Neuroendocrine prostate cancer (NEPC) is the most virulent subtype, and the frequency of NEPC is increasing due to more widespread use of potent androgen receptor (AR)-targeting agents like abiraterone and enzalutamide (enza). Currently, there are no effective treatments for NEPC, and men with NEPC are commonly excluded from clinical trials due to NEPC?s aggressiveness, demonstrating an urgent need to develop more effective therapies for NEPC patients. Our supporting studies demonstrate NEPC tumors may be particularly reliant on the protein lysine specific demethylase 1 (LSD1) and that LSD1 inhibition is a promising strategy to treat NEPC. However, before LSD1 inhibitor trials may begin in NEPC patients, several critical questions must be answered that this proposal will address. LSD1 is a histone demethylase and regulator of differentiation in stem cells and cancer. Previously, we determined LSD1 cooperates with co-activators to primarily activate gene expression in prostate adenocarcinoma (adenoca) cells and that LSD1?s catalytic function was not critical. Importantly, our studies in NEPC demonstrate: LSD1 is even more highly expressed vs. adenoca; in NEPC, LSD1 primarily represses expression of genes linked with prostatic epithelial differentiation?not with its catalytic function but rather by cooperating with co-repressor proteins; NEPC cells are particularly susceptible to an allosteric LSD1 inhibitor that re-activates expression of prostatic epithelial differentiation genes and re-sensitizes AR+ NEPC cells to enza. We hypothesize that LSD1 promotes NEPC survival by repressing factors and pathways that promote epithelial differentiation and activating other factors and pathways that promote NEPC differentiation. LSD1 inhibition is a promising approach to block NEPC cell survival. The objectives of this proposal are to clarify mechanisms by which LSD1 promotes survival of NEPC so we may develop a novel, safe, and effective therapeutic strategy? LSD1 inhibition.
Aim 1 : Identify an LSD1 inhibitor gene response signature and determine mechanisms by which LSD1 blocks gene expression in NEPC.
Aim 2 : Treat NEPC tumors in vivo with LSD1 inhibition and determine the effect on tumor growth and differentiation. A predicted outcome of these studies is: clarification of how LSD1 promotes the lineage switch to NEPC tumors so we can target that switch, identification of LSD1 inhibition response biomarkers to determine the biologically optimal dose in future phase I trials, and development of rational LSD1 inhibitor drug combinations to maximize tumor control, quality of life, and survival for patients with NEPC tumors in the near-term.
|Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cie?lik, Marcin et al. (2018) Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression. Nat Genet 50:814-824|
|Hussain, Maha; Daignault-Newton, Stephanie; Twardowski, Przemyslaw W et al. (2018) Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol 36:991-999|
|Salami, Simpa S; Hovelson, Daniel H; Kaplan, Jeremy B et al. (2018) Transcriptomic heterogeneity in multifocal prostate cancer. JCI Insight 3:|
|Zhao, Shanshan; Leonardson, Amy; Geybels, Milan S et al. (2018) A five-CpG DNA methylation score to predict metastatic-lethal outcomes in men treated with radical prostatectomy for localized prostate cancer. Prostate :|
|Niknafs, Yashar S; Pandian, Balaji; Gajjar, Tilak et al. (2018) MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data. Neoplasia 20:1144-1149|
|Xiao, Lanbo; Tien, Jean C; Vo, Josh et al. (2018) Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer. Cancer Res 78:5731-5740|
|Piert, Morand; Shankar, Prasad R; Montgomery, Jeffrey et al. (2018) Accuracy of tumor segmentation from multi-parametric prostate MRI and 18F-choline PET/CT for focal prostate cancer therapy applications. EJNMMI Res 8:23|
|Wu, Yi-Mi; Cie?lik, Marcin; Lonigro, Robert J et al. (2018) Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173:1770-1782.e14|
|Blattner, Mirjam; Liu, Deli; Robinson, Brian D et al. (2017) SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling. Cancer Cell 31:436-451|
|Palapattu, Ganesh S; Salami, Simpa S; Cani, Andi K et al. (2017) Molecular Profiling to Determine Clonality of Serial Magnetic Resonance Imaging/Ultrasound Fusion Biopsies from Men on Active Surveillance for Low-Risk Prostate Cancer. Clin Cancer Res 23:985-991|
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