A new therapy proves effective against brain metastasis

June 11, 2018, The National Centre for Cancer Research
Metastatic cells in the brain (in green. GFP) surrounded by reactive astrocytes (in white. GFAP) some of which activate STAT3 pathway (red nuclei- pSTAT3). pSTAT3+ reactive astrocytes help cancer cells to develop and grow in the brain by modulating local immunity. Credit: CNIO

A study published in Nature Medicine by a team led by Manuel Valiente, head of the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO), shows that the administration of silibinin in patients with brain metastasis reduces lesions without causing any adverse effects. This preliminary trial provides proof of concept that this compound could be a new effective and safe alternative to treat brain metastasis.

"We have demonstrated, taking into account all the considerations relevant to a compassionate use trial such as ours, that we can successfully treat ," says Valiente. "This treatment could also be valid for any type of metastasis, regardless of the primary tumour that generated it," he added.

It is estimated that between 10 percent and 40 percent of primary tumours generate metastasis in the brain, a situation that worsens patient prognosis considerably. Few advances have been made in terms of treatment; currently, brain metastasis is still being treated with surgery and/or radiotherapy. In recent years, some alternatives have appeared in terms of targeted therapies or immunotherapy, but the percentage of who might benefit from these therapies is just 20 percent in the best-case scenario.

The tumour microenvironment as a critical factor in metastasis

The role of the cellular context (microenvironment) in which a tumour develops is becoming increasingly important, not only with a view to understanding how cancer cells grow, but also to know how to attack them. In the brain, an inhospitable environment for any foreign element, the role of the microenvironment is relevant and understudied.

Valiente and his group have been studying this brain microenvironment for years, focusing in particular on two elements: One, a population of cells known as astrocytes, which respond to damage by entering into a reactive state and which are associated with metastasis. Two, the STAT3 gene, which research has established is involved with brain metastasis. As shown in this research, the activation of STAT3 is significant in a subpopulation of reactive astrocytes that are key to establishing a pro-metastatic environment.

When this gene is eliminated from the reactive astrocytes, the viability of brain metastasis is compromised. With this information on the table, Valiente's research group used a novel drug screening strategy developed by them called METPlatform. This tool is capable of analysing the relationship between hundreds of compounds and the metastatic cells found in the target organ simultaneously; in this case, in the brain.

"This strategy allows us to assess experimental drugs as well as those that are already in use for other types of pathologies that might or might not be linked to cancer. We believe that by using METPlatform we can be more efficient in developing new therapeutic options, since we can study the metastatic cell growing in the organ being colonised," explained Valiente.

One of the compounds tested in this preparation was silibinin, whose anti-tumour potential had previously been established by Joaquim Bosch, Head of the Lung Cancer Unit at Catalonia's Cancer Institute (ICO) in Girona, and co-author of this study. "In 2016, we reported positive brain responses in two patients with no other treatment options who received silibinin, but we did not know how it worked. Thanks to this research, led by Valiente's group, we now understand how it acts at the level of the brain," said Bosch.

A new therapeutic concept with encouraging results

Following the good results obtained by blocking STAT3 with silibinin in mice, the authors established a cohort of 18 patients with lung cancer and brain metastasis for whom compassionate use of this drug was granted in combination with standard treatment. 75 percent of the patients reacted positively at the level of brain metastasis. Three patients (20 percent) displayed a total response, and 10 (55 percent) a partial response. Average survival rate was 15.5 months, whereas in the control group (composed of patients treated for this disease in the same institution during 2015-2016) it was four months.

"Our treatment mainly targets the brain environment that has been altered by metastasis. This is a new therapeutic concept," said Valiente. "We are also attacking an alteration that is only seen when there is brain metastasis, and which is necessary for its viability," he added.

"We have explored whether therapies targeting organ-specific survival mechanisms could be a novel approach to treat brain metastasis," explains Neibla Priego, first author of the study.

