Targeting LSD1 in Prostate Cancer

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，这表明配体和AR无关的PCa进展机制的重要性。该提案评估了染色质修饰酶LSD1介导配体和AR非依赖性CRPC存活的新假设（扩展了其先前确定的作为配体介导的AR活性驱动因子的功能）。具体来说，我们发现i. LSD1过表达在转移性CRPCs中普遍存在，包括AR+和AR-肿瘤；2。与配体无关的LSD1靶基因的主要类别涉及控制细胞周期和增殖；ⅲ。LSD1通过促进cMyc驱动的肿瘤生长，以ar轴独立的方式起作用。我们的数据重塑了LSD1作为配体介导的PCa生长驱动因素的公认范式，并将其作为不依赖配体的AR+ CRPC和AR无CRPC进展的核心驱动因素。这些数据有力地表明，在临床环境中，抑制LSD1不仅会抑制ar通路依赖的PCa，还会抑制生长并可能阻止完全雄激素不依赖型CRPC的发展，从而建立了LSD1抑制作为一个重要的、基于机制的治疗靶点的理论基础。为了充分阐明LSD1在驱动CRPC中的作用，本项目将：1。在去势敏感和去势抵抗PCa模型中，确定c-Myc在lsd1介导的不依赖配体的增殖途径中的作用；2. 在不依赖配体的AR+和AR-临床前CRPC模型中，确定使用新的LSD1抑制剂SP-2509单独或联合MDV3100抑制LSD1的抗肿瘤效果；和3。在一项针对转移性CRPC患者的I期临床试验中，确定新的LSD1抑制剂SP-2509的生物学效应、安全性和抗肿瘤活性。需要靶向和翻译关键机制，如LSD1的活性，它能够同时阻断ar依赖和ar独立的进展和耐药机制的发展，这是一种至关重要的创新方法，将产生具有直接临床转化相关性的新数据。

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.