Leveraging circulating tumour DNA (ctDNA) to dissect the evolutionary genomic dynamics of drug resistance in prostate cancer.

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1. Scientific/medical context of research?Prostate cancer is the commonest male cancer (41,000 diagnosed in 2010) and the second commonest (10,700 died in 2010) cause of male cancer death in the UK. One man dies of prostate cancer every hour in the UK. The growth of the prostate is dependent on male hormones (androgens). Prostate cancer develops when prostate cells grow uncontrollably. This is initially dependent on androgens. If diagnosed early prostate cancer can be cured by surgery and/or radiotherapy. However, 30% of cases will relapse and more than 20% of cases will present with widespread (metastatic) disease that is incurable. Initial treatment strategies to lower hormone (androgen) levels provide robust responses in 90% of cases (hormone naïve prostate cancer). However, with time, cancers develop other mechanisms of resistance despite low (castrate) levels of testosterone - known as castration resistant prostate cancer (CRPC). Unfortunately, this advanced form of prostate cancer is currently incurable. Over the last two years, two novel treatments have become available as treatment options for CRPC along with chemotherapy. These agents are Abiraterone acetate and Enzalutamide. These agents have been proven to prolong survival in patients with CRPC. Eventually, prostate cancer progresses despite these new drugs and chemotherapy: a proportion of patients respond for a number of years and others progress very rapidly.2. What is the research trying to achieve?Understanding why these agents stop working or drug resistance requires an understanding of DNA changes (genomic) and identifying these changes over time. Treatments for prostate cancer can influence the growth of prostate cancer and understanding this would require analysis of multiple cancer biopsies. This is an impractical solution as performing multiple biopsies is difficult and more importantly uncomfortable to the patient. This proposal will aim to identify these abnormalities with a simple blood test that can be done regularly. This blood test will be able to serially/sequentially monitor tumour gene changes and identify abnormalities in the androgen receptor and other genomic changes that associate with resistance. 3. Why is the research important?Better drugs and management strategies are urgently required. Understanding and identifying causes of resistance at different time points throughout the disease course will allow us to institute early treatment changes and therefore improve patient outcome. Additionally new drugs can be developed to target these mechanisms and also implement a personalised treatment approach for the patients using a non-invasive technique and identify the right treatment for the right patient groups and reduce unnecessary side-effects with ineffective treatments. 4. Who is carrying out the research?Dr Anuradha Jayaram is a clinical research fellow in the Prostate Cancer Targeted Therapy group at the Royal Marsden Hospital in London. She completed her medical degree and specialist oncology training in Ireland. Her career ambition is to be an academic medical oncologist with a laboratory focused on translational research within the field of prostate cancer. This fellowship will be carried out under the supervision of Professors Mel Greaves, Dr Gerhardt Attard and Professor Ros Eeles who are key opinion leaders within the fields of cancer evolution, prostate cancer targeted therapy and prostate cancer genetics. Dr Sharp will be based in the Centre for Cancer and evolution at the Institute of Cancer Research, the top rated academic unit worldwide. The fellowship will initiate a consortium (sponsors and collaborators) of international leaders within the fields of circulating biomarkers and molecular characterisation in prostate cancer medicine to ensure the greatest scientific and clinical impact of this fellowship.