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Silibilina, el fármaco de la esperanza contra la metástasis cerebral Células en torno a una metástasis cerebral en modelo animal Europa Press
Investigadores del Centro Nacional de Investigaciones Oncológicas (CNIO) han descubierto que el cáncer pervierte un tipo de células cerebrales , los astrocitos, y los hace producir una proteína que trabaja a favor del tumor; un fármaco , la silibinina , inhibe esta proteína, y podría ser usado para contribuir a tratar la metástasis cerebral con inmunoterapia.
El trabajo, se publica en la revista 'Cancer Discovery' , de la Asociación Estadounidense para la Investigación del Cáncer , propone por tanto un nuevo tratamiento para las metástasis cerebrales que no responden o responden mal a la inmunoterapia, y aportan un biomarcador para predecir en qué casos aplicarlo.
"La metástasis cerebral plantea un grave problema clínico", explica Manuel Valiente , jefe del grupo de Metástasis Cerebral del CNIO y director del estudio que ahora publica sus resultados. "Los pacientes con metástasis cerebral avanzada, es decir, aquellos que ya perciben los síntomas de la metástasis, no responden bien a la inmunoterapia. Pero, además, con cada vez más frecuencia sucede que pacientes que sí respondían bien a la inmunoterapia recaen, y a menudo es por nuevas metástasis en el cerebro", añade Valiente, receptor de una subvención del Consejo Europeo de Investigación (ERC)
Astrocitos, células que trabajan a favor del cáncer Es decir, la inmunoterapia con anticuerpos bloqueantes no parece el sistema óptimo para la metástasis cerebral. Una posible causa es la existencia de la barrera hematoencefálica, una especie de membrana permeable que filtra la sangre que entra al cerebro para defenderlo de tóxicos. Pero esta barrera vascular también dificulta la entrada de los anticuerpos que se usan en inmunoterapia. Sin anticuerpos, la inmunoterapia no funciona.
El grupo del CNIO propone ahora una hipótesis muy innovadora para combatir este problema. "Hemos descubierto que un tipo de células cerebrales llamadas astrocitos actúan como inmuno-moduladores, es decir, interactúan con el sistema inmunitario en el cerebro, y en los casos de metástasis cerebral hacen un mal uso de esta función porque están influidos por el tumor", explica Neibla Priego, primera firmante del artículo.
Pervertidos por el cáncer, los astrocitos se ponen de parte de las células tumorales cuando hay metástasis cerebral. La interacción de los astrocitos con el sistema inmunitario, algo que debería ser un proceso normal de inmuno-modulación, se convierte en un mecanismo que alimenta el cáncer, porque los astrocitos dificultan el trabajo de las células defensivas y les impiden matar a las tumorales.
La silibina inhibe la producción de la molécula TIMP El grupo del CNIO ha identificado una molécula clave en el proceso, llamada TIMP1. "Los astrocitos pro-tumorales producen TIMP1, y esta proteína interviene en la inhabilitación de las células defensivas que deberían acabar con las células cancerígenas", señala Priego.
Una vez demostrado que esa molécula, TIMP1 , actúa sobre las células del sistema inmunitario y las hace más ineficaces, el equipo del CNIO propone usarla como biomarcador, para detectar metástasis cerebrales afectadas por este mecanismo de inmunosupresión. "TIMP1 es un buen biomarcador, porque en los pacientes con metástasis cerebral se secreta en cantidades significativamente más altas en el líquido cefalorraquídeo", asegura Priego.
Un ensayo clínico en marcha El grupo de Manuel Valiente propone una alternativa terapéutica que tiene a los astrocitos como diana: el uso combinado de inmunoterapia con inhibidores que impidan la producción de la molécula TIMP1. "Hay un fármaco llamado silibinina, que se ha utilizado ya en uso compasivo, que inhibe la producción de la molécula TIMP. Ya hay un ensayo clínico en marcha para probar su eficacia terapéutica en metástasis cerebral. Esperamos tener los resultados en 2025", señala Valiente.
El objetivo es combinar la inhibición de TIMP1 con la inmunoterapia tradicional , "lo que aumentaría la potencia de la estrategia terapéutica y facilitaría su incorporación a los protocolos clínicos", dice Valiente.
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