Targeting LSD1 in Prostate Cancer

项目总结(见说明)： 尽管新的AR途径抑制剂如阿比特龙和MDV3100被引入，但临床反应是短暂的，许多患者没有反应，这表明了配体和AR非依赖性机制在PCa进展中的重要性。这一建议评估了染色质修饰酶LSD1介导配体和非AR依赖的CRPC存活的新假设(扩展了其作为配体介导的AR活性的驱动因素的功能)。具体地说，我们发现1.LSD1过度表达在转移性CRPC中普遍存在，包括AR+和AR-肿瘤；与配体无关的LSD1靶基因的主要类别涉及细胞周期和增殖的控制；LSD1通过促进cMyc驱动的肿瘤生长，以不依赖AR轴的方式发挥作用。我们的数据重塑了LSD1作为配体介导的PCA生长的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发展的中心驱动因素。这些数据有力地表明，在临床环境中抑制LSD1不仅会抑制AR途径依赖的PCa，而且会抑制其生长，并有可能阻止向完全雄激素非依赖性CRPC的进展，从而建立了抑制LSD1作为重要的、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中的活性，本项目将：1.确定c-Myc在LSD1介导的去势敏感和去势抵抗的PCa模型中诱导配体非依赖性增殖途径中的作用；2.确定新的LSD1抑制剂SP-2509单独或与MDV3100联合在非配体非依赖性AR+和AR-临床前CRPC模型中抑制LSD1的抗肿瘤效果；以及3.在男性转移性CRPC的I期试验中确定新的LSD1抑制剂SP-2509的生物学效应、安全性和抗肿瘤活性。靶向和翻译关键机制的需要，如LSD1的活性，能够同时阻断AR依赖和AR非依赖的进展和耐药机制的发展，是一种至关重要的创新方法，将产生直接与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.