DDRESPONSE

The DNA damage response and breast cancer

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 Obiettivo del progetto (Objective)

'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'

Introduzione (Teaser)

A successful anticancer strategy should be able to discriminate between normal and cancer cells. By targeting the DNA damage response pathway, a European initiative brings forward a promising cancer-specific approach.

Descrizione progetto (Article)

Our DNA is continuously being damaged, a phenomenon that may lead to cell death or even cancer. However, our cells have evolved sophisticated mechanisms, collectively known as the DNA damage response, to repair DNA lesions. Cancer treatment by chemotherapy and radiotherapy also aims to selectively induce death in the rapidly proliferating cancer cells by damaging their DNA.

Accumulating evidence indicates that cancer cells are defective in their DNA damage response machinery, opening up new avenues for therapeutic exploitation. A recent breakthrough study has shown that breast cancer cells lacking the familial genes BRCA1/2 are sensitive to apoptosis following inhibition of the PARP1 enzyme that repairs single-strand DNA breaks.

Scientists on the EU-funded project 'The DNA damage response and breast cancer' (http://www.ddresponse.eu/ (DDRESPONSE)) hope to extend these findings and identify additional inhibitors of the DNA damage response. Also, they wish to identify markers other than the lack of BRCA1/2 that could be associated with a dysfunctional DNA damage response. Therefore, scientists are constructing a list of markers that could reliably predict the outcome of treatment with PARP inhibitors. A considerable part of DDRESPONSE efforts is also dedicated to finding epigenetic markers by determining how epigenetic alterations in cancer cells may influence the activity of the DNA damage response.

The research teams have also successfully established cultures of primary breast and ovarian cancer cells to characterise their DNA damage response mechanisms. Using high-resolution microscopy, they have managed to visualise complexes of DNA repair proteins. An additional assay has been developed that screens DNA damage repair and could hence be used to select cancers eligible for PARP inhibition.

Lack of toxicity of PARP inhibition in normal tissue renders this approach highly cancer-specific. By assessing the status of the DNA damage response in individual patients, clinicians envision the personalisation of anticancer therapy.