Sub-clonal RNASH2B/RB1 loss, luminal-to-basal transformation, and novel therapeutic vulnerabilities in metastatic prostate cancer

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Advanced prostate cancer is characterised by the emergence of resistance to hormone therapy, and is invariably fatal. The biological mechanisms underlying the evolution to an aggressive, treatment-resistant state are diverse, and have not yet been fully characterised. Further understanding of these mechanisms will allow the development of targeted treatment strategies.Our DNA is exposed to damage in various forms each day, and relies on our body's innate mechanisms to repair this, and protect our genetic code. Recent evidence has identified defects in the ability to repair damage to DNA in 20-30% of advanced prostate cancer patients. This results in the accumulation of DNA damage, which makes cancer cells dependent on alternative pathways for survival, which we can exploit therapeutically, with agents targeting DNA repair pathways, such as PARP and ATR inhibitors. However, there is a need for more robust tests to easily identify patients who may benefit from such therapies.DNA repair defects enable the accumulation of DNA damage, which can be expressed as proteins (neo-antigens) on the cancer cell. These make the cancer more visible to the immune system, and therefore more vulnerable to treatments which act on immune cells to trigger an anti-cancer immune response, such as immune checkpoint inhibitors.A new DNA repair defect, RNASEH2B loss, commonly present in advanced prostate cancer, has recently been identified, and is associated with heightened sensitivity to PARP/ATR inhibition. It is located on chromosome 13, close to RB1, a gene which is frequently deleted in aggressive forms of PC, at a late stage in the disease evolution, and is associated with poor outcomes. Our preliminary data suggests these genes are often deleted together, and this may contribute to the development of aggressive 'basal/neuroendocrine' PC cells which drive hormone resistance. We hypothesise that patients with RNASEH2B loss represent a novel cohort of patients with distinct biology who may respond to PARP/ATR inhibitors and/or immunotherapy. Here, I seek to explore the incidence of this co-deletion in prostate cancer, and its impact on tumour evolution and sensitivity to PARP/ATR inhibitors and immunotherapy. I hope to demonstrate that RNASEH2B/RB1 loss is identifiable within peripheral blood samples, and can be easily measured to identify candidates for treatment. If I demonstrate enhanced sensitivity to PARPi, ATRi or immunotherapy in pre-clinical models, I will endeavour to establish a proof of concept phase II trial of PARPi +/- ATRi (arm 1) and immunotherapy (arm 2) in RNASEH2B/RB1 deficient prostate cancer.I envisage that this research will enable better molecular stratification of advanced prostate cancer, and identify and target aggressive, resistant PC cells to enable us to develop novel therapeutic strategies to transform the treatment and outcomes for patients.