# Investigating and Targeting Replication Stress in  Small Cell Lung Cancer

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $1,893,978

## Abstract

PROJECT SUMMARY/DESCRIPTION
Small-cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal
form of lung cancer. Despite an initially high response rate to chemotherapy and chemoimunotherapy, the
majority of SCLC patients with extensive stage disease invariably relapse within one year. Although SCLC is
currently managed as a single disease with platinum-based chemotherapy remaining the cornerstone of
treatment, studies have identified that SCLC display both inter- and intra-tumoral heterogeneity with distinct
transcriptome changes. However, the specific molecular determinants of response remains unclear, especially
as the tumor evolves from a naïve chemo-responsive state to an acquired chemo-resistant state following
chemotherapy. Effective therapeutic strategies are urgently needed to improve clinical outcomes.
We will address this knowledge gap in overall Aim 1 by understanding how a critical determinant of
chemosensitivity, Schlafen family member 11 (SLFN11), informs the degree of chemo-responsiveness in SCLC
subtypes. In overall Aim 2, we will study how different replication stress response pathways and replication fork
modulators work in concert to regulate chemo-sensitivity. Finally, in overall Aim 3 we will integrate insights
gained from work performed in support of overall Aims 1 and 2 to develop strategies to target replication stress
response pathways in combating acquired chemo-resistance in SCLC to yield deeper and more durable
responses with improved tolerability.
The research work will be highly coordinated within the Program Project framework with three Core facilities.
The experiments, progress and direction of the science within each Project will be monitored with feedback via
the Administrative Core A. Establishment of different SCLC cell lines, PDX, and GEM models will be supported
by Core B. Advanced microscopy and computational approaches for each project will be supported by Core C.
The Project/Core leaders have complementary expertise: John Poirier (functional genomics, Project 1, Core B),
Tony Huang (molecular biology, Project 2, Core A), Eli Rothenberg (biophysics, Project 3, Core C), David
Fenyo (computational biology, Core C), and Kwok-Kin Wong (cancer biology, Project 4, Core B). This ensemble
of complementary expertise fosters cross-fertilization of ideas beneficial to the whole team, and makes work
possible that can only be accomplished by a Program Project grant. This team also already has a long track
record of productive collaboration. The results obtained by this Program Project will provide a fundamental
advancement in the understanding of the molecular mechanisms underpinning DNA replication stress and SCLC
therapeutics, and will pave the way for the design of novel cancer therapy targeting relapsed SCLC patients.

## Key facts

- **NIH application ID:** 10848843
- **Project number:** 1P01CA288368-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Tony Tung Huang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,893,978
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848843

## Citation

> US National Institutes of Health, RePORTER application 10848843, Investigating and Targeting Replication Stress in  Small Cell Lung Cancer (1P01CA288368-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848843. Licensed CC0.

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