# Mechanisms by which LSD1 Promotes Neuroendocrine Differentiation and Small Cell Lung Cancer

> **NIH NIH R37** · DANA-FARBER CANCER INST · 2024 · $436,924

## Abstract

PROJECT SUMMARY/ABSTRACT
 Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor currently without any approved targeted
therapies. Inhibitors of the histone demethylase LSD1 are currently in clinical trials in SCLC inspired by strong
preclinical data demonstrating that some SCLCs are highly and selectively sensitive to LSD1 inhibition. However,
only a minority of SCLCs are highly sensitive to LSD1 inhibition, while most SCLCs are inherently resistant. The
molecular basis for why some SCLCs are highly dependent on LSD1 is not understood. Understanding the
causative mechanisms for why some SCLCs are highly sensitive to LSD1 inhibitors could identify predictive
biomarkers to select patients more likely to respond to LSD1 inhibitors or identify rational combination strategies
to make LSD1 inhibitors more effective.
 Using unbiased positive selection CRISPR/Cas9 loss of function screening with LSD1 inhibitors, we have
uncovered novel causative mechanisms by which LSD1 inhibitors regulate SCLC, which include mechanisms
by which LSD1 regulates neuroendocrine differentiation in SCLC, target genes that are bound and repressed by
LSD1 and required for LSD1 inhibitor sensitivity, and also identified a rational combination strategy to overcome
resistance to LSD1 inhibitors.
 The broad long-term objective of our proposal is to elucidate the molecular mechanisms by which LSD1
promotes SCLC tumorigenesis and neuroendocrine differentiation (aims 1 and 3), and test a rational combination
strategy to make LSD1 inhibition more effective in SCLC (aim 2). To accomplish this, we will combine in vitro
mechanistic approaches to rigorously dissect the mechanisms by which LSD1 drives SCLC proliferation and
neuroendocrine differentiation with an in vivo autochthonous immunocompetent SCLC genetically-engineered
mouse model (GEMM) that we developed using CRISPR/Cas9 that can be used to delete LSD1 at tumor initiation
and study its function during SCLC tumorigenesis. Using these LSD1 isogenic SCLC GEMMs, we will interrogate
how loss of LSD1 blocks neuroendocrine differentiation, promotes lineage plasticity, and increases tumor
immunogenicity. Together, these studies will provide important biological insights into how SCLCs utilize LSD1
to drive tumorigenesis and neuroendocrine differentiation, which ultimately could lead to the identification of
predictive biomarkers to select patients more likely to respond to LSD1 inhibitors. Lastly, this research could
provide the preclinical foundation for a rational combination therapeutic strategy to make LSD1 inhibitors more
effective for SCLC patients.

## Key facts

- **NIH application ID:** 10749039
- **Project number:** 5R37CA269990-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Matthew Gilbert Oser
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,924
- **Award type:** 5
- **Project period:** 2022-12-06 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749039

## Citation

> US National Institutes of Health, RePORTER application 10749039, Mechanisms by which LSD1 Promotes Neuroendocrine Differentiation and Small Cell Lung Cancer (5R37CA269990-02). Retrieved via AI Analytics 2026-07-21 from https://api.ai-analytics.org/grant/nih/10749039. Licensed CC0.

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