Descrizione del progetto
Esaminare i meccanismi molecolari alla base della resistenza alla radioterapia
La radioterapia è un trattamento antitumorale diffuso ma, nonostante il suo successo, viene ostacolata dalla comparsa di resistenza locale e di metastasi a distanza. L’obiettivo chiave del progetto TETHER, finanziato dall’UE, è quello di svelare i meccanismi molecolari alla base della resistenza alla radioterapia. I ricercatori effettueranno l’editing genetico in modelli murini e organoidi unici, al fine di mappare la rete funzionale dei geni che svolgono un ruolo significativo nella resistenza alla radioterapia. La definizione dei meccanismi impiegati dalle cellule tumorali per sottrarsi alla radioterapia forniranno importanti informazioni nella progettazione di approcci personalizzati volti a migliorare la risposta al trattamento dei pazienti colpiti dal cancro.
Obiettivo
"More than 50% of the cancer patients undergo irradiation as part of their cancer treatment. Although radiotherapy (RT) significantly contributes to cancer cure, local therapy resistance and the subsequent emergence of distant metastasis remain major obstacles for its success. The molecular mechanisms underlying tumor cell-intrinsic RT resistance are ill-defined. It is therefore crucial to better define these mechanisms and identify new vulnerabilities of RT-resistant tumors in order to decrease the current annual cancer mortality of >1.3 million persons in EU member states alone.
In the TETHER project, I will address the problem of RT resistance by synergizing the power of genetic essentiality analyses with unique mouse models and organoids that we have established. We recently found that members of the shieldin and CST complexes are essential for tumor cells to survive irradiation, while causing PARP inhibitor resistance when lost in BRCA1-deficient tumors. Based on this unexpected finding, I have started a new line of research to dissect the RT ""essentialome"". As I show with the discovery and functional characterization of ERCC6l2 as a novel DNA repair factor in this network, the technology we have in place is perfectly suited to tackle this question. In addition, we will apply distinct CRISPR/Cas9-based tests to map the functional interactome of genes that are essential for RT resistance.
To follow the plasticity and RT escape of tumor cells in vivo, we have also developed innovative model systems. Similar to the situation in cancer patients, we observe that residual cancer cells in our mouse models escape the deadly effects of RT by local resistance or metastasis formation. Thus, these models provide a unique opportunity to explore and target RT escape mechanisms. I am convinced that the combination of these state-of-the-art approaches will yield highly useful information for designing individualized approaches to improve RT response in cancer patients.
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Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
3012 Bern
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