# Molecular features promoting sensitivity to LSD1i in castration-resistant prostate cancer

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $606,756

## Abstract

Prostate cancer (PCa) remains an incurable disease once progression to the metastatic castration-resistant
(mCRPC) state occurs; killing >30,000 U.S. men/yr. Unfortunately, each of the FDA-approved agents for mCRPC
produces only modest increases in overall survival followed by the emergence of a resistant and more aggressive
phenotype. Thus, there urgent unmet need for innovative therapies with novel mechanisms of action that allow
discrimination between normal and PCa cells.
 Herein, we put forward an innovative strategy to selectively exploit selective vulnerabilities in neuroendocrine
prostate cancer (NEPC), a highly aggressive variant of mCRPC with poor prognosis, using an orally-dosed and
highly specific lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat, in clinical development for unrelated
indications to maximize near-term patient benefit. The prevalence of NEPC is increasing in mCRPC patients
following prolonged treatment with potent androgen receptor (AR) axis-targeted therapies (e.g., abiraterone,
enzalutamide) as an adaptive mechanism of resistance. Comprehensive genome-scale analyses integrated with
pharmacogenomics pipelines will provide a rich mechanistic understanding of the genetic and epigenetic
features underlying the sensitivity differential between NEPC and AR+ prostate cancer (ARPC) subtypes to LSD1
inhibition (LSD1i). It should be noted that although NEPC is more sensitive, LSD1i also has significant activity
against ARPC tumors, which has important clinical implications for the growing number of advanced mCRPC
patients with heterogeneous lesions encompassing mixed molecular and pathological subtypes. LSD1-depedent
vulnerabilities are identified that will guide patient selection for a precision medicine approach. Additionally,
combination therapy targeting LSD1-induced synthetic lethal susceptibilities are rationally designed to provide
more potent and durable responses to extend the clinical utility of these well-tolerated clinically-tested agents
with favorable safety and pharmacokinetic profiles.
 Our proposed work has both conceptual and technical innovations. We will 1) validate LSD1 as a target in
NE+ and AR+ tumors via comprehensive mechanistic interrogation using unique patient-derived xenograft and
organoid (PDX/O) models; 2) compare responders vs. non-responders across subtypes to inform patient
selection in future biomarker-driven clinical trials using state-of-the-art genome-wide profiling technologies; 3)
dissect the functional effects of LSD1i in advanced preclinical model systems using these same advanced
profiling strategies; 4) identify rational combination therapies based on LSD1i-induced synthetic lethal
vulnerabilities to produce durable responses using a high-throughput PDO screening platform; and 5) use
clinical-grade drugs to maximize near-term therapeutic potential against this highly aggressive lethal mCRPC
variant emerging as a resistance mechanism to standard-of-care therapies with increa...

## Key facts

- **NIH application ID:** 10802475
- **Project number:** 1R01CA279993-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** William Nathaniel Brennen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,756
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802475

## Citation

> US National Institutes of Health, RePORTER application 10802475, Molecular features promoting sensitivity to LSD1i in castration-resistant prostate cancer (1R01CA279993-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10802475. Licensed CC0.

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