The Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO) is one of the world’s leading groups conducting research into a disease that urgently requires better treatments.
Its work is fuelling a paradigm shift and outlining a horizon with therapies that will improve patients’ lives.
“In five or ten years, there will be more and better treatments,” says Manuel Valiente, head of the CNIO group. “There will also be strategies in place to reduce the cognitive effects of brain metastasis, which greatly diminish quality of life.”
Two clinical trials, a tool to determine which drug works best for each patient, and the first bank of living samples of brain metastases are some of the achievements of the CNIO group.
In his conferences, Manuel Valiente asks the audience which results from his laboratory at the Spanish National Cancer Research Centre (CNIO) they would like him to talk about. But it’s hard to decide. With his group, he is changing the way we understand the most common form of brain cancer with the worst prognosis, brain metastasis. His discoveries are spearheading a lively area of research, through advances that will bring “innovative therapeutic strategies,” writes Valiente himself in a review he has authored along with researchers from Europe and the United States.
“We are very hopeful and excited,” Valiente confirms. Brain metastasis has been seen as the final stage of aggressive cancer with no options; historically, clinical trials exclude patients with brain metastasis precisely because of their poor prognosis. But the scenario in changing.
“These findings have reshaped therapeutic strategies, leading to clinical trials that specifically address [brain metastasis],” says the review in Trends in Cancer. “Collectively, these advances are transforming the clinical landscape, offering new hope for the prevention and management” of this disease.
Ten years of bold research
Valiente joined CNIO in 2015, determined to improve the lives of people with brain metastases. Ten years later, the research conducted by his group has led to two ongoing clinical trials, a tool to determine which drug works best for each patient, and results that are fuelling paradigm shifts. Several of these results are about to be presented.
One of the group’s major projects, ALTERbrain, which has received nearly two million euros in funding from the European Research Council, is coming to an end. It has shown that metastasis often interferes with the activity of neurons, hijacking them, and this can cause serious cognitive problems that worsen quality of life.
Until now, no attempt had even been made to address the impact of metastasis on thinking and behaviour, as it was attributed solely to the physical presence of the tumour in the brain, known as the ‘mass effect’. Now Valiente is optimistic: “I’m sure that within five to ten years, we will find therapeutic strategies to reduce and/or prevent this brain dysfunction.”
“Specific therapies need to be found”
Metastasis is the process by which a tumour colonises other organs, and it is more lethal than the primary cancer. Valiente studies brain metastasis because he feels a “fascination” for this organ and because of his desire to improve the lives of people with an orphan tumour that lacks specific treatments, despite its high incidence. Trained as a veterinarian and a doctor in Neurosciences, he began studying with Joan Massagué at the Memorial Sloan Kettering Cancer Center in New York.
“There is an unmet clinical need. Specific therapies need to be found, urgently,” he says. Up to 30% of cancer patients develop brain metastases, especially from breast, lung, skin and colon/rectal tumours. But there is no specific treatment for these individuals beyond surgery and radiotherapy.
Paradoxically, as improvements in the treatment of primary cancers prolong survival, there is more time for brain metastasis to appear. That’s why the incidence of this disease is increasing.
“We are missing out on therapeutic opportunities”
The results from the CNIO group are driving a major conceptual shift: brain metastasis is a distinct disease entity, not just an extension of the primary tumour, as it has been understood until now. This shift affects the search for treatments.
The data suggest that treating metastasis according to the tumour from which it originates, as per the current approach, is “insufficient,” says Valiente. “We see that there are potentially effective drugs to treat metastases that are not necessarily ‘on the table’ for oncology consultants, because they are not the ones that correspond to the treatment of the primary tumour. Our findings suggest that we are missing out on therapeutic opportunities.”
The CNIO group has achieved this result thanks to the world’s first ever bank of living samples of brain metastases, RENACER, and a platform for personalised drug testing developed from these samples, METPlatform. Both resources, the sample repository and the platform, are innovative research tools celebrated by the international neuro-oncology community.
A living sample bank to search for the best drug for each patient
“RENACER was developed in response to a pressing need”, Valiente explains. “When studying brain metastasis, the first thing is to provide patients with more options, and for that, we needed samples. The ones sent to us by the two hospitals we were collaborating with were not enough. With the CNIO Biobank, we launched an initiative to create a national network without knowing whether it would work, and it has been a great success. The response was immediate. In four years, 21 hospitals from all over Spain have contributed samples; now we hope to expand the network to Europe”.
The logistics involved in keeping the samples alive are very sophisticated. The samples are taken from the operating theatre in a special container, in their culture medium, at a temperature of between 4 and 8 degrees centigrade, and reach the CNIO Biobank in less than 24 hours. There, they are processed, cultivated, analysed and stored.
The effort is worth it, among other things because in living samples, we can study how each cancer responds to each drug. This is where the METPlatform comes into play. Once the platform has obtained regulatory approval, it will allow samples left over after the necessary clinical use for the patient’s diagnosis to be used to test multiple therapeutic options before applying them to the same patient.
METPlatform “takes precision medicine to the next level, putting together a therapeutic strategy that goes beyond the primary tumour – which generally does not kill the patient – and allows us to focus on metastasis, which is associated with the majority of cancer-related deaths,” says Valiente.
For him, developing RENACER and METPlatform “has been very rewarding, allowing us to move beyond the laboratory, beyond scientific publications: creating a network that connects the patient, the clinician, the researcher, the biobank. It’s a really different way of working. We can start projects directly from the patients,” says Valiente. “It’s exciting to know that there are so many people working on a common project.”
Ongoing clinical trials
The drug testing platform facilitated the discovery in 2018 of a drug already in use, silibinin, which has shown activity in samples from patients with brain metastasis, and was validated in a compassionate use or expanded access clinical trial at Hospital Universitario Josep Trueta. Shortly after, a multicentre randomised phase II clinical trial was initiated in Italy, which is expected to yield results later this year.
It is not the only trial being conducted based on the results of CNIO. In 2022, thanks to RENACER samples, the Metastatic Brain group discovered a molecular mechanism that prevents radiotherapy from being effective, as well as a drug that could reverse the situation. They started a multicentre clinical trial led by Hospital 12 de Octubre, which has already presented non-toxicity results at scientific conferences.
Avoiding the effects of metastasis on the mind and behaviour
The line of research that is making strong progress and is now a priority in the Brain Metastasis group at CNIO is related to the cognitive effects of this disease.
In 2023, they shook this area of research by demonstrating that when cancer spreads to the brain, it alters brain chemistry and interferes with communication between neurons, through a collaboration with the group led by Liset Menéndez de La Prida, director of the CSIC Cajal Institute of Neuroscience.
Now, thanks to these new findings, “we are understanding the molecular bases that could explain why some brain metastases alter neuronal communication, while others don’t”. This is the first step to design strategies to prevent the phenomenon.
And, once again, RENACER will be essential. Valiente aspires in the near future to associate these samples with a cognitive evaluation of donor patients.
“We are exploring innovative strategies based on online testing and others using artificial intelligence,” he explains. “The goal is always the same: research focused on improving the lives of people with brain metastases.”
About the National Cancer Research Centre (CNIO)
The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.