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

基本信息

批准号：
9152986
负责人：
Leigh Ellis
金额：
$ 50.58万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/9152986
关键词：
Accounting Acetates Acute Address Androgen Receptor Androgens 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 Engineering Epigenetic Process Exhibits Gene Expression Generations Genetically Engineered Mouse Goals Growth Health Histology Human Human Cell Line 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 Pharmacotherapy 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 abiraterone base clinically relevant combat deprivation design effective therapy genetic approach improved in vivo inhibitor/antagonist innovation loss of function men mortality mouse model novel novel therapeutic intervention pre-clinical trial preclinical study receptor expression research study resistance mechanism response steroid metabolism targeted treatment therapeutic target therapy resistant tumor tumor progression

项目摘要

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.

转移性前列腺癌用现有疗法无法治愈，并且导致所有前列腺癌死亡。鉴于前列腺癌是男性和女性中最常见的内脏癌，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）是最普遍有用的治疗方法。尽管这种分子靶向疗法最初有效，然而，ADT 耐药性疾病患者将不可避免地复发。 ADT 的明确特征形式耐药性包括雄激素受体 (AR) 的改变，导致持久性耐药，有时甚至是配体耐药独立的 AR 信号传导以及维持瘤内雄激素水平的类固醇代谢变化足够用于 AR 信号传输。新一代药物，如卓越的 AR 拮抗剂 enzalutamide 或 CYP17A1 抑制剂醋酸阿比特龙可对抗这些 ADT 耐药机制并延长男性患者的寿命疾病反复发作，但事实证明反应是短暂的。因此，延迟或逆转 ADT 耐药性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 封锁的改进，一种独特的涉及向具有神经内分泌特征的 AR 阴性癌症的转分化的耐药形式（NEPC）越来越受到关注。 NEPC 在没有上升的情况下进展为非典型内脏转移 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 的改善。 NEPC 转分化的分子机制是尚不清楚，也没有可用于治疗的靶向疗法。我们提供来自人类细胞系的数据小鼠模型表明 RB1 丢失是促进 NEPC 反式分化的关键决定因素。我们建议 Rb1 损失缓解了对基因表达表观遗传重编程的限制，从而促进反式分化为 AR 阴性、ADT 抗性 NEPC。如果属实，NEPC 反分化应该是可逆。与这一预测一致，初步数据表明一些表观遗传调节药物可以恢复 NEPC 中的 AR 表达和恩杂鲁胺敏感性。拟议研究的具体目标是挑战中心假设，描述引起 NEPC 转分化的机制，评估其通过跨物种分析确定临床相关性，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目前对前列腺癌进展、治疗的基本理解的主要空白抵抗力，以及 RB1 功能丧失在这些过程中所起的作用。