The key objective of this Marie Curie project is to explore the ‘synthetic lethality’ and ‘synthetic viability’ principles applied to DNA damage response (DDR) mechanisms and help derive new therapies and/or biomarkers for personalized treatment of breast and prostate cancer. As these tumors are major causes of mortality and morbidity in Europe, and this multifaceted project in an outstanding host environment provide unique opportunities for training, this ‘SYNvia’ proposal directly addresses the prevailing medical needs and issues relevant for this Work Programme. The emerging potential of drugs/inhibitors to block certain DDR pathways is illustrated by the successful clinical trials with PARP1 inhibitors on BRCA1/2-deficient breast/ovarian tumours. This documents the power of combined interference with different DDR processes: ‘synthetic lethality’ (synthesis of cancer-specific defect of one DNA repair pathway with a drug to inhibit another repair mechanism) to combat cancer. The host laboratory made several discoveries in the DDR/cancer field, including examples of synthetic lethality, and contribution to the first example of synthetic viability, the latter causing resistance to cisplatin or PARP inhibitors in BRCA-defective cancers through loss of 53BP1. Here, we will use high-content siRNA-based functional screens to pinpoint novel synthetic viability and lethality combinations of the down-regulated genes with promising inhibitors of, respectively, PARP1 or the key DDR kinases ATM, ATR and DNA-PK. A range of cell and molecular biology and imaging methods will serve to validate selected combinations, combined with mouse xenograft experiments and tumour microarrays to test candidate biomarkers. As all tools and methods are available, this ambitious project is feasible. Given that tumours commonly harbour DDR defects, this project will help exploit our knowledge of the DDR to optimize and further personalize cancer treatment, while minimizing side effects.
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