Project description
The impact of genetic background on response to chemotherapy
Cells ensure genomic stability through various mechanisms that repair DNA damage induced by drugs or ultraviolet radiation. One of these, global-genome nucleotide excision repair (GG-NER) detects bulky DNA lesions anywhere in the genome independently of transcription and repairs them. The EU-funded REAP project is interested to understand how mutations in the GG-NER pathway affect the outcome of platinum drugs such as oxaliplatin and cisplatin. Researchers will investigate the mutations that affect this differential recognition of platinum lesions by GG-NER. The generated insight will improve the outcome of existing chemotherapy protocols through genetic profiling of cancer patients.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
1090 Wien
Austria