Grant: Project Grant

In its most aggressive form, prostate cancer has already spread to the bone and/or lymph nodes at the time of first diagnosis. These sites of cancer outside the prostate are called metastases, and cause most cancer-related deaths. People with metastases at first diagnosis have what is termed 'de novo' metastatic prostate cancer, and have a very poor prognosis. Excitingly, new and emerging therapies can significantly improve life expectancy. However, potentially toxic drugs should be applied discriminately, only where patient quality or quantity of life will be significantly improved. This is not currently the case in prostate cancer management: patients receive treatments that are not personalised against their cancer. The major barrier to improved patient stratification is that we do not understand the relationship and composition of the prostate and metastatic cancers in de novo metastatic disease. This is because affected patients do not undergo surgery to remove their prostate or metastases, so historically there has been little cancerous tissue to study. We have compiled the first standardized cohort of surgically-removed tumours from people at first diagnosis with de novo metastatic prostate cancer, before they begin other treatment. This includes the whole prostate, individual metastases, and also tumour DNA shed into the blood (a 'liquid biopsy'). We plan to use custom DNA sequencing approaches and novel computational algorithms to understand how these coexisting primary and metastatic cancers are related to each other. We will identify the precise regions of the primary cancer that gave rise to lethal metastatic disease. Our work will establish a framework for identifying the molecular features of metastatic prostate cancer at first diagnosis. This framework can then be used in clinical trials to implement therapeutic strategies that are more tailored to patient-specific disease biology, reducing the mortality and morbidity of aggressive prostate cancer.