# Modeling tumor heterogeneity and treatment resistance in small cell lung cancer

> **NIH NIH R50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $116,847

## Abstract

PROJECT SUMMARY
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid onset of
chemoresistance and poor clinical outcomes. Recent advances in immunotherapy have changed
the standard of care for SCLC for the first time in over 30 years. Dr. Allison Stewart (Resarch
Specialist) and Dr. Lauren Byers (Unit Director) in the Department of Thoracic Head and Neck
Medical Oncology at University of Texas M.D. Anderson Cancer Center aim to address major,
unmet needs in SCLC, including development of novel therapeutic targets, investigation of
approaches to enhance response to immunotherapy, and the study of heterogeneity and its
contribution to drug resistance. Mechanisms underlying treatment-resistance remain obscure due
to scarcity of tissue samples from relapsed patients. To address this deficiency, Dr. Stewart has
led efforts to establish novel SCLC models and analyze serial blood and tumor biopsies from
patients using innovative genomic, transcriptomic, and proteomic assays to study mechanisms
driving treatment resistance to chemotherapy, immunotherapy, or targeted therapies in SCLC.
Patient liquid biopsies are non-invasive, facilitate both serial and post-relapse tissue sampling
and contain sufficient circulating tumor cells (CTCs) for generation of CTC-derived xenograft
(CDX) models of SCLC, as well as for direct single-cell transcriptional profiling. CDXs mirror
patient disease by expression of SCLC markers, sites of metastatic disease and platinum
response. Intratumoral heterogeneity (ITH) of SCLC and its contribution to clinical outcomes has
not been fully characterized. To investigate ITH, single-cell analyses (including single-cell
RNAseq) were performed on novel platinum-sensitive and -resistant SCLC CDX models, as well
as longitudinal analyses of CDX models and patient CTCs over the course of therapy. Dr. Stewart
has demonstrated that refractory SCLC is characterized by increased heterogeneity and the
development of multiple, disparate resistant cell populations within the same patient. In order to
address the scarcity of SCLC tissue samples, especially paired and post-relapse samples, Dr.
Byers has spearheaded an effort to integrate serial tissue acquisition into the design of all SCLC-
focused clinical trials at MDACC. Dr. Stewart's goal is to coordinate a SCLC platform by working
with multi-disciplinary teams, including a clinical team (identify and consent patients), a laboratory
processing team (process/bank specimens, as well as generate animal models), an experimental
analysis team (perform experiments with CTCs, tumor specimens and animal models) and a
bioinformatics team (scientific analysis) to establish a repository of SCLC specimens for
understanding treatment resistance and developing methods to recognize patient response.

## Key facts

- **NIH application ID:** 10254303
- **Project number:** 5R50CA243698-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Catherine Allison Stewart
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $116,847
- **Award type:** 5
- **Project period:** 2020-09-04 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254303

## Citation

> US National Institutes of Health, RePORTER application 10254303, Modeling tumor heterogeneity and treatment resistance in small cell lung cancer (5R50CA243698-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10254303. Licensed CC0.

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