# Tumor-barcoding coupled with high-throughput sequencing of a novel chemoradiation resistant SCLC mouse model

> **NIH NIH U01** · JOHNS HOPKINS UNIVERSITY · 2021 · $153,517

## Abstract

PROJECT ABSTRACT
Limited stage small cell lung cancer (LS SCLC), which is the only curable form of SCLC, is remarkably
sensitive to etoposide plus cisplatin combined with radiation (XRT) with response rates of 90%, but recurrence
is nearly universal. LS SCLC has only a 20-25% 5-year overall survival and ultimately a strategy for improving
long-term outcome in SCLC needs to successfully target the population of cells within tumors destined to
survive through standard therapy to inevitably give rise to recurrent disease. However, there is a considerable
gap in understanding the specific mechanisms responsible for chemoradiation (chemoXRT) resistance in
SCLC. Our project is unique among the current portfolio of SCLC funded programs in that we have focused on
chemoXRT resistance to increase cure rates in LS SCLC. Recently, our work has suggested using patient-
derived xenograft (PDX) models of SCLC may be an important tool to elucidate these mechanisms of
chemoresistance. This approach identified a strongly synergistic anti-SCLC interaction that led to an approved
CTEP trial based on our preclinical data - (NCI #10070: PI Hann). Our parent U01 had three Specific Aims: (1)
Characterize natural history of response of experimental models of SCLC to chemoXRT in vivo. – where we
proposed to determine response rates and recurrence natural histories from a panel of PDXs and available
SCLC genetically engineered mouse models (GEMMs); (2) Characterization of molecular underpinnings of
SCLC chemoXRT resistance – where we proposed constructing gene regulatory networks and gene
expression profiles associated with chemoXRT resistance; and , (3) Pharmacologic and genetic validation of
candidate genes for SCLC chemoXRT resistance in vitro and in vivo – where we proposed to validate novel
gene candidates for conferring chemoXRT resistance using pharmacologic and genetic approach with SCLC
PDX-derived organoids and available SCLC GEMMs. In this revision proposal, we propose additional Specific
Aims that are highly complementary to the parent U01 objectives but are completely novel. SCLC has recently
been stratified into four molecular subgroups. Currently, there are no GEMMs that reliably represent the
SCLC-Y (or -YAP1) subtype and using our novel epithelial-mesenchymal transition (EMT) GEMMs we propose
to create a novel SCLC GEMM for the community. Using novel inducible Twist1 and SNAI1 mouse models we
will examine whether Twist1 (or SNAI1) can accelerate autochthonous SCLC tumor development and are
casual for chemoXRT resistance. Lastly, our revision proposal leverages a new technique, tumor barcoding
with barcode deep-sequencing (Tuba-seq), to overcome all of the barriers that limited the feasibility of using
SCLC GEMMs for quantitative pharmacogenomic analysis. We will use Tuba-seq, an innovative technique
enabling lineage tracing and direct quantification of chemoXRT treatment effects on different genetic
backgrounds in vivo to profile the pharmcogenetic landsca...

## Key facts

- **NIH application ID:** 10201805
- **Project number:** 3U01CA231776-03S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** CHRISTINE L. HANN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $153,517
- **Award type:** 3
- **Project period:** 2018-09-03 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201805

## Citation

> US National Institutes of Health, RePORTER application 10201805, Tumor-barcoding coupled with high-throughput sequencing of a novel chemoradiation resistant SCLC mouse model (3U01CA231776-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201805. Licensed CC0.

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