Project 2: Reversing resistance caused by lineage plasticity through epigenetic therapy

项目2：通过表观遗传疗法逆转谱系可塑性引起的耐药性

基本信息

批准号：
9446577
负责人：
Yu Chen
金额：
$ 43.33万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9446577
关键词：
Address Androgen Antagonists Androgen Receptor Androgen Suppression Androgens Biological Markers Bypass Cancer Model Cancer Patient Castration ChIP-seq Characteristics Chromatin Clinical Clinical Trials Combined Modality Therapy Data Data Set Dependence Development Disease Doxycycline Drug Addiction Drug Targeting Drug resistance EP300 gene EZH2 gene Enhancers Epigenetic Process Evaluation Gene Expression Profile Genes Genetic Goals Growth Heterogeneity Human In Vitro LNCaP Malignant neoplasm of prostate Mediating Memorial Sloan-Kettering Cancer Center Modeling Neurosecretory Systems Organoids Pathway interactions Patients Pharmaceutical Preparations Prostate Proteins RB1 gene Receptor Signaling Research Resistance Rest Role Signal Transduction System TP53 gene Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Transcriptional Regulation Translations Up-Regulation Xenograft Model base castration resistant prostate cancer clinical effect clinically relevant drug sensitivity epigenome gastrointestinal in vivo inhibitor/antagonist innovation insight knock-down neuroendocrine phenotype novel overexpression patient subsets preclinical study pressure prevent prostate cancer model resistance mechanism response response biomarker screening therapeutic candidate therapeutic target transcriptome tumor tumor growth

项目摘要

Prostate cancer is characterized by dependence on androgens for growth and drugs that target the androgen receptor has been the mainstay of therapy. Under selection pressure of treatment, prostate cancer evolves resistance mechanisms to grow despite therapy. In a subset of patients, the loss of prostate lineage specification results in resistance to all therapy directed at the androgen receptor and there are few therapeutic options. We have recently identified two mechanism of lineage plasticity prostate cancer that are reversible by epigenetic therapy. The overall goal is to develop combination therapy to reverse or prevent lineage plasticity and prolong response. First, we have observed that tumors with combined TP53 and RB1 loss progress to androgen receptor independent disease that required activity of EZH2. This suggests that EZH2 is a therapeutic target for this subset of prostate cancer. Second, we discovered that a subset of prostate cancer aberrantly express HNF4G and HNF1A, master regulators of the gastrointestinal lineage, and bypass the prostate lineage requirement for androgen signaling. Inhibition with BET inhibitors inhibit this pathway and re- sensitize prostate cancer to androgen receptor directed therapy. In Aim 1, we will test the in vivo activity of EZH2 inhibition in AR-negative prostate cancer in combination with the antiandrogen enzalutamide. In Aim 2, we will test the in vivo activity of BET inhibition in HNF4G/HNF1A positive prostate cancer in combination with enzalutamide. In Aim 3, we will perform preclinical studies of epigenetic inhibitor of BET, EZH2, and P300/CBP in a large panel of patient-derived models of prostate cancer that reflect the clinical heterogeneity of human prostate cancer. For our studies, we will use clinically relevant drugs that are either in clinical trials or are first in class with clinical potential. The proposed research is innovative because it tests a novel paradigm that loss of prostate lineage is reversible and druggable, and is significant because of the potential to rapidly develop novel treatment to patients with few options.

前列腺癌的特点是生长依赖雄激素和针对雄激素的药物受体已成为治疗的支柱。在治疗的选择压力下，前列腺癌发生演变尽管接受治疗，耐药机制仍会增强。在一部分患者中，前列腺谱系丧失规范导致对所有针对雄激素受体的治疗产生耐药性，并且几乎没有治疗方法选项。我们最近发现了两种可逆的谱系可塑性前列腺癌机制：表观遗传疗法。总体目标是开发联合疗法来逆转或防止谱系可塑性并延长反应时间。首先，我们观察到 TP53 和 RB1 联合缺失的肿瘤进展为需要 EZH2 活性的雄激素受体非依赖性疾病。这表明 EZH2 是该前列腺癌亚型的治疗靶点。其次，我们发现前列腺癌的一个子集异常表达 HNF4G 和 HNF1A，胃肠道谱系的主要调节因子，并绕过前列腺谱系对雄激素信号传导的要求。 BET 抑制剂抑制该途径并重新使前列腺癌对雄激素受体定向治疗敏感。在目标 1 中，我们将测试其体内活性与抗雄激素恩杂鲁胺联合治疗 AR 阴性前列腺癌中的 EZH2 抑制作用。在目标 2 中，我们将测试 BET 抑制在 HNF4G/HNF1A 阳性前列腺癌中的体内活性恩杂鲁胺。在目标3中，我们将进行BET、EZH2和P300/CBP表观遗传抑制剂的临床前研究在一大组源自患者的前列腺癌模型中，反映了人类的临床异质性前列腺癌。对于我们的研究，我们将使用处于临床试验中或首次的临床相关药物具有临床潜力的课堂。所提出的研究具有创新性，因为它测试了一种新颖的范式，即损失前列腺谱系的变化是可逆的且可通过药物治疗，并且由于具有快速发展的潜力而具有重要意义为几乎没有选择的患者提供新的治疗方法。