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：
10397535
负责人：
DAVID W. GOODRICH
金额：
$ 10.93万
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/10397535
关键词：
ASCL1 gene Acetates Address Androgen Metabolism Androgen Receptor Androgens Automobile Driving CYP17A1 gene Cancer Patient Cells Characteristics Clinical Collection DNA Methyltransferase Inhibitor DNA Sequence Alteration Data Development Disease Resistance EZH2 gene Engineering Epigenetic Process Epithelial Experimental Models Genetic Goals Human Human Cell Line Incidence Knowledge Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Metastatic Prostate Cancer Modeling Molecular Mus 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 base 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 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）在治疗转移性前列腺腺癌（PADC）方面有效，但所有患者不可避免地会因castrate抗性前列腺癌（CRPC）复发。大多数CRPC仍取决于雄激素受体（AR）信号传导，但明显的部分缺乏AR表达，成为AR信号传导独立和异常表达神经内分泌谱系标记（NEPC）。 NEPC的发生率随着越来越多的患者受益于Enzalutamide和Enzalutamide和乙酸阿比罗酮。这表明越来越严格的AR信号阻塞正在推动 NEPC。这是一个重要的临床问题，因为NEPC具有侵略性和致命性。开发有效对相关分子机制的了解有限，可以阻碍疗法。 NEPC显然来自 ARPOS CRPC在携带两者的患者中具有克隆起源。我们已经确定了遗传 RB1/TRP53肿瘤抑制基因的失活，以促进ARPOS PADC转化为 NEPC通过表观遗传重编程因子的压抑。抑制这些重编程因素逆转NEPC转化并恢复ADT敏感性，表明表观遗传变化是涉及。我们假设Notch-Ascl1信号传导的变化会触发表观遗传重新编程NEPC转换。该假设作为途径具有临床影响可以想象可以通过治疗来操纵以延迟或逆转NEPC转换，从而扩展某些患者的有益ADT临床反应的持续时间。我们建议使用新颖的三个特定目标前列腺癌小鼠模型和独特的人类临床标本来检验该假设，表征了如何 PADC细胞转变为NEPC细胞，并探索用于治疗的新型治疗方法前列腺癌的致命形式。我们将：1）测试是否足以维持雄激素依赖的PADC表型； 2）表征前列腺癌细胞如何从PADC转移到NEPC； 3）确定表观遗传调节药物是否反向NEPC转化和ADT抗性 Notch-ASCL1信号传导。该项目的长期目标是通过推进对谱系可塑性的机械理解，作为获得性治疗抗性的机制。