Targeting LSD1 in Prostate Cancer

项目总结（见说明）： 尽管引入了新的AR通路抑制剂，如阿比特龙和MDV 3100，但临床应答是短暂的，许多患者没有应答，这证明了配体和AR非依赖性机制在PCa进展中的重要性。该提案评估了染色质修饰酶LSD 1介导配体和AR非依赖性CRPC存活的新假设（扩展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。LSD 1过表达在转移性CRPC中普遍存在，包括AR+和AR-肿瘤; ii.配体非依赖性LSD 1靶基因的主要类别涉及细胞周期和增殖的控制;和iii. LSD 1通过促进cMyc驱动的肿瘤生长以AR轴独立的方式起作用。我们的数据重新塑造了LSD 1作为配体介导的PCa生长驱动因素的公认范式，并将其作为配体非依赖性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LSD 1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非依赖性CRPC，从而确立了LSD 1抑制作为重要的基于机制的治疗靶点的基本原理。为了充分阐明LSD 1在驱动CRPC中的活性，本项目将：1。确定c-Myc在去势敏感和去势抵抗PCa模型中LSD 1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，确定使用新的LSD 1抑制剂SP-2509单独或与MDV 3100组合抑制LSD 1的抗肿瘤功效;和3.确定新的LSD 1抑制剂SP-2509在转移性CRPC男性中的I期试验中的生物学效应，安全性和抗肿瘤活性。需要靶向和翻译关键机制，如LSD 1的活性，它能够同时阻断AR依赖性和AR非依赖性进展和耐药机制的发展，这是一种至关重要的创新方法，将产生直接临床翻译相关的新数据。

PROJECT SUMMARY (See instructions): 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 LSD1 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.