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抵抗，并且总是致命的。进化为侵袭性、耐药状态的生物学机制多种多样，尚未完全确定其特征。对这些机制的进一步了解将有助于开发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，并依赖于我们身体固有的机制来修复这种损伤，并保护我们的遗传密码。最近的证据表明，在20-30%的晚期前列腺癌患者中，修复DNA损伤的能力存在缺陷。这会导致DNA损伤的积累，使癌细胞依赖于替代的生存途径，我们可以利用针对DNA修复途径的药物，如PARP和ATR抑制剂，在治疗上利用这些途径。然而，需要更强大的测试来轻松识别可能从这种治疗中受益的患者。DNA修复缺陷使DNA损伤积累，DNA损伤可以在癌细胞上以蛋白质(新抗原)的形式表达。这些使癌症更容易被免疫系统发现，因此更容易受到作用于免疫细胞以触发抗癌免疫反应的治疗，如免疫检查点抑制剂。最近发现了一种新的DNA修复缺陷，RNASEH2 B丢失，常见于晚期前列腺癌，与对PARP/ATR抑制的高度敏感性有关。它位于13号染色体上，靠近RB1基因，在疾病进化的后期，RB1基因在侵袭性PC中经常缺失，与不良预后有关。我们的初步数据表明，这些基因经常一起缺失，这可能有助于侵略性的“基础/神经内分泌”PC细胞的发展，从而驱动激素抵抗。我们假设RNASE2B缺失的患者代表了一组具有不同生物学特征的患者，他们可能对PARP/ATR抑制剂和/或免疫治疗有反应。在这里，我试图探索前列腺癌中这种联合缺失的发生率，以及它对肿瘤演变以及对PARP/ATR抑制剂和免疫治疗的敏感性的影响。我希望证明RNASE2B/RB1缺失可以在外周血样本中识别出来，并且可以很容易地测量出来，以确定候选治疗。如果我在临床前模型中表现出对PARPI、ATRI或免疫疗法的增强敏感性，我将努力建立PARPI+/-ATRI(ARM 1)和免疫疗法(ARM 2)在RNASH 2B/RB1缺陷前列腺癌中的概念验证II期试验。我预计这项研究将使晚期前列腺癌能够更好地进行分子分层，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.