Targeting LSD1 in Prostate Cancer

靶向 LSD1 治疗前列腺癌

基本信息

批准号：
8555009
负责人：
Joshi James Alumkal
金额：
$ 14.9万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-19 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8555009
关键词：
Androgens Apoptosis Automobile Driving Biological Biopsy Bromodomain Castration Categories Cell Cycle Regulation Cell Death Cell Line Cell Proliferation Cell Survival Cells Chromatin Clinical Data Dependency Development Drug Kinetics Enrollment Enzymes Evaluation Gene Targeting Growth Implant In Vitro Ligands Malignant neoplasm of prostate Measures Mediating Modeling Mus Neurosecretory Systems Outcome Pacific Northwest Pathway interactions Patients Phase Phase I Clinical Trials Property Proteins RNA Interference Resistance Role Safety Shapes Signal Transduction Specificity The Sun Translating Xenograft Model Xenograft procedure abiraterone addiction base c-Myc Staining Method c-myc Genes clinically relevant improved in vivo inhibitor/antagonist innovation insight men novel overexpression phase 1 study pre-clinical preclinical study prevent response therapeutic target tumor tumor growth

项目摘要

Despite the introduction of new AR pathway inhibitors such as abiraterone and MDV3100, clinical responses are transitory and many patients do not respond, demonstrating the importance of ligand and AR-independent mechanisms of PCa progression. This proposal evaluates the novel hypothesis that the chromatin modifying enzyme LSD1 mediates survival of ligand and AR-independent CRPC (extending its previously identified function as a driver of ligand-mediated AR activity). Specifically, we find that i. LSD1 overexpression is ubiquitous in metastatic CRPCs, including AR+ and AR- tumors; ii. the predominant category of ligand-independent LSD1 target genes involves control of the cell cycle and proliferation; and iii. LSD1 acts in an AR-axis independent manner by promoting cMyc driven tumor growth. Our data re-shape the accepted paradigm of LSD1 as a driver of ligand-mediated PCa growth, and additionally place it as a central driver in the progression of both ligand-independent AR+ CRPC and AR null CRPC. These data strongly suggest that suppression of LSDI in the clinical setting will not only inhibit AR-pathway dependent PCa, but will inhibit the growth and potentially prevent progression to fully-androgen independent CRPC, thereby establishing the rationale for LSD1 inhibition as an important, mechanism-based therapeutic target. To fully elucidate the activity of LSD1 in driving CRPC, this project will: 1. Determine the role of c-Myc in LSD1-mediated induction of ligand-independent proliferation pathways in castration sensitive and castration resistant PCa models; 2. Determine the anti-tumor efficacy of LSD1 suppression using the new LSD1 inhibitor SP-2509, alone or in combination with MDV3100, in ligand-independent AR+ and AR- preclinical CRPC models; and 3. Determine the biological effects, safety, and anti-tumor activity of the new LSD1 inhibitor SP-2509 in a phase I trial in men with metastatic CRPC. The need to target and translate key mechanisms such as the activity of LSD1, which is capable of simultaneously interdicting development of both AR-dependent and AR-independent mechanisms of progression and resistance, is an innovative approach of paramount importance and will yield novel data of immediate clinical translational relevance.

尽管引入了新的AR途径抑制剂，例如Abiraterone和MDV3100，但临床反应是短暂的，许多患者没有反应，这表明PCA进展的配体和非AR独立机制的重要性。该提案评估了新的假设，即染色质修饰酶LSD1介导配体和非AR依赖性CRPC的存活率（扩展了其先前鉴定为配体介导的AR活性的驱动器）。具体来说，我们发现我。 LSD1的过表达在转移性CRPC中无处不在，包括AR+和AR肿瘤； ii。配体独立于LSD1靶基因的主要类别涉及控制细胞周期和增殖。和iii。 LSD1通过促进CMYC驱动的肿瘤生长以独立的AR轴作用。我们的数据将LSD1的公认范式重新形成为配体介导的PCA生长的驱动力，并将其作为核心驱动器，在与配体无关的AR+ CRPC和AR NULL CRPC的进展中。这些数据强烈表明，在临床环境中对LSDI的抑制不仅会抑制AR-Pathway依赖性PCA，而且会抑制生长并有可能阻止进展到完全独立的CRPC，从而确立LSD1抑制作用的基本原理，作为一个重要的，机械机制的治疗靶标。为了充分阐明LSD1在驱动CRPC中的活性，该项目将：1。确定C-MYC在LSD1介导的castration敏感和cast割耐受性PCA模型中，在LSD1介导的LIGAND非依赖性增殖途径的诱导中的作用； 2。使用新的LSD1抑制剂SP-2509（单独或与MDV3100）组合，在不依赖配体的AR+和Ar-prinlinical CRPC模型中确定LSD1抑制的抗肿瘤功效；和3。在转移性CRPC男性的I期试验中，确定新LSD1抑制剂SP-2509的生物学效应，安全性和抗肿瘤活性。靶向和翻译关键机制（例如LSD1的活性）的需求，LSD1的活性能够同时阻止发展AR依赖性和抗AR的进展和抵抗机制，这是一种最重要的重要性的创新方法，将产生直接临床转化相关性的新数据。