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Overall strategy and general description

The major discovery on which this project is based, is the selective killing of tumours, carrying a defect in the homologous recombination (HR) repair genes BRCA1 and 2, because of their exquisite sensitivity to inhibitors of the single strand break repair protein PARP, which by itself leaves normal tissue virtually untouched. This is the most desired way of combating cancer but also a prime example of personalised cancer therapy. DDResponse intends to further develop the use of this specific inhibitor by generating tools that identify patients eligible for this very promising treatment, avoid undesired effects of normal tissue and optimise the use in combination with other treatments. At the same time this project aims to expand the concept of synthetic lethality to other combinations of DDR pathways and anti-cancer treatments to identify other patient populations which may equally benefit from highly selective and effective targeted therapies. To accomplish these goals our overall strategy involves 5 defined approaches described in highly integrated work packages:

  1. In depth analysis of high-throughput '-omics' databases of numerous highly defined breast tumours to identify DDR biomarkers that reveal the BRCA1/2 status and in a broader perspective the functioning of the HR repair pathway as a whole in order to predict sensitivity of tumours to PARP inhibitors and other therapeutic interventions targeting the DDR. The consortium has one of the most extensive breast cancer biobanks available, including data on mRNA and miRNA expression profiles and proteomics, combined with detailed clinical follow-up information (partner 1, Erasmus MC). In addition, we will use experimentally versatile cell lines.
  2. Genetic (synthetic lethality) and proteomic screens of model organisms (C. elegans, S. cerevisiae) and mammalian cell lines will be carried out to discover novel therapeutic approaches that exploit individual tumour-specific DNA repair deficiencies. These approaches may extend the spectrum of tumours targeted by PARP inhibitors and may lead to novel drugs that exploit other DDR defects in tumours.
  3. To improve the therapeutic ratio of PARP and other DDR inhibitors (with or without additional anti-cancer treatments) normal bone marrow stem and progenitor cells will be used to establish normal tissue toxicity profiles. Conversely, we intend also to select predictive biomarkers that indicate subsets of human breast and ovarian tumours resistant to standard genotoxic chemotherapy, in order to avoid overtreatment of such patients. Mouse models will be used to dissect interactions of repair pathways in various tissues, which will be important to get a better understanding of the relative contributions of various DDR pathways in different tissues and cell types.
  4. We will develop innovative protocols that use viable organotypic slices of normal tissue and tumour specimens such that their DDR can be quantitatively and functionally determined ex vivo following exposure to genotoxic agents and DDR inhibitors. This will enable diagnosis and treatment in a tailor-made fashion.
  5. Building upon the methods for ex vivo DDR assays, we intend to perform a comprehensive analysis of breast and ovarian tumour specimens and correlate the ex vivo DDR parameters with relevant clinical observations and pathology results.
These ambitious strategies will optimise and customise the use of drugs that target the DDR and each of them requires input, expertise and infrastructure of multiple partners in a concerted, synergistic fashion.