# Developing ASCL1 and NeuroD1 lineage oncogene targeted therapy for small cell lung cancer

> **NIH NIH U01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $605,070

## Abstract

Developing ASCL1 and NEUROD1 lineage oncogene targeted therapy for small cell lung cancer (SCLC)
This application focuses on developing new targeted therapy for SCLC focusing on two key lineage oncogenes
involved in SCLC pathogenesis and malignant behavior, ASCL1 and NEUROD1. Nearly 90% of SCLCs
express ASCL1, NEUROD1 or both. In the preclinical models, including human SCLC lines and xenografts and
genetically engineered mouse models (GEMMs) of SCLC, tumors that express either ASCL1 or NEUROD1
appear “addicted” to their expression and function. The presence of ASCL1 or NEUROD1 also are associated
with expression of important downstream oncogenes and regulatory genes. If ASCL1/NEUROD1 are removed
(through genetic knockdown) SCLCs undergo many logs of tumor cell kill. Using state of the art technology in
human preclinical models, we propose to systematically study the dependency of a large number of SCLC
lines and xenografts (including patient derived xenografts, PDXs, and circulating tumor cell derived xenografts,
CDXs) on ASCL1 and NEUROD1 through genetic knockdown, and systematically test the ability of blocking
genetically and pharmacologically downstream potentially “druggable” targets of these two transcription factors
to kill SCLCs. We have three specific aims: Aim 1. Determine ASCL1 and NEUROD1 expression patterns
and clinical and molecular correlates in preclinical SCLC models and tumor specimens; Aim 2. Determine
ASCL1 and NEUROD1 genetic dependency phenotypes, potential molecular biomarkers predicting response,
and frequency and mechanisms of resistance in SCLC preclinical models; Aim 3. Determine the role of ASCL1
and NEUROD1 directly regulated “downstream” targets as vulnerabilities that can be exploited for therapeutic
effect using in vivo xenograft shRNA mini-library “drop out” screens and selected drugs that inhibit downstream
“druggable” targets. As part of these aims we will also determine if resistance to ASCL1 or NEUROD1 targeted
therapy in SCLCs develops using CRISPR-CAS9 technology including potential mechanisms of this
resistance, and we will explore the possible use of ASCL1 and NEUROD1 expression as SCLC enrollment
biomarkers for developing “precision medicine” to predict the response of such targeted therapy in individual
SCLCs. We have developed a large amount of preliminary data on which this application is based including 1)
assembling the world’s largest collection of clinically and molecularly annotated human SCLC lines and
xenografts, as well as important GEMMs of SCLC, 2) generating a comprehensive list of directly regulated
downstream targets of ASCL1 and NEUROD1 through ChipSeq/RNASeq and chromatin landscape studies,
and 3) developing experimental approaches to systematically study the dependency of SCLCs on ASCL1 and
NEUORD1 downstream targets. We have assembled a world class team of investigators, including a patient
advocate, with complementary skills to assure the successful completion of this project. The fin...

## Key facts

- **NIH application ID:** 10240702
- **Project number:** 5U01CA213338-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JOHN D. MINNA
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $605,070
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240702

## Citation

> US National Institutes of Health, RePORTER application 10240702, Developing ASCL1 and NeuroD1 lineage oncogene targeted therapy for small cell lung cancer (5U01CA213338-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10240702. Licensed CC0.

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