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，转移性前列腺癌不可避免地发展为一致致命的去势抵抗性前列腺癌（CRPC）。在本应用概述的研究中，我们证明了染色质修饰酶赖氨酸特异性去甲基酶1 （LSD1）是致死性CRPC进化的驱动因素。该应用程序旨在确定LSD1激活关键CRPC细胞存活途径的机制，并确定一种新的LSD1抑制剂在人类CRPC异种移植模型中的抗肿瘤功效。重要的是，在支持性研究中，我们证明了LSD1作为独立于雄激素或雄激素受体的CRPC细胞存活驱动因子的新作用。也就是说，LSD1抑制能有效降低缺乏雄激素或不表达雄激素受体的CRPC细胞的存活。这些新发现与先前的报道不同，先前的报道表明lsd1诱导的组蛋白去甲基化促进了前列腺癌中雄激素受体对雄激素反应通路的调节。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CRPC患者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，LSD1激活这些关键途径而不使其规范组蛋白底物去甲基化，而且LSD1激活这些途径依赖于特定的共激活剂。最后，先前的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的功能，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

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.