Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer

转移性前列腺癌是不可治愈的可用疗法，并占所有前列腺癌死亡率。 这是一个重大的健康问题，因为前列腺癌是男性最常见的内脏癌， 是西方社会癌症死亡的第二大原因。雄激素剥夺疗法（ADT）是 最常用的治疗方法。尽管这种分子靶向治疗最初有效， 然而，患者将不可避免地复发ADT耐药疾病。ADT的良好表征形式 耐药性包括雄激素受体（AR）的改变，导致持续的，有时配体 独立的AR信号传导以及类固醇代谢的变化，维持瘤内雄激素水平 足够的AR信号。较新一代的药物，如上级AR拮抗剂恩杂鲁胺或 CYP17A1抑制剂醋酸阿比特龙对抗这些ADT耐药机制，延长男性患者的寿命。 复发性疾病，但反应已被证明是短暂的。因此，延迟或逆转ADT抵抗是 这是一个重要的治疗目标，因为它被证明可以延长患者的生存期。随着AR封锁的改善，一个独特的 涉及对具有神经内分泌特征的AR阴性癌症的转分化的抗性形式 （NEPC）越来越多地被观察到。NEPC进展伴不典型内脏转移， PSA，目前在约25%的前列腺癌尸检中观察到。发病率可能会增加， 更多患者受益于ADT改善。NEPC反式分化的分子机制是 目前还不清楚，也没有靶向治疗方法可以治疗它。我们提供了来自人类细胞系的数据， 小鼠模型表明RB1缺失是促进NEPC转分化的关键决定因素。我们建议 Rb 1缺失解除了对基因表达的表观遗传重编程的限制，从而促进 转分化为AR阴性、ADT耐药NEPC。如果为真，NEPC转分化应 可逆的与这一预测相一致，初步数据表明，一些表观遗传调节药物可以恢复 NEPC中的AR表达和Enzalutamide敏感性。拟议研究的具体目标是 挑战中心假设，表征导致NEPC转分化的机制，评估其 通过跨物种分析确定其临床相关性，并使用临床前试验测试其作为治疗靶点的效用。 成功完成这些目标将解决前列腺癌临床管理中的一个关键问题 并将填补我们对前列腺癌进展、治疗和预后的基本理解方面的主要空白， 抗性，以及RB1功能丧失在这些过程中发挥的作用。

Metastatic prostate cancer is incurable with available therapies and accounts for all prostate cancer mortality. This is a significant health problem given that prostate cancer is the most common visceral cancer in men and the second leading cause of cancer death in western societies. Androgen deprivation therapy (ADT) is the most generally useful therapy available. Despite the initial effectiveness of this molecularly targeted therapy, however, patients will inevitably relapse with ADT resistant disease. Well characterized forms of ADT resistance include alterations in androgen receptor (AR) leading to persistent and sometimes ligand independent AR signaling as well as changes in steroid metabolism that maintain intratumoral androgen levels sufficient for AR signaling. Newer generation drugs like the superior AR antagonist enzalutamide or the CYP17A1 inhibitor abiraterone acetate counter these ADT resistance mechanisms and extend life in men with recurrent disease, but responses have proven short lived. Delaying or reversing ADT resistance, therefore, is an important therapeutic goal as it is proven to extend patient survival. As AR blockade has improved, a unique form of resistance involving trans differentiation to an AR negative cancer with neuroendocrine features (NEPC) is increasingly observed. NEPC progresses with atypical visceral metastasis in the absence of rising PSA, and is observed currently in about 25% of prostate cancer autopsies. Incidence is likely to increase as more patients benefit from improved ADT. Molecular mechanisms underlying NEPC trans differentiation are not clear, nor are there targeted therapies available to treat it. We present data from human cell lines and mouse models suggesting RB1 loss is a key determinant facilitating NEPC trans differentiation. We suggest Rb1 loss relieves a constraint on epigenetic reprogramming of gene expression thereby facilitating trans differentiation to AR negative, ADT resistant NEPC. If true, NEPC trans differentiation should be reversible. Consistent with this prediction, preliminary data indicates some epigenetic modulating drugs restore AR expression and enzalutamide sensitivity in NEPC. The specific goals of the proposed research are to challenge the central hypothesis, characterize mechanisms causing NEPC trans differentiation, assess their clinical relevance by cross-species analysis, and test their utility as therapeutic targets using pre-clinical trials. Successful completion of these goals will address a critical issue in the clinical management of prostate cancer and will fill major current gaps in our fundamental understanding of prostate cancer progression, therapeutic resistance, and the role that RB1 loss of function plays in these processes.