Descripción del proyecto
El bloqueo de la reparación del ADN activa la inmunidad antineoplásica
La reparación de los errores de emparejamiento (MMR, por sus siglas en inglés) del ADN es una vía biológica conservada que desempeña una función esencial en el mantenimiento de la integridad genómica al detectar y corregir errores que surgen durante la replicación del ADN. Curiosamente, los tipos de cáncer con deficiencias de MMR responden satisfactoriamente a la inmunoterapia y presentan un pronóstico, en general, favorable. El equipo del proyecto TARGET, financiado con fondos europeos, considera que esto se debe a que estos tipos de cáncer acumulan mutaciones y segregan neoantígenos que activan la inmunovigilancia. El consorcio comprobará si bloquear los MMR con fármacos puede provocar una respuesta inmunitaria antineoplásica y detener el crecimiento tumoral. Los resultados incluirán conocimientos fundamentales sobre la inmunidad contra el cáncer y sentarán la base para el desarrollo de una nueva categoría de fármacos antineoplásicos.
Objetivo
This project will test for the first time the hypothesis that therapeutic inactivation of DNA repair pathways in cancer cells can be exploited for patient benefit by reawakening an anti-tumor immune response.
Genomic instability and molecular heterogeneity, which occur in cancer cells with DNA repair deficiencies, fuel tumour progression and are associated with poor outcome. An exception is represented by Mismatch repair (MMR) deficient cancers as these tumours are exceedingly genetically heterogeneous but show favourable prognosis and remarkable response to immunotherapy.
The molecular basis for the clinical outcome of MMR deficient cancers has long remained a mystery. Only recently it has become apparent that their biological properties are associated with increased levels of mutations, which unleash adaptive immunity and trigger immunosurveillance.
We have reported that when MMR is impaired, cancers cells grow in immune-deficient mice but are unable to do so in immune competent animals. MMR inactivation increased the mutational burden and led to dynamic mutational profiles, resulting in persistent renewal of neoantigens and engagements of antigen-specific T cells.
These data suggest an unprecedented high risk-high gain approach: the pharmacological blockade of proteins involved in DNA-repair as an anticancer therapy. This unconventional strategy builds on the concept that the immune system can identify and selectively target tumor cells carrying DNA alterations.
Using in vitro and in vivo functional assays we will systematically assess whether and how inactivation of DNA repair genes provokes an immune response and restrict cancer growth. Notably, TARGET will discover and develop inhibitors of MMR and other DNA repair proteins that induce tumor immunity.
The identification of DNA repair pathways which, when disabled, reawaken the immune system will provide transformative knowledge and could lead to the development of an entirely new class of anticancer drugs.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
10124 Torino
Italia