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 通路抑制剂，如阿比特龙和 MDV3100，但临床反应是短暂的，许多患者没有反应，这证明了配体和 AR 独立机制对 PCa 进展的重要性。该提案评估了新的假设，即染色质修饰酶 LSD1 介导配体和 AR 独立 CRPC 的存活（扩展了其先前确定的作为配体介导的 AR 活性驱动程序的功能）。具体来说，我们发现 i. LSD1 过表达在转移性 CRPC 中普遍存在，包括 AR+ 和 AR- 肿瘤；二.不依赖配体的 LSD1 靶基因的主要类别涉及细胞周期和增殖的控制；和 iii. LSD1 通过促进 cMyc 驱动的肿瘤生长，以独立于 AR 轴的方式发挥作用。我们的数据重新塑造了 LSD1 作为配体介导的 PCa 生长驱动因素的公认范式，并且另外将其作为配体独立的 AR+ CRPC 和 AR null CRPC 进展的中心驱动因素。这些数据强烈表明，在临床环境中抑制 LSDI 不仅会抑制 AR 途径依赖性 PCa，而且会抑制生长并可能阻止进展为完全雄激素独立的 CRPC，从而确立了 LSD1 抑制作为重要机制的基本原理。基于治疗目标。为了充分阐明LSD1在驱动CRPC中的活性，该项目将： 1.确定c-Myc在去势敏感和去势抵抗PCa模型中LSD1介导的配体非依赖性增殖途径诱导中的作用； 2. 在配体非依赖性 AR+ 和 AR- 临床前 CRPC 模型中，确定使用新型 LSD1 抑制剂 SP-2509 单独或与 MDV3100 联合使用 LSD1 抑制的抗肿瘤功效； 3. 在患有转移性 CRPC 的男性中进行的 I 期试验中确定新型 LSD1 抑制剂 SP-2509 的生物效应、安全性和抗肿瘤活性。需要针对和翻译关键机制，例如 LSD1 的活性，它能够同时阻止 AR 依赖性和 AR 独立的进展和抵抗机制的发展，是一种至关重要的创新方法，并将产生以下新数据：直接的临床转化相关性。