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

晚期前列腺癌的特点是出现对激素治疗的耐药性，并且总是致命的。进化到侵袭性、耐药状态的生物学机制是多种多样的，尚未完全表征。进一步了解这些机制将有助于制定有针对性的治疗策略。我们的DNA每天都会受到各种形式的损伤，并依靠我们身体的先天机制来修复它，保护我们的遗传密码。最近有证据表明，20-30%的晚期前列腺癌患者存在修复DNA损伤的能力缺陷。这导致DNA损伤的积累，这使得癌细胞依赖于其他途径生存，我们可以利用治疗方法，利用靶向DNA修复途径的药物，如PARP和ATR抑制剂。然而，需要更可靠的测试来容易地识别可能从这种疗法中受益的患者。DNA修复缺陷导致DNA损伤的积累，这些损伤可以在癌细胞上以蛋白质（新抗原）的形式表达。这使得癌症更容易被免疫系统发现，因此更容易受到免疫细胞引发抗癌免疫反应的治疗的影响，比如免疫检查点抑制剂。一种新的DNA修复缺陷，RNASEH2B缺失，通常存在于晚期前列腺癌中，最近被发现，并与PARP/ATR抑制敏感性增高有关。它位于13号染色体上，靠近RB1，该基因在侵袭性PC中，在疾病发展的晚期经常被删除，并与不良预后相关。我们的初步数据表明，这些基因经常一起被删除，这可能有助于侵略性的“基础/神经内分泌”PC细胞的发展，从而驱动激素耐药性。我们假设RNASEH2B缺失患者代表了一个具有独特生物学特征的新患者群体，他们可能对PARP/ATR抑制剂和/或免疫治疗有反应。在这里，我试图探讨这种共缺失在前列腺癌中的发生率，以及它对肿瘤进化和对PARP/ATR抑制剂和免疫治疗的敏感性的影响。我希望证明RNASEH2B/RB1丢失在外周血样本中是可识别的，并且可以很容易地测量以确定治疗的候选者。如果我在临床前模型中证明对PARPi、ATRi或免疫治疗的敏感性增强，我将努力在RNASEH2B/RB1缺陷前列腺癌中建立PARPi +/- ATRi（第1组）和免疫治疗（第2组）的概念验证II期试验。我设想这项研究将使晚期前列腺癌的分子分层更好，并识别和靶向侵袭性，耐药的PC细胞，使我们能够开发新的治疗策略来改变患者的治疗和结果。

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.