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：
8879069
负责人：
Joshi James Alumkal
金额：
$ 31.66万
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/8879069
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 Non-Histone Chromosomal Proteins Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Proteins Publications RNA Interference RNA Sequences 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 in vivo inhibitor/antagonist loss of function men mutant notch protein novel overexpression 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）：尽管采用药物雄激素剥夺疗法或去势治疗，转移性前列腺癌仍不可避免地进展为均致致命的去势抵抗性前列腺癌（CRPC）。在本申请概述的研究中，我们证明染色质修饰酶赖氨酸特异性去甲基化酶 1 (LSD1) 是进化为致死性 CRPC 的驱动因素。该应用旨在确定 LSD1 激活关键 CRPC 细胞存活途径的机制，并确定新型 LSD1 抑制剂在人类 CRPC 异种移植模型中的抗肿瘤功效。重要的是，在支持研究中，我们证明了 LSD1 作为独立于雄激素或雄激素受体的 CRPC 细胞存活驱动因素的新作用。也就是说，LSD1抑制有效降低缺乏雄激素或不表达雄激素受体的CRPC细胞的存活率。这些新发现与之前的报道不同，之前的报道表明 LSD1 诱导的组蛋白去甲基化促进前列腺癌中雄激素受体对雄激素反应途径的调节。事实上，我们证明 LSD1 在人类 CRPC 肿瘤中普遍过度表达，并且 LSD1 激活关键通路的表达，这些通路在来自 CRPC 或其他致命癌症患者的肿瘤样本中丰富。重要的是，我们迄今为止的工作表明，LSD1 激活这些关键通路时不会使其经典组蛋白底物去甲基化，而且 LSD1 对这些通路的激活依赖于特定的共激活剂。最后，先前类别的 LSD1 抑制剂缺乏效力和特异性。在这里，我们证明了一种新的抑制剂特异性抑制 LSD1 功能，并在体外和体内有效抑制 CRPC 细胞存活，而没有明显的体内毒性。这表明该抑制剂具有进行人体临床试验的潜力。我们假设 LSD1 通过激活关键癌细胞生存途径的表达来促进向 CRPC 的进化。 LSD1 不是通过典型的组蛋白去甲基化来激活这些途径，而是通过招募和去甲基化驱动这些途径中基因转录的非组蛋白蛋白共激活剂。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（目标 1），使用植入去势、免疫缺陷的人 CRPC 异种移植物确定有效且特异性 LSD1 抑制剂的抗肿瘤功效。小鼠并确定 LSD1 抑制剂治疗诱导的新兴耐药机制（目标 2），并确定关键共激活剂促进 LSD1 诱导基因激活的机制以及这些机制是否共激活剂受 LSD1 诱导的蛋白质去甲基化调节（目标 3）。我们将直接将这些结果应用于：1）未来的第一阶段临床试验将测量药效学标志物，表明 LSD1 在致命性 CRPC 男性肿瘤中的关键功能受到抑制；2) 未来的研究涉及抑制 LSD1 抑制剂治疗诱导的新兴耐药机制的药物。