A study published in Nature Medicine by a team led by researchers at the Spanish National Cancer Research Centre (CNIO), with the participation of Mind the Byte, 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 brain metastasis”, highlights Valiente, from CNIO. “This treatment could also be valid for any type of brain metastasis, regardless of the primary tumour that generated it”, he added.
One of the biggest challenges in oncology is brain metastasis. It is estimated that between 10% and 40% 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 patients who might benefit from these therapies is just 20% 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 so we can know how to attack them. In the brain, an inhospitable environment for any element that is foreign to it, the role of the microenvironment is as relevant as it is unknown.
Scientists have been studying this aspect for years, focusing in particular on two elements. On the one hand, on a population of cells known as astrocytes, which respond to damage by entering into a reactive state and which are associated with metastasis. And on the other, on the STAT3 gene, which has already been proved to be 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 to this drug was granted in combination with standard treatment. 75% of the patients reacted positively at the level of brain metastasis. Three patients (20%) displayed a total response, and 10 (55%) 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.
Scientists led by Melchor Sanchez-Martinez, Scientific Director at Mind the Byte, were responsible for the structural studies of STAT3 protein and its binding to silibinin. Combining homology modelling, in silico mutagenesis, docking studies and molecular dynamics, they computationally explored how the interaction occurs and how this is affected by the different STAT3 mutations. This information supports in vivo results and will help further improve the design of new inhibitors.
Original article: Priego N; Zhu L; Monteiro C; Mulders M; Wasilewski D; Bindeman W; Doglio L; Martínez L; Martínez-Saez E; Ramón y Cajal S; Megías D; Hernández-Encinas E; Blanco-Aparicio C; Martínez L; Zarzuela E; Muñoz J, Fustero-Torres C, Pineiero E; Hernández-Laín A; Bertero L; Poli V; Sanchez-Martinez M; Menendez JA; Soffietti R; Bosch-Barrera J, Valiente M. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nature Medicine 2018 [ePub ahead of Print]. https://doi.org/10.1038/s41591-018-0044-4.
Text adapted from CNIO’s press release (link).
Image: The picture shows 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. CNIO.