Grant: Project Grant

Inhibiting androgen receptor (AR) signalling is the standard of care to treat aggressive prostate cancer. Yet while treatment is initially effective the cancer almost always develops resistance. This treatment resistant form of prostate cancer frequently remain dependent on AR signalling. However, the AR activity is markedly different and binds to thousands of new DNA sites. While we can readily identify these new binding sites we don't know why they change or how they contribute to prostate cancer growth. Our project therefore is aimed at identifying exactly which of these DNA binding sites enable the tumor cell to seed throughout the body and cause lethal metastatic disease. We have formed an international team of expert scientists, with complementary areas of expertise to jointly solve this tremendous clinical challenge. First, we will use advanced DNA-activity-technologies, to interrogate each of these 17,000 'DNA switches' one-by-one to determine if they have the capacity to be active in prostate cancer cells. Second, we will use state-of-the-art molecular biology techniques to determine how these DNA switches change during in progression to resistance. After identifying those specific 'switches' we will validate our findings in several experimental models. Finally, we will identify what drives this change in AR activity. Overall our studies will greatly improve our understanding of the biology that drives lethal metastatic prostate cancer, and explain the differences in prognosis between patients. These results will reveal novel therapeutic avenues tailored to the unique biology of the tumour and also represent a major step towards curative treatment of metastatic prostate cancer.