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.
Lysine specific demethylase 1 (LSD1) is increasingly recognized as a critical regulator of gene expression in cancer, and we propose to evaluate the original concept that LSD1 activates expression of critical pathways in lethal, castration-resistan prostate cancer (CRPC) cells independently of demethylation of its canonical histone substrates. Significantly, our pre-clinical studies to date with a new and specific LSD1 inhibitor demonstrate safety and potent suppression of CRPC growth and survival. Thus, identifying LSD1-dependent mechanisms that drive CRPC progression and emergent resistance mechanisms induced by LSD1 inhibitor treatment will inform the optimal design of 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 future studies with drugs that suppress emergent resistance mechanisms induced by LSD1 inhibitor treatment.
|King, Carly J; Woodward, Josha; Schwartzman, Jacob et al. (2017) Integrative molecular network analysis identifies emergent enzalutamide resistance mechanisms in prostate cancer. Oncotarget 8:111084-111095|
|Coleman, Daniel J; Van Hook, Kathryn; King, Carly J et al. (2016) Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor. Oncotarget 7:40690-40703|