Description du projet
De nouvelles cibles thérapeutiques pour le cancer du sein triple négatif
Le cancer du sein triple négatif (CSTN) est un sous‑type de cancer qui se définit par l’absence d’expression de trois marqueurs immunohistochimiques (ER, PR et HER2) et qui est associé à un mauvais pronostic. De récentes preuves révèlent l’activation de six protéines kinases dans le CSTN qui pourraient servir de nouvelles cibles de la maladie. Le projet P70-IMMUNEBREAST, financé par l’UE, se concentre sur la protéine ribosomique à type de kinase S6 (P70S6K) et sur son lien avec la réponse immunitaire et les résultats de la maladie. Les scientifiques entendent décoder l’impact de la modulation de P70S6K sur les lymphocytes infiltrant la tumeur et sur la progression de la tumeur. La chimiothérapie et l’immunothérapie conventionnelles n’apportant pas satisfaction, les résultats du projet ont le potentiel de dévoiler de nouvelles cibles thérapeutiques pour le CSTN.
Objectif
Breast cancer is the most common cancer among women with significant death rates and economic impact. In daily routine clinics, breast cancer is usually classified on the basis of three immunohistochemical markers (ER, PR and HER2). Triple-negative breast cancer (TNBC) is a subtype defined by the negativity of all these markers, which shows an adverse clinical course. It is characterized by a considerable gene expression heterogeneity that leads to a lack of availability of targeted therapies. Positive clinical trials relying on various forms of immunotherapy have shifted the paradigm of diverse malignancies from cytotoxics to novel immunomodulator drugs. The results in TNBC, however, are not as positive. In a recent taxonomic effort of the hosting group, TNBC has been re-classified on the basis of the activation status of six protein kinases, which in turn constituted novel targets for this disease. One of them, the 70-kDa ribosomal protein S6 kinase (P70S6K), which was associated with an adverse clinical outcome, showed negative correlation with tumor-infiltrating lymphocytes (TILs) abundance. The fact that P70S6K has been associated with immunosuppressive mechanisms and that there is a positive correlation between the number of TILs and the clinical outcomes in TNBC, suggests that the role of P70S6K may be related to pleiotropic and/or opposing properties of tumor progression. By using a combination of multiparametric flow cytometry, bulk/single-cell gene expression analysis and in vivo experiments in mouse models, this proposal aims to unravel the impact of P70S6K modulation over the already known relevant immune-oncology targets/axes as well as the therapeutic consequences of P70S6K blockade in TNBC. These studies will provide a better understanding of the lymphocyte-related responses modulated by P70S6K, with the potential to find new therapies for patients suffering from TNBC and possibly a broader range of malignances.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
28029 Madrid
Espagne