Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer

转移性前列腺癌是现有治疗方法无法治愈的，也是前列腺癌死亡的主要原因。 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， 在西方社会，癌症死亡的第二大原因。雄激素剥夺疗法(ADT)是 最普遍有效的治疗方法是可用的。尽管这种分子靶向治疗最初是有效的， 然而，患者不可避免地会复发，患有ADT耐药疾病。ADT的特征形式很好 耐药包括雄激素受体(AR)的改变，导致持久的，有时甚至是配体 独立的AR信号以及维持肿瘤内雄激素水平的类固醇代谢的变化 足以发送AR信号。新一代药物，如高级AR拮抗剂苯扎鲁胺或 CYP17A1抑制剂醋酸阿比特龙对抗这些ADT抵抗机制并延长男性患者的生命 复发的疾病，但反应被证明是短暂的。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时间。随着AR封锁的改善，一个独特的 对具有神经内分泌特征的AR阴性癌症的转分化耐药形式 (NEPC)越来越多地被观察到。无上升的NEPC进展为不典型的内脏转移 PSA，目前在约25%的前列腺癌尸检中观察到。发病率可能会随着 更多的患者受益于ADT的改善。NEPC反式分化的分子机制是 不清楚，也没有针对性的治疗方法可用来治疗它。我们展示了来自人类细胞系的数据， 小鼠模型表明，RB1缺失是促进NEPC反式分化的关键决定因素。我们建议 Rb1缺失解除了对基因表达的表观遗传重编程的限制，从而促进了 反式分化为AR阴性、ADT耐药的NEPC。如果为真，则NEPC转换差异化应为 可逆的。与这一预测一致，初步数据表明，一些表观遗传调节药物恢复了 AR在NEPC中的表达及对苯扎鲁胺的敏感性拟议研究的具体目标是 挑战中心假说，表征导致NEPC反式分化的机制，评估其 通过跨物种分析进行临床相关性分析，并使用临床前试验测试其作为治疗靶点的有效性。 这些目标的成功实现将解决前列腺癌临床治疗中的一个关键问题 将填补目前我们对前列腺癌进展、治疗方面的基本认识的主要空白 抗性，以及RB1功能丧失在这些过程中所起的作用。

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.