Project description
Understanding mechanisms of drug resistance in homologous recombination-deficient cancer
Drug resistance represents the major cause of death among cancer patients, including those with tumours that are defective in DNA repair by homologous recombination (HR). The emergence of resistance of primary or secondary tumours greatly minimises therapeutic options and reduces patient survival rates. The ERC-funded SYNVIA project will investigate therapy resistance by using genetically engineered mouse models for BRCA1- and BRCA2-deficient breast cancer. These models closely mimic human disease and the emerging tumours lack HR-directed DNA repair. Cancer cells in these models eventually acquire resistance to chemotherapy or targeted drug treatments, providing a unique opportunity to study therapy escape mechanisms. The combination of the project’s state-of-the-art approaches will provide new information to overcome therapy resistance in human cancer patients.
Objective
Although various effective anti-cancer drug treatments have become available over the last decades, drug resistance remains the major cause of death of cancer patients. Striking examples are patients with tumors that are defective in DNA repair by homologous recombination (HR). Despite initial responses to cancer therapy, resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. The molecular mechanisms underlying this therapy escape are often poorly understood.
In the SYNVIA project I will address the problem of therapy escape by using powerful genetically engineered mouse models for BRCA1- and BRCA2-deficient breast cancer, which closely mimic the human disease. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair. Similar to the situation in cancer patients, we observe that cancer cells in these models eventually escape the deadly effects of chemotherapy or novel targeted drugs. Thus, these resistance models provide a unique opportunity to explore therapy escape mechanisms.
I propose an approach that will take the in vivo analysis of therapy resistance mechanisms to a new level. By synergizing the advantages of next generation sequencing with functional genetic screens in tractable model systems, I will explore novel mechanisms that cause resistance of HR-deficient cancers by the loss of another gene (“synthetic viability”). I provide evidence that new mechanisms of resistance can be identified with this approach. In an innovative step, I will generate genome-wide alterations using the revolutionizing CRISPR/Cas technology. Mutations will also be introduced into 3D tumor organoid cultures, as we found that these are more physiologically relevant. I am convinced that the combination of these state-of-the-art approaches will yield highly useful information for designing effective approaches to circumvent or reverse therapy escape in human cancer patients.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- social sciencessociologydemographymortality
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesclinical medicineoncologybreast cancer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
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Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
3012 Bern
Switzerland