Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer

利用 RB1 缺陷治疗致命性神经内分泌前列腺癌

• 批准号: 9763338
• 负责人: Leigh Ellis
• 金额: $ 49.06万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763338
• 关键词: Acetates; Acute; Address; Androgen Receptor; Autopsy; CYP17A1 gene; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chromatin; Clinical; Clinical Management; DNA Sequence Rearrangement; Data; Diagnosis; Disease; Disease Resistance; Drug Targeting; Effectiveness; Epigenetic Process; Exhibits; Gene Expression; Generations; Genetically Engineered Mouse; Goals; Growth; Health; Histology; Human; Human Cell Line; Human Engineering; In Vitro; Incidence; Life; Ligands; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Carcinoma; Neurosecretory Systems; Patients; Pharmaceutical Preparations; Play; Prevalence; Process; Prostate Adenocarcinoma; Publishing; RB1 gene; Receptor Activation; Receptor Signaling; Recurrence; Recurrent disease; Relapse; Research; Resistance; Resistance development; Role; Societies; Testing; Therapeutic; Tumor Burden; Tumor Suppressor Genes; Variant; Visceral; Visceral metastasis; abiraterone; androgen deprivation therapy; base; clinically relevant; combat; design; effective therapy; experimental study; genetic approach; human data; improved; in vivo; inhibitor/antagonist; innovation; intratumoral androgen; loss of function; men; molecular targeted therapies; mortality; mouse model; novel; novel therapeutic intervention; preclinical study; preclinical trial; prostate cancer metastasis; prostate cancer model; prostate cancer progression; receptor expression; resistance mechanism; response; steroid metabolism; targeted treatment; therapeutic target; therapy resistant; tumor

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.

前列腺癌可治疗，可用疗法和所有前列腺癌死亡率。 考虑到前列腺癌是男性最常见的内脏癌，这是一个重大的健康问题 西方社会癌症死亡的第二大原因。雄激素剥夺疗法（ADT）是 最有用的疗法可用。尽管该分子靶向治疗具有最初的有效性，但 但是，患者不可避免地会因抗ADT疾病而复发。 ADT的特征形式很好 抗性包括改变雄激素受体（AR），导致持续性，有时是配体 独立的AR信号传导以及维持肿瘤内雄激素水平的类固醇代谢的变化 足够用于AR信号。较新的一代药物，例如上级AR拮抗剂Enzalutamide或 CYP17A1抑制剂阿比罗酮乙酸可以对抗这些ADT耐药机制，并延长了男性的生命 复发性疾病，但事实证明，反应短暂。因此，延迟或逆转ADT阻力是 事实证明，这是一个重要的治疗目标，可以延长患者的生存。随着AR封锁的改善，一个独特的 具有神经内分泌特征的AR阴性癌症的跨性别分化的抗性形式 （NEPC）越来越多地观察到。 NEPC在没有上升的情况下随着非典型内脏转移的 PSA，目前在大约25％的前列腺癌尸检中观察到。发病率可能会增加 更多的患者受益于改善ADT。 NEPC跨分化为基础的分子机制是 不清楚，也没有针对性的疗法来治疗它。我们从人类细胞系中介绍数据， 提示RB1损失的小鼠模型是促进NEPC反式分化的关键决定因素。我们建议 RB1损失可缓解对基因表达的表观遗传重编程的限制，从而促进 反式分化为AR负ADT抗ADT NEPC。如果是真的，NEPC跨分化应该是 可逆。与此预测一致，初步数据表明一些表观遗传调节药物还原 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跨分化的机制，评估其 通过跨物种分析进行临床相关性，并使用临床前试验测试其作为治疗靶标的效用。 成功完成这些目标将解决前列腺癌临床管理的关键问题 并将填补我们对前列腺癌进展，治疗性的基本理解的主要空白 电阻，RB1在这些过程中的功能丧失起作用。