Local and systemic therapy

Research models

Local and systemic therapy

Related projects

Publications

A clinically-compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.

Zhu L, et al. EMBO Molecular Medicine. (2022).

Link to Publication

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

Priego N et al. Nature Medicine. (2018).

Link to Publication

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.

Monteiro C, Miarka L, et al. Nature Medicine (2022).

Link to publication

Protocol to generate murine organotypic brain cultures for drug screening and evaluation of anti-metastatic efficacy

Lucía Zhu, Lauritz Miarka, Patricia Baena, María Perea-García, Manuel Valiente. STAR Protocols (2023)

Link to publication

Protocol to generate murine organotypic brain cultures for drug screening and evaluation of anti-metastatic efficacy

STAR Protocols (2023)

First author/s: Zhu L et al.
Corresponding author/s: Valiente M

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Nature Medicine (2022)

First author/s: Monteiro C, Miarka L et al.
Corresponding author/s: Valiente M

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Nature Medicine (2018)

First author/s: Priego N et al.
Corresponding author/s: Valiente M

A clinically-compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

EMBO Molecular Medicine (2022)

First author/s: Zhu L et al.
Corresponding author/s: Valiente M

A drug targeting a pro-tumoral compartment of the microenvironment (pSTAT3+ astrocytes, Priego et al, Nat Med 2018) is effective against melanoma brain metastasis (B16/F10-BrM) after systemic administration.

Local and systemic therapeutic approaches face different limitations to show full potential in the brain:

Neurosurgery: The disease usually comes back (see Resistance/ Local relapse)
Radiotherapy: Not real impact on the progression (see Resistance/ Radiation)
Chemotherapy: Most chemotherapeutics simply do not enter in the brain
Targeted therapies: Similar permeability issues as with chemotherapy. In addition, a very limited number of genetic abnormalities could be targeted with available drugs, thus most patients with brain metastases are not eligible for this therapeutic strategy. In order to solve the many clinical limitations explained above experimental models could be exploited to clarify the underlying molecular mechanisms that could later generate new strategies.
Immunotherapy: Current strategies (blocking antibodies) are not optimal for the brain plus there is limited knowledge on the immune system in the brain.

It is obvious that many clinical limitations require experimental models to be able to provide underlying molecular mechanisms and thus new strategies.

We have followed very different approaches to study various aspects of therapeutic failure. Traditional experimental models have been improved with neurosurgeries or irradiation protocols mimicking the clinical situation. Additionally, systemic therapies have been also incorporated. By doing so, we interrogate both cancer cells and the surrounding microenvironment at the molecular level to design approaches that make these therapies work better.

Over the years we have been able to study the process of relapse post-surgery, identify biomarkers of response to radiotherapy and radiosensitizers, identify available drugs that had never been used against brain metastasis but that turned out to be effective, improve the delivery of targeted drugs to the brain and expand immunotherapy strategies to work better in the brain.

By focusing on brain metastasis, we aim to demonstrate that either available or new strategies delivered locally or systemically could be used effectively to challenge this unmet clinical need. Our approach is focused on the brain but we are aware that most patients have metastatic disease spread to other organs and that the metastatic brain could also have important implications out of the central nervous system.