Left: Manuel Valiente, head of the CNIO Brain Metastasis group. /Laura M. Lombardía. CNIO. Right: CNIO researcher Laura Álvaro-Espinosa. / Christian Esposito. MadMoviex. CNIO
A team from the Spanish National Cancer Research Centre (CNIO) has discovered a novel way in which tumor cells alter the brain to establish themselves and spread cancer.
They also demonstrate that a drug that prevents this process already exists and is approved for other conditions.
The finding is published in the journal ‘Cancer Research’.
Almost one-third of cancer patients develop brain metastases. This stage has traditionally been considered the final, incurable stage of aggressive cancer, to the point that patients who reached it were excluded from clinical trials due to their poor prognosis. In recent years, groups such as the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO) have opened new avenues for treating brain metastases.
The CNIO team, led by Manuel Valiente, has broadened the scope of its research to focus on what happens in the environment surrounding brain metastases. Over the last decade, findings from this laboratory have led to the conclusion that metastasis occurs when tumor cells create an environment suited to their needs, and to do so, “they must alter the brain themselves,” explains Valiente.
When tumor cells reach the brain, most are eliminated because they lack the means to grow in this organ; only a few possess the necessary abilities to reshape the brain and adapt it to their needs. Tumor cells begin to alter the tissue, activate molecular pathways that should be inactive, and, ultimately, create an environment favorable only to themselves. This allows them to spread uncontrollably and reproduce the tumor.
Valiente’s group has already uncovered how several of these molecular changes occur, and is testing drugs to block them and thus prevent this abnormal remodeling in the brain.
They have now discovered another mechanism that could be valuable in treating brain metastases from various types of tumors, as well as other non-tumor conditions affecting the brain. Furthermore, this mechanism can be targeted by a drug that penetrates the brain effectively and is well tolerated, as it is approved for the treatment of asthma in other countries.
The finding is published today in the journal Cancer Research, with Laura Álvaro-Espinosa as first author. Valiente aims to initiate a clinical trial in the medium term.
Defensive cells hijacked by cancer
The new target is a protein called MIF produced by tumor cells in the brain. The new study shows that MIF binds to a molecular structure called CD74, found on the surface of macrophages and microglia, a type of cell responsible for alerting the immune system.
In normal conditions these CD74-expressing cells would fight metastasis, as they are part of the immune system; but when MIF bounds to them, metastatic cells make them work to the advantage of the cancer. That is, MIF reprograms CD74-expressing macrophages and microglia to drive tumor growth.
In their search for a way to prevent MIF from transforming CD74-expressing macrophages, the CNIO team found the drug ibudilast, which is known to block the binding of MIF to CD74. Their results show that ibudilast slows metastasis in both animal models and fresh patient samples derived from different primary tumors.
“We demonstrate that microglia and CD74+ macrophages are reprogrammed, shifting from a potentially antitumor nature to a pro-metastatic one in the brain,” the researchers say.
Also in Alzheimer’s and Multiple Sclerosis
The authors also highlight another observation from their study: the functional shift of CD74+ cells due to MIF action is also detected in neurodegenerative and neuroinflammatory diseases, such as Alzheimer’s and multiple sclerosis. The new finding could also be relevant for these diseases, as has recently been observed in primary brain tumors, such as glioblastoma.
For Valiente, “MIF-mediated reprogramming may be a common vulnerability in various brain diseases, a shared mechanism that can be therapeutically targeted.”
The findings of the CNIO Brain Metastasis Group suggest that changes occurring in this organ may provide clues not only about metastasis but also about other degenerative and neuroinflammatory diseases.
The Value of the World’s First Bank of Fresh Brain Metastasis Samples
This finding is further proof of the value of two major achievements by the CNIO group: the creation of the world’s first bank of fresh brain metastasis samples, RENACER; and the drug testing platform that these samples have enabled to be developed, METPlatform.
Both resources—the repository and the platform—are innovative research tools celebrated by the international neuro-oncology community, and have already led to several clinical trials currently underway.
An urgent clinical need
Valiente notes that finding specific therapies for brain metastases is urgent, as this represents “an unmet clinical need.” Up to 30% of cancer patients develop brain metastases, particularly from breast, lung, skin, and colorectal tumors. However, there is currently no specific treatment for these patients beyond surgery and radiation therapy.
