Description du projet
L’impact du bagage génétique sur la réponse à la chimiothérapie
Les cellules assurent la stabilité génomique grâce à divers mécanismes qui réparent les lésions de l’ADN induites par les médicaments ou le rayonnement ultraviolet. L’un d’eux, la réparation par excision des nucléotides du génome global (GG-NER), détecte les lésions importantes de l’ADN n’importe où dans le génome, indépendamment de la transcription, puis les répare. Le projet REAP, financé par l’UE, entend comprendre comment les mutations de la voie GG-NER affectent les effets des médicaments à base de platine tels que l’oxaliplatine et le cisplatine. Les chercheurs étudieront les mutations qui affectent cette reconnaissance différentielle des lésions dues au platine par la GG-NER. Les connaissances ainsi acquises permettront d’améliorer les résultats des protocoles de chimiothérapie actuels grâce au profilage génétique des patients atteints d’un cancer.
Objectif
DNA damage-inducing platinum drugs, such as oxaliplatin and cisplatin, are used to treat about half of all patients receiving chemotherapy. Although potentially very efficient, many patients develop resistance for yet unrecognized reasons. Better understanding of the DNA damage response (DDR) to platinum-DNA lesions is therefore much needed for improving treatment outcomes.
By performing DDR-dedicated CRISPR/Cas9 knockout screens, the applicant has shown that some cancer cells deficient in the major repair of bulky DNA lesions, global-genome nucleotide excision repair (GG-NER), are insensitive to oxaliplatin but sensitive to cisplatin. This striking difference remains as of yet unreported, but might explain differential responses of tumors to drugs. The aim of this proposal is to understand why GG-NER is unable to repair oxaliplatin lesions in particular genetic backgrounds. To do so, unbiased identification of genes differently mutated or expressed in oxaliplatin-sensitive versus insensitive cells will be followed by validation and in-depth functional characterization of identified targets. The ambition is to extrapolate experimental observations to translational knowledge. Validated targets will be studied in patient-derived tumor tissues as compared to nonmalignant tissues and related to patients’ treatment responses. Identification of genetic factors that regulate platinum lesions recognition by GG-NER will contribute to the understanding of molecular principles of platinum drugs cytotoxicity and might thus have considerable benefit on current cancer treatment schemes.
The novelty of the pilot data, the unique multidisciplinary design of the project, the use of state-of-the-art molecular techniques and a collaboration with multiple European experts will ensure high scientific impact. Both, the applicant and the host will greatly benefit from the vital knowledge transfer. This project follows the European Union's commitment to cancer research.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
1090 Wien
Autriche