Projektbeschreibung
Ergründung der molekularen Mechanismen hinter der Strahlentherapieresistenz
Die Strahlenbehandlung ist eine übliche und wirksame Form der Krebsbehandlung. Doch ihr Potenzial wird durch die Entstehung von lokalen Resistenzen und Fernmetastasen eingeschränkt. Hauptziel des EU-finanzierten Projekts TETHER ist es daher, die molekularen Mechanismen zu entschlüsseln, die der Strahlentherapieresistenz zugrunde liegen. Durch Geneditierung an einzigartigen Mausmodellen und Organoiden werden die Forschenden das funktionelle Netzwerk der Gene kartieren, die an der Strahlentherapieresistenz entscheidend beteiligt sind. Die Entschlüsselung der Mechanismen, über die Krebszellen die Strahlentherapie umgehen, wird wichtige Erkenntnisse für personalisierte Behandlungsansätze liefern, mit denen sich die Therapieantwort bei Krebskranken verbessern lässt.
Ziel
"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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Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
3012 Bern
Schweiz