# Project 3: Identifying Determinants of Sensitivity to LSD1 Inhibition in SCLC

> **NIH NIH P50** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $348,059

## Abstract

Project Summary/Abstract – Project 3
Small cell lung cancer (SCLC) leads to >30,000 deaths in the USA each year and therapies resulting in
durable responses are greatly needed. This proposal is focused on a potent and selective LSD1 inhibitor,
ORY1001. In preliminary data, we found efficacy of ORY1001 as monotherapy in a subset of patient derived
xenograft (PDX) models of SCLC. PDX models differed greatly in sensitivity to ORY1001, with one model
exhibiting complete and durable regression upon ORY1001 treatment. We found that strong tumor regression
was linked to robust NOTCH pathway activation, which led to suppression of ASCL1, a transcription factor
critical for SCLC. We hypothesize that robust activation of NOTCH and suppression of ASCL1 drives strong
response to LSD1 inhibition in a subset of SCLC models. We also hypothesize that mutation in chromatin
regulating genes may contribute to robust NOTCH pathway activation and increased sensitivity to LSD1
inhibition in SCLC. Specific Aim 1: To use genetically engineered mouse and PDX models to test the efficacy
of ORY1001 in SCLC. We will expand our PDX studies to identify additional strongly responding models and
will include models with mutations in chromatin regulating genes such as CREBBP and KMT2D that we
hypothesize may contribute to strong responses. This aim will also test a novel Crebbp-deficient genetically
engineered mouse model of SCLC that we generated to clearly determine whether inactivation of Crebbp
increases response to LSD1 inhibition in SCLC. Specific Aim 2: To understand roles for LSD1-NOTCH-ASCL1
axis in control of SCLC cell viability. We will use tumors from PDX and GEM models treated in vivo and PDX
tumors treated ex vivo with ORY1001 to interrogate roles for a NOTCH-ASCL1 axis in conferring strong
responses to ORY1001 in SCLC. We will also perform studies in PDX models of SCLC studied ex vivo, to
identify and better understand differences between strongly responding and non-responsive models. This Aim
will include RNAseq and ChIPseq studies that will identify key differences between these groups. Specific Aim
3. Perform an Investigator Initiated clinical trial to test ORY1001 in SCLC patients. Here, we will study
circulating tumor cells (CTCs) for biomarkers of response to LSD1 inhibition in a clinical trial. The design of this
trial may be modified based on work performed in SCLC model systems as we identify potential biomarkers
that may predict responsiveness. This work aims to direct LSD1 inhibition to SCLC patients most likely to
benefit.

## Key facts

- **NIH application ID:** 9986731
- **Project number:** 5P50CA228944-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** David MacPherson
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,059
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986731

## Citation

> US National Institutes of Health, RePORTER application 9986731, Project 3: Identifying Determinants of Sensitivity to LSD1 Inhibition in SCLC (5P50CA228944-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986731. Licensed CC0.

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