NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化

基本信息

批准号：
10641672
负责人：
DAVID W. GOODRICH
金额：
$ 62.91万
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：
2019
资助国家：
美国
起止时间：
2019-05-22 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641672
关键词：
ASCL1 gene Acetates Address Androgen Metabolism Androgen Receptor Androgens Automobile Driving CYP17A1 gene Cancer Patient Cells Characteristics Clinical Collection Combined Modality Therapy DNA Methyltransferase Inhibitor DNA Sequence Alteration Data Development Disease Resistance Drug Modulation EZH2 gene Engineering Epigenetic Process Epithelium Experimental Models Genetic Goals Human Human Cell Line Incidence Knowledge Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Metastatic Prostate Cancer Modeling Molecular Mouse Cell Line Mutation Neuroendocrine Prostate Cancer Neurosecretory Systems Pathway interactions Patients Pharmaceutical Preparations Phenotype Positioning Attribute Prostate Prostate Adenocarcinoma Prostate Cancer therapy Publishing RB1 gene Receptor Signaling Relapse Research Resistance Science Signal Transduction Specimen TP53 gene Testing Therapeutic Time Tissues Tumor Suppressor Genes Variant Work abiraterone androgen deprivation therapy androgen independent prostate cancer androgen sensitive antagonist cancer cell castration resistant prostate cancer cell transformation derepression design effective therapy enzalutamide improved individual patient inhibitor molecular targeted therapies mouse model novel novel strategies novel therapeutic intervention novel therapeutics phenotypic biomarker prostate cancer cell receptor expression relapse patients response single cell analysis therapeutically effective therapy resistant treatment response

项目摘要

Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC), but all patients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent on androgen receptor (AR) signaling, but a significant fraction lack AR expression, become AR signaling independent, and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of NEPC variants among CRPC has increased as more patients benefit from improved ADTs like enzalutamide and abiraterone acetate. This suggests increasingly stringent AR signaling blockade is driving development of NEPC. This is an important clinical problem because NEPC is aggressive and lethal; development of effective therapies is hampered by limited understanding of relevant molecular mechanisms. NEPC clearly arises from ARpos CRPC as they share clonal origin in patients that harbor both. We have determined that genetic inactivation of the RB1/TRP53 tumor suppressor genes cooperate to facilitate transformation of ARpos PADC to NEPC through derepression of epigenetic reprogramming factors. Inhibiting these reprogramming factors reverses NEPC transformation and restores ADT sensitivity, demonstrating that epigenetic changes are involved. We hypothesize that a change in NOTCH-ASCL1 signaling triggers the epigenetic reprogramming underlying NEPC transformation. This hypothesis has clinical ramifications as the pathway could conceivably be manipulated therapeutically to delay or reverse NEPC transformation, extending the duration of beneficial ADT clinical responses in some patients. We propose three specific aims using novel prostate cancer mouse models and unique human clinical specimens to test this hypothesis, characterize how PADC cells transform into NEPC cells, and explore novel therapeutic approaches for the treatment of this lethal form of prostate cancer. We will: 1) Test if NOTCH signaling is sufficient to maintain an androgen dependent PADC phenotype; 2) Characterize how prostate cancer cells transition from PADC to NEPC; 3) Determine whether epigenetic modulating drugs reverse NEPC transformation and ADT resistance via NOTCH-ASCL1 signaling. The long term goal of this project is to improve prostate cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic resistance.

雄激素剥夺疗法（ADT）可有效治疗转移性前列腺癌（PADC），但所有去势抵抗性前列腺癌（CRPC）患者不可避免地会复发。大多数 CRPC 仍依赖于雄激素受体 (AR) 信号传导，但很大一部分缺乏 AR 表达，成为 AR 信号传导独立且异常表达的神经内分泌谱系标记物（NEPC）。 NEPC的发生率随着越来越多的患者受益于改进的 ADT（如恩杂鲁胺和醋酸阿比特龙。这表明日益严格的 AR 信号封锁正在推动 AR 的发展国家电力委员会。这是一个重要的临床问题，因为 NEPC 具有侵袭性和致命性；发展有效的对相关分子机制的了解有限阻碍了治疗。 NEPC 显然源自 ARpos CRPC 因为它们在同时携带这两种疾病的患者中具有相同的克隆起源。我们已经确定遗传 RB1/TRP53 肿瘤抑制基因失活协同促进 ARpos PADC 转化为 NEPC 通过表观遗传重编程因子的去抑制。抑制这些重编程因子逆转 NEPC 转化并恢复 ADT 敏感性，表明表观遗传变化涉及。我们假设 NOTCH-ASCL1 信号的变化触发了表观遗传重新编程潜在的 NEPC 转换。该假设具有临床影响作为途径可以想象，可以通过治疗手段来延迟或逆转 NEPC 转化，从而延长一些患者中有益的 ADT 临床反应的持续时间。我们利用新颖的方式提出了三个具体目标前列腺癌小鼠模型和独特的人类临床标本来检验这一假设，描述如何 PADC细胞转化为NEPC细胞，探索治疗该疾病的新方法前列腺癌的致命形式。我们将： 1) 测试 NOTCH 信号传导是否足以维持雄激素依赖性 PADC 表型； 2）表征前列腺癌细胞如何从PADC转变为NEPC； 3）确定表观遗传调节药物是否逆转 NEPC 转化和 ADT 耐药 NOTCH-ASCL1 信号传导。该项目的长期目标是通过以下方式改善前列腺癌治疗：推进对谱系可塑性作为获得性治疗抵抗机制的机制理解。