clinical protocols,” says Valiente.