In spite of the positive results, further trials must be conducted with this compound before it can be incorporated into . Researchers have been trying to launch such trials for months, but so far, they have not been able to secure the funding they need in order to do so. "This present research describes the first targeted therapy for brain metastasis that acts by attacking its tumour microenvironment. However, more data are needed before it can be incorporated into clinical practice. The 18 patients treated so far indicate that it would be feasible to administer this treatment and that it could be very relevant at a clinical level. Clinical trials, with silibinin or with drugs that act against this target, are crucial if we wish to make this new therapeutic option available to patients," concluded Bosch, head of the clinical study, and Valiente, research director.

Patients with brain metastasis have traditionally been excluded from clinical trials because of their poor prognosis. "It now appears that there is a move toward not excluding them given their growing importance in clinical practice. In this regard, we hope that with METPlatform we will be able to help build confidence so that new drugs can be evaluated on these patients," adds Valiente.

Explore further: Breast cancer: Discovery of a protein linked to metastasis

More information: Neibla Priego et al, STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis, Nature Medicine (2018). DOI: 10.1038/s41591-018-0044-4

Related Stories

Breast cancer: Discovery of a protein linked to metastasis

May 7, 2018
Jean-François Côté, a researcher at the Montreal Clinical Research Institute (IRCM) and professor at Université de Montréal's Faculty of Medicine, studies metastasis, the leading cause of cancer-related death. Recently, ...

Lymphatic endothelial cells promote melanoma to spread

May 1, 2018
The lymph vessel endothelial cells play an active role in the spread of melanoma, according to the new study conducted at the University of Helsinki. The researchers found that growing human melanoma cells in co-cultures ...

Brain metastasis persists despite improved targeted treatment for HER2 breast cancer

December 8, 2016
While new targeted treatments developed across the past two decades have led to dramatic survival improvements for women with HER2-positive metastatic breast cancer, University of North Carolina Lineberger Comprehensive Cancer ...

Genetic screening of brain metastases could reveal new targets for treatment

September 27, 2015
Unravelling the genetic sequences of cancer that has spread to the brain could offer unexpected targets for effective treatment, according to new research presented to the 2015 European Cancer Congress [1] today (Sunday) ...

MRI scans predict patients' ability to fight the spread of cancer

December 12, 2017
A simple, non-invasive procedure that can indicate how long patients with cancer that has spread to the brain might survive and whether they are likely to respond to immunotherapy has been developed by researchers in Liverpool.

Researchers identify compound to prevent breast cancer cells from activating in brain

March 22, 2018
Researchers at Houston Methodist used computer modeling to find an existing investigational drug compound for leukemia patients to treat triple negative breast cancer once it spreads to the brain.

Recommended for you

Ovarian cancer cells switched off by 'unusual' mechanism

June 19, 2018
Scientists at the Ovarian Cancer Action Research Centre at Imperial College London have discovered a mechanism that deactivates ovarian cancer cells.

Breast cancer could be prevented by targeting epigenetic proteins, study suggests

June 19, 2018
Researchers at the Princess Margaret Cancer Centre in Toronto have discovered that epigenetic proteins promote the proliferation of mammary gland stem cells in response to the sex hormone progesterone. The study, which will ...

Targeting the engine room of the cancer cell

June 18, 2018
Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug ...

Researchers create novel combination as potential therapy for high-risk neuroblastoma

June 18, 2018
Researchers at VCU Massey Cancer Center in Richmond, Virginia, have identified a promising target to reverse the development of high-risk neuroblastoma and potentially inform the creation of novel combination therapies for ...

Study suggests well-known growth suppressor actually fuels lethal brain cancers

June 18, 2018
Scientists report finding a potentially promising treatment target for aggressive and deadly high-grade brain cancers like glioblastoma. But they also say the current lack of a drug that hits the molecular target keeps it ...

Genomics offers new treatment options for infants with range of soft tissue tumors

June 18, 2018
The genetic causes of a group of related infant cancers have been discovered by scientists at the Wellcome Sanger Institute, the University of Wuerzburg and their collaborators. Whole genome sequencing of tumours revealed ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.