The Role of LSD1 in the Evolution of Castration Resistant Prostate Cancer

描述（由申请人提供）：尽管采用药物雄激素剥夺疗法或去势治疗，转移性前列腺癌仍不可避免地进展为一致致死性去势抵抗性前列腺癌（CRPC）。在本申请中概述的研究中，我们证明了染色质修饰酶赖氨酸特异性脱甲基酶1（LSD 1）是进化为致死性CRPC的驱动因素。本申请旨在确定LSD 1激活关键CRPC细胞存活途径的机制，并确定新型LSD 1抑制剂在人CRPC异种移植模型中的抗肿瘤疗效。重要的是，在支持性研究中，我们证明了LSD 1作为CRPC细胞存活的驱动因素的新作用，其独立于雄激素或雄激素受体。也就是说，LSD 1抑制有效地降低了缺乏雄激素或不表达雄激素受体的CRPC细胞的存活。这些新的发现与先前的报道不同，先前的报道表明LSD 1诱导的组蛋白去甲基化促进前列腺癌中雄激素受体对雄激素反应途径的调节。事实上，我们证明了LSD 1在人类CRPC肿瘤中普遍过表达，并且LSD 1激活了CRPC或其他致命癌症患者肿瘤样本中富集的关键途径的表达。重要的是，我们迄今为止的工作表明，LSD 1激活这些关键途径而不使其典型的组蛋白底物去甲基化，而且LSD 1对这些途径的激活依赖于特定的共激活剂。最后，先前类别的LSD 1抑制剂缺乏效力和特异性。在这里，我们证明了一种新的抑制剂特异性地抑制LSD 1功能，并在体外和体内有效地抑制CRPC细胞存活，而没有明显的体内毒性。这表明 这种抑制剂的人体临床试验的潜力。我们假设LSD 1通过激活关键癌细胞存活途径的表达来促进CRPC的演变。LSD 1不是通过典型的组蛋白去甲基化来激活这些通路，而是通过招募和去甲基化非组蛋白共激活因子来驱动这些通路中的基因转录。为了验证这些假设，我们将确定LSD 1诱导的组蛋白去甲基化在激活关键CRPC细胞存活途径中的作用（目的1），使用植入去势免疫缺陷小鼠的人CRPC异种移植物确定有效且特异性的LSD 1抑制剂的抗肿瘤功效，并鉴定LSD 1抑制剂治疗诱导的紧急耐药机制（目的2），并确定关键辅激活因子促进LSD 1诱导的基因激活的机制，以及这些辅激活因子是否受LSD 1诱导的蛋白质去甲基化的调控（目的3）。我们将把这些结果直接应用于：1）未来的第一阶段 临床试验，将测量药效学标志物，表明LSD 1在患有致死性CRPC的男性肿瘤中的关键功能受到抑制，以及2）未来的药物研究，这些药物抑制由LSD 1抑制剂治疗诱导的紧急耐药机制。

DESCRIPTION (provided by applicant): Despite treatment with pharmacological androgen deprivation therapy, or castration, metastatic prostate cancer inevitably progresses to uniformly fatal, castration-resistant prostate cancer (CRPC). In studies outlined in this application, we demonstrate that the chromatin-modifying enzyme lysine specific demethylase 1 (LSD1) is a driver of evolution to lethal CRPC. This application is designed to identify mechanisms by which LSD1 activates critical CRPC cell survival pathways and to determine the anti-tumor efficacy of a new LSD1 inhibitor in a human CRPC xenograft model. Importantly, in supporting studies we demonstrate a novel role for LSD1 as a driver of CRPC cell survival independently of androgens or the androgen receptor. That is, LSD1 suppression potently reduces survival of CRPC cells that are devoid of androgens or that do not express the androgen receptor. These novel findings are distinct from prior reports that demonstrate that LSD1-induced histone demethylation facilitates androgen receptor regulation of androgen-responsive pathways in prostate cancer. Indeed, we demonstrate that LSD1 is universally overexpressed in human CRPC tumors and that LSD1 activates the expression of critical pathways that are enriched in tumor samples from patients with CRPC or other fatal cancers. Importantly, our work to date demonstrates that LSD1 activates these critical pathways without demethylating its canonical histone substrates but also that activation of these pathways by LSD1 is dependent on specific co-activators. Finally, prior classes of LSD1 inhibitors have lacked potency and specificity. Here, we demonstrate that a new inhibitor specifically suppresses LSD1 function and potently suppresses CRPC cell survival in vitro and in vivo without appreciable in vivo toxicity. This demonstrates the potential for human clinical trials with this inhibitor. We hypothesize that LSD1 promotes evolution to CRPC by activating expression of critical cancer cell survival pathways. LSD1 activates these pathways not by canonical histone demethylation but by recruiting and demethylating non-histone protein co-activators that drive transcription of genes in these pathways. To test these hypotheses, we will determine the role of LSD1-induced histone demethylation in activating critical CRPC cell survival pathways (Aim 1), determine the anti-tumor efficacy of a potent and specific LSD1 inhibitor using human CRPC xenografts implanted in castrated, immunodeficient mice and identify emergent resistance mechanisms induced by LSD1 inhibitor treatment (Aim 2), and determine mechanisms by which critical co-activators facilitate LSD1-induced gene activation and whether these co-activators are regulated by LSD1-induced protein demethylation (Aim 3). We will directly apply these results to: 1) a future phase I clinical trial that will measure pharmacodynamic markers indicating suppression of LSD1's critical function in tumors from men with lethal CRPC and 2) future studies with drugs that suppress emergent resistance mechanisms induced by LSD1 inhibitor treatment.