Predictive biomarkers of response to DNA repair targeting agents in sporadic prostate cancer

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Prostate cancer is the commonest cancer in men, but despite recent advances with new drugs approved over the last few years, there is a lack of tests to select individually the best treatment for each patient. We observe in the daily clinical practice how some patients with prostate cancer have a very indolent course of disease whereas others may have a very aggressive type of cancer and may not respond to standard therapies. Our research aims to provide a tool to identify early who are the patients who may have a disease with worst prognosis and may need a different treatment, by assessing how the tumour cells repairs its integrity after damages.A group of proteins (each of them codified by one gene) is involved in the response of the cell to some types of damage, in a process called "DNA repair". We now know that a proportion of patients with advanced prostate cancer would have one or more genetic switches in the different genes involved in this DNA repair system. PARP inhibitors are a class of drugs in current development to treat cancer in patients; the biggest success so far has occurred in treating patients with particular inherited switches in the DNA repair genes BRCA1/2. People with this BRCA mutations are more likely to develop beast, ovarian or prostate tumours, among other cancers and it has been shown that these people develop a very aggressive subtype of prostate cancer, with quicker progression and worst outcome. Some studies in the laboratory have shown that when a cell has one or more defects in other genes involved in the DNA repair system, it could also become equally responsive to PARP inhibition. Indeed, there is clinical evidence of some benefit of PARP inhibition in ovarian cancer in patients without BRCA1/2 inherited mutations. At the Institute of Cancer Research, together with The Royal Marsden NHS Trust, we are currently running clinical trials of PARP inhibitors for patients with advanced prostate cancer without an inherited BRCA mutation.The research project we present aims to:a) Determine the frequency of defects in the genes involved in DNA repair in sporadic (non-hereditary) prostate cancers and to determine how relevant are these defects in terms of determining the prognosis of the patient or the likelihood of responding to standard treatments.b) Analyse the differences in the genomic profile from the patients with sporadic prostate cancer who have benefited from PARP inhibitors to those who have not responded to these drugs.b) Evaluate in laboratory cell models how these genetic switches impact in the capacity of the cells to repair DNA damage and how these determine the sensitivity to different treatments.d) Set up a laboratory test that can be performed in any patient with prostate cancer to predict if their particular disease is likely to be sensitive to PARP inhibitors. These test will be used to optimise the recruitment of advanced prostate cancer patients for large clinical trials with PARP inhibitors.