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

描述(申请人提供)：尽管接受药物雄激素剥夺疗法或去势治疗，转移性前列腺癌不可避免地进展为一致致命的去势抵抗前列腺癌(CRPC)。在本申请中概述的研究中，我们证明染色质修饰酶赖氨酸特异性脱甲基酶1(LSD1)是进化为致死性CRPC的驱动因素。这项应用旨在确定LSD1激活关键的CRPC细胞生存途径的机制，并确定一种新的LSD1抑制剂在人CRPC异种移植模型中的抗肿瘤效果。重要的是，在支持性研究中，我们展示了LSD1作为独立于雄激素或雄激素受体的CRPC细胞存活的驱动因素的新作用。也就是说，抑制LSD1可以有效地降低缺乏雄激素或不表达雄激素受体的CRPC细胞的存活率。这些新的发现与以前的报告不同，这些报告表明LSD1诱导的组蛋白去甲基化促进了前列腺癌雄激素受体对雄激素反应途径的调节。事实上，我们证明了LSD1在人类CRPC肿瘤中普遍过表达，并且LSD1激活了在CRPC患者或其他致命癌症患者的肿瘤样本中丰富的关键通路的表达。重要的是，我们到目前为止的工作表明，LSD1在不去甲基化其典型的组蛋白底物的情况下激活这些关键途径，但LSD1对这些途径的激活依赖于特定的共激活因子。最后，以前的LSD1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LSD1功能，并在体外和体内有效地抑制CRPC细胞的存活，而没有明显的体内毒性。这演示了 使用这种抑制剂进行人体临床试验的可能性。我们假设LSD1通过激活关键癌细胞生存通路的表达来促进向CRPC的进化。LSD1激活这些途径不是通过典型的组蛋白去甲基化，而是通过招募和去甲基化非组蛋白蛋白共激活子来驱动这些途径中基因的转录。为了验证这些假说，我们将确定LSD1诱导组蛋白去甲基化在激活关键的CRPC细胞生存途径中的作用(目标1)，利用植入去势的免疫缺陷小鼠的人CRPC异种移植瘤来确定有效和特异的LSD1抑制剂的抗肿瘤效果，并确定LSD1抑制剂治疗诱导的紧急耐药机制(AIM 2)，并确定关键共激活子促进LSD1诱导的基因激活的机制以及这些共激活子是否受到LSD1诱导的蛋白去甲基化的调节(目标3)。我们将把这些结果直接应用于：1)未来的第一阶段 将进行一项临床试验，其药效学指标将表明LSD1‘S在致死性慢性前列腺癌患者肿瘤中的关键功能受到抑制；2)未来将进行药物研究，以抑制LSD1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.