# Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC

> **NIH NIH U01** · JOHNS HOPKINS UNIVERSITY · 2022 · $599,374

## Abstract

PROJECT ABSTRACT
Limited stage small cell lung cancer (LS SCLC), the only curable form of SCLC, is remarkably sensitive to
etoposide plus cisplatin combined with thoracic radiotherapy with response rates > 70%; however, therapy-
refractory recurrence is common. LS SCLC has less than a 25% 5-year overall survival (OS) and ultimately a
strategy for improving long-term SCLC outcomes needs to successfully target tumor cell populations that
survive standard therapy and give rise to recurrent disease. There is, however, a considerable gap in
understanding the specific mechanisms responsible for chemoradiotherapy resistance in SCLC. Our project is
unique among the current portfolio of SCLC funded programs in that we have focused on
chemoradioresistance 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 mechanisms of therapy
resistance. This approach was remarkably successful, identifying a tolerable and strongly synergistic anti-
SCLC interaction that led to a CTEP-approved trial based on our preclinical data - (NCI #10070; Study Chair:
Hann). In this research program, we will test key hypotheses via three specific aims that will provide more
mechanistic insights into the rapidly emergent chemoradiation resistance observed in LS SCLC.
One central hypothesis of this proposal is that adaptive gene expression changes mediate rapid emergence of
the chemoradiation resistance phenotype in LS SCLC. We have developed a novel chemoradiation treatment
regimen with SCLC PDX models to facilitate these studies. Development and characterization of this novel
model involves a unique collaboration between medical oncologists, radiation oncologists, bioinformaticians,
medical physicists, veterinarians and molecular/cell biologists that is extremely well suited to develop an
integrated program dedicated to resolving questions of SCLC chemoradioresistance. Finally, we have already
identified novel gene targets that are correlated with SCLC chemoradioresistance.
Our research program is organized as follows: Aim #1: Characterize natural history of response of
experimental models of SCLC to chemoradiation in vivo. We will determine response rates and recurrence
patterns of a panel of SCLC PDXs and transgenic mouse models. Aim #2: Characterization of molecular
underpinnings of SCLC chemoradiation resistance. We will reconstruct gene regulatory networks and gene
expression profiles associated with chemoradiation resistance and develop small-scale predictive classifiers for
therapy response to be validated in follow-up studies. Aim #3: Pharmacologic and genetic validation of
candidate genes for SCLC chemoradiation resistance in vitro and in vivo. We will validate our novel gene
candidates for conferring chemoradiation resistance using pharmacologic and genetic approach with SCLC
PDX-derived organoids and SCLC transgenic mouse models.

## Key facts

- **NIH application ID:** 10469686
- **Project number:** 5U01CA231776-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** CHRISTINE L. HANN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $599,374
- **Award type:** 5
- **Project period:** 2018-09-03 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469686

## Citation

> US National Institutes of Health, RePORTER application 10469686, Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC (5U01CA231776-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469686. Licensed CC0.

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