# Targeting LSD1 in Neuroendocrine Prostate Cancer

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $230,315

## Abstract

Project Summary/Abstract 
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.

## Key facts

- **NIH application ID:** 10479955
- **Project number:** 5P50CA186786-09
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joshi James Alumkal
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $230,315
- **Award type:** 5
- **Project period:** 2014-09-11 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10479955

## Citation

> US National Institutes of Health, RePORTER application 10479955, Targeting LSD1 in Neuroendocrine Prostate Cancer (5P50CA186786-09). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10479955. Licensed CC0.

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