The Role of LSD1 in the Evolution of Castration Resistant Prostate Cancer

LSD1 在去势抵抗性前列腺癌演变中的作用

基本信息

批准号：
9090037
负责人：
Joshi James Alumkal
金额：
$ 31.69万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090037
关键词：
Androgen Receptor Androgens Binding Castration Categories Cell Cycle Regulation Cell Maintenance Cell Survival ChIP-seq Chromatin Clinical Trials Critical Pathways Dependency Disease Elements Enhancers Enzymes Evolution Family member Future Gene Activation Gene Expression Gene Expression Microarray Analysis Gene Expression Regulation Gene Targeting Genes Genetic Transcription Growth Health Histones Human Immunodeficient Mouse Implant In Vitro Ligands Lysine Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Metastatic Prostate Cancer Mus Mutate Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Proteins Publications RNA Interference Recruitment Activity Regulation Regulator Genes Reporting Resistance Role Safety Sampling Signal Pathway Specificity Systems Biology Testing Toxic effect Work Xenograft Model Xenograft procedure cancer cell castration resistant prostate cancer demethylation deprivation design embryonic stem cell genetic signature in vivo inhibitor/antagonist loss of function men mutant non-histone protein notch protein novel overexpression pharmacodynamic biomarker pre-clinical preclinical study prostate cancer cell prostate cancer cell line resistance mechanism transcriptome sequencing tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Despite treatment with pharmacological androgen deprivation therapy, or castration, metastatic prostate cancer inevitably progresses to uniformly fatal, castration-resistant prostate cancer (CRPC). In studies outlined in this application, we demonstrate that the chromatin-modifying enzyme lysine specific demethylase 1 (LSD1) is a driver of evolution to lethal CRPC. This application is designed to identify mechanisms by which LSD1 activates critical CRPC cell survival pathways and to determine the anti-tumor efficacy of a new LSD1 inhibitor in a human CRPC xenograft model. Importantly, in supporting studies we demonstrate a novel role for LSD1 as a driver of CRPC cell survival independently of androgens or the androgen receptor. That is, LSD1 suppression potently reduces survival of CRPC cells that are devoid of androgens or that do not express the androgen receptor. These novel findings are distinct from prior reports that demonstrate that LSD1-induced histone demethylation facilitates androgen receptor regulation of androgen-responsive pathways in prostate cancer. Indeed, we demonstrate that LSD1 is universally overexpressed in human CRPC tumors and that LSD1 activates the expression of critical pathways that are enriched in tumor samples from patients with CRPC or other fatal cancers. Importantly, our work to date demonstrates that LSD1 activates these critical pathways without demethylating its canonical histone substrates but also that activation of these pathways by LSD1 is dependent on specific co-activators. Finally, prior classes of LSD1 inhibitors have lacked potency and specificity. Here, we demonstrate that a new inhibitor specifically suppresses LSD1 function and potently suppresses CRPC cell survival in vitro and in vivo without appreciable in vivo toxicity. This demonstrates the potential for human clinical trials with this inhibitor. We hypothesize that LSD1 promotes evolution to CRPC by activating expression of critical cancer cell survival pathways. LSD1 activates these pathways not by canonical histone demethylation but by recruiting and demethylating non-histone protein co-activators that drive transcription of genes in these pathways. To test these hypotheses, we will determine the role of LSD1-induced histone demethylation in activating critical CRPC cell survival pathways (Aim 1), determine the anti-tumor efficacy of a potent and specific LSD1 inhibitor using human CRPC xenografts implanted in castrated, immunodeficient mice and identify emergent resistance mechanisms induced by LSD1 inhibitor treatment (Aim 2), and determine mechanisms by which critical co-activators facilitate LSD1-induced gene activation and whether these co-activators are regulated by LSD1-induced protein demethylation (Aim 3). We will directly apply these results to: 1) a future phase I clinical trial that will measure pharmacodynamic markers indicating suppression of LSD1's critical function in tumors from men with lethal CRPC and 2) future studies with drugs that suppress emergent resistance mechanisms induced by LSD1 inhibitor treatment.

描述（由申请人提供）：尽管用药理学雄激素剥夺治疗或cast割治疗了转移性前列腺癌，但不可避免地会发展为统一致命的，耐castration的前列腺癌（CRPC）。在此应用中概述的研究中，我们证明了染色质赖氨酸特异性脱甲基酶1（LSD1）是致命CRPC进化的驱动因素。该应用旨在识别LSD1激活关键CRPC细胞存活途径的机制，并确定人类CRPC异种移植模型中新型LSD1抑制剂的抗肿瘤疗效。重要的是，在支持研究中，我们证明了LSD1作为CRPC细胞存活的驱动力的新作用，独立于雄激素或雄激素受体。也就是说，LSD1抑制有效降低了没有雄激素或不表达雄激素受体的CRPC细胞的存活。这些新的发现与先前的报道不同，这些报告表明，LSD1诱导的组蛋白脱甲基化促进了前列腺癌中雄激素反应途径的雄激素受体调节。确实，我们证明了LSD1在人CRPC肿瘤中普遍过表达，并且LSD1激活了CRPC或其他致命癌症患者富含肿瘤样品的关键途径的表达。重要的是，迄今为止，我们的工作表明，LSD1在不脱甲基的情况下激活这些关键途径，而LSD1通过LSD1激活这些途径取决于特定的共激活因子。最后，LSD1抑制剂的先前类缺乏效力和特异性。在这里，我们证明了一种新的抑制剂特异性抑制了LSD1功能，并有效抑制了在体外和体内的CRPC细胞存活，而没有可观的体内毒性。这证明了使用该抑制剂进行人类临床试验的潜力。我们假设LSD1通过激活关键癌细胞存活途径的表达来促进CRPC的进化。 LSD1不是通过规范组蛋白去甲基化而是通过募集和去脱甲基化的非固定蛋白蛋白共激活剂来激活这些途径，从而驱动这些途径中基因转录的转录。为了检验这些假设，我们将确定LSD1诱导的组蛋白去甲基化在激活关键CRPC细胞存活途径中的作用（AIM 1），使用植入在castrated，castrated的，免疫缺陷的，免疫缺失的人CRPC的抗肿瘤的抗肿瘤疗效和特定的LSD1抑制剂的抗肿瘤疗效小鼠并确定由LSD1抑制剂治疗诱导的新出现的抗性机制（AIM 2），并确定关键共激活因子促进LSD1诱导的基因激活的机制，以及这些共激活因子是否受到LSD1诱导的蛋白质脱甲基的调节（AIM 3）。我们将将这些结果直接应用于：1）未来的第一阶段临床试验将测量指示LSD1致命CRPC男性肿瘤的关键功能和2）未来对抑制LSD1抑制剂治疗引起的新出现抗药性机制的研究的临床试验。