Descrizione del progetto
Nuovi bersagli terapeutici per il tumore al seno triplo negativo
Il tumore al seno triplo negativo (TNBC, triple-negative breast cancer) è un sottotipo definito dall’assenza di espressione di tre marcatori immunoistochimici (ER, PR e HER2) ed è associato a prognosi infausta. Prove recenti indicano che l’attivazione di sei protein-chinasi nel TNBC potrebbero fungere da nuovi bersagli per la malattia. Il progetto P70-IMMUNEBREAST, finanziato dall’UE, concentra la propria attenzione sulla proteina ribosomiale S6 chinasi (P70S6K) e sulla sua correlazione con la risposta immunitaria e il decorso della malattia. Gli scienziati puntano a svelare l’impatto esercitato dalla modulazione di P70S6K sui linfociti infiltranti il tumore e sulla progressione dello stesso. Con il fallimento della chemioterapia e dell’immunoterapia convenzionali, i risultati del progetto dispongono del potenziale per svelare nuovi bersagli terapeutici per il TNBC.
Obiettivo
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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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
28029 Madrid
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