DREMATURE · DNA repair mechanisms and therapy resistance of BRCA2-deficient cancers
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-01-01 → 2019-12-31
- EU contribution
- €187,420
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
DNA repair mechanisms and therapy resistance of BRCA2-deficient cancers
Despite the current advances in cancer therapy, most patients with disseminated cancer still die because their tumors become resistant to the available drugs. Thus, drug resistance remains a major challenge in clinical oncology. Because tumor cells often have alterations in DNA repair mechanisms, therapies that target DNA are usually effective and quite selective for this type of cells. Examples of these malignancies are ovarian and breast cancer with deficiency in the repair of DNA double strand breaks due to mutations in BRCA1 or BRCA2 genes. They are especially sensitive to PARP inhibitors (PARPi), a recently approved targeted therapy that leads to DNA double strand breaks in BRCA mutated cells. However, resistance is an inevitable fact also in the context of those type of cancers. The precise mechanisms underlying resistance to novel targeted drugs such as PARPi are poorly understood. The overall goal of the DREMATURE project was to identify new mechanisms by which BRCA2-deficient breast cancer cells develop drug resistance to PARPi and thereby gain novel insights into the basic DNA damage response processes. Based on the results of this action, I expect that, eventually, new tools can be implemented in the clinic to predict and explain patient resistance to PARPi. Moreover in the case of patients who do not respond to PARPi, I predict that based on these results, that a personalized strategy can be developed to increase the sensitivity of the cancer cells to this treatment.
Data: CORDIS, © European Union
Project objective
Despite the existence of various novel anti-cancer treatments, drug resistance remains a major cause of death in patients with disseminated cancer. To increase specificity and efficacy, modern treatment strategies in molecular oncology employ the “synthetic lethality” concept. An example are BRCA1/2-deficient breast and ovarian cancers that lack DNA repair by homologous recombination (HR). Due to this defect, tumor cells rely more on other DNA repair pathways. When such alternative pathways are jammed, e.g. by poly(ADP-ribose) polymerase inhibitors (PARPi), normal cells with intact HR can survive, whereas cancer cells die. However, even with this sophisticated treatment strategy, resistance to PARPi still occurs and greatly reduces patient survival. The mechanisms driving this resistance are still largely unknown. The main goal of this project is to advance the knowledge on therapy resistance by using a genetically engineered mouse model of BRCA2-deficient breast cancer, which closely mimics the human disease. Like in patients, cancer cells in these animals eventually escape from therapy. I will start by synergizing the next generation sequencing analysis of spontaneous resistant mouse tumors with functional genetic screens using the CRISPR/Cas9 technology. This combination has yielded interesting candidate genes whose loss of function may cause resistance. Two promising candidates, MDC1 and Claspin, will be further investigated using innovative and physiologically relevant 3D tumor organoid cultures. Moreover, I will apply my expertise in modern imaging technology to develop novel approaches to visualize DNA repair dynamics in resistant tumors in vitro and in vivo. I am convinced that by understanding basic resistance mechanisms, smart biosensors can be built to image the DNA damage response and eventually improve clinical decision making. I believe this project will have an impact on the design of strategies to overcome therapy escape in human cancer patients.
Original text from CORDIS.
Participants
- UNIVERSITAET BERN · BernCoordinatorSwitzerland
Links
- View on CORDIS
- DOI: 10.3030/743290
- https://www.itpa.vetsuisse.unibe.ch/research/therapy_escape_of_cancer/index_eng.html
Data: CORDIS, © European Union