DDRESPONSE · The DNA damage response and breast cancer

We will exploit the DNA damage response (DDR) to assess and predict individual susceptibility and response focussed on breast cancer and breast cancer therapies. The 1st targeted therapy based on the DDR is inhibition of PARP by olaparib, which induces synthetic lethality in cancer cells with a specific DDR defect. Our members discovered olaparib, which is currently in Phase II trials. Its use in DDR deficient cancers represents a truly personalised healthcare approach. Due to the complexity of the DDR more therapeutically exploitable cases of synthetic lethality are to be discovered, which may be applied to specific tumours and patients. To this end our objectives include: To determine key differences in the DDR between cancer and normal cells, because they constitute important targets for directed individual therapy; establish the roles of DDR mechanisms as these relate to damage induced by anti-cancer therapies to explain inter-individual variation in therapy response; define how different DDR pathways compensate for one another, because this may suggest how targeting one DDR component with a drug could have marked cytotoxic effects on a cancer but not on normal cells; develop and validate markers for functionality of the DDR in fresh tumour biopsies, directly from the clinic, for selection of patients for personalised treatment.Collectively, this consortium has an unrivalled depth and breadth of expertise. We have access to a wide range of new and emerging technologies, while we bring complementary strengths to the project with regard to topics, models, materials, techniques and clinical links, which include the two largest cancer hospitals in Denmark and the Netherlands. Thus, the consortium represents the ‘state-of-the-art’ and has the scope to evolve their knowledge of the DDR into new and exciting areas for assessment of individual susceptibility and prediction of individual responses to cancer therapies, as well as development of new anti-cancer therapies