# Novel approach to attenuate small cell lung cancer growth and metastasis

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $508,682

## Abstract

Abstract
Small cell lung cancer (SCLC) is highly aggressive and metastatic malignancy. Unfortunately, no single
targeted therapy has shown clinical activity in SCLC and its 5-year survival rate is only 6-8%. Therefore, there
is an urgent need to develop innovative strategies against SCLC. In recent years, microRNAs (miRs) have
been shown to play significant roles in cancer at the post-translational/transcriptional level by silencing gene
expression. Our preliminary data showed reduced expression of miR-1 in SCLC cell lines as well as patient
samples. We also observed that miR-1 is inversely associated with CXCR4 in SCLC cell lines and in patient
samples. CXCR4/CXCL12-signaling axis has been explored as a major metastatic signaling axis for various
cancers including lung cancer. However, not much is known about the role of miR-1 in regulating CXCR4 in
SCLC. Our central hypothesis, based on our preliminary data, is that downregulation of miR-1
contributes to SCLC growth and metastasis by upregulating CXCR4. In this application, we propose to
develop nanoformulation platform for dual-targeting polymeric CXCR4 antagonist (PCX) nanoparticles (NPs)
containing miR-1 mimics for targeting SCLC. We will pursue three specific aims to test our hypothesis. Aim 1 will
focus to establish functional miR-1 and CXCR4 axis in SCLC using cell lines and patient samples. These
studies will help us to define the novel role of miR-1 downregulation and CXCR4 upregulation for the early
detection of SCLC. Additionally, we will perform global transcriptome (miRNA-Seq/RNA-Seq) integrative
analysis to explore novel miRs and their targets in SCLC. Aim 2 will be focused on optimization and
characterization of PCX-miR-1NPs in SCLC. Since SCLC is highly aggressive and metastatic, we will evaluate
whether PCX-miR-1 NPs simultaneously restore miR-1, block the CXCL12/CXCR4 axis, and thereby inhibit
metastasis of SCLC in preclinical mouse models. Aim 3 will be designed to analyze therapeutic efficacy of PCX-
miR-1NPs in SCLC spontaneous RP (Rbf/f; Tp53f/f; Rosa) mouse model. Upon nasal infection of Ad-cre, RP mice
develop tumors that recapitulate human SCLC characteristics. These tumors are highly aggressive and
metastatic, and therefore, PCX-miR-1 NPs will serve as ideal nanoformulation-based therapy for the management
of SCLC. In addition, cisplatin treatment has been shown to enhance drug resistance through increase
CD133+/CXCR4+ cell populations in lung cancer. In this aim, we will also analyze if PCX-miR-1 NPs enhance
cisplatin sensitization by reprogramming cancer-associated fibroblasts. Additionally, we will identify novel targets
of miR-1 for SCLC using global transcriptome analysis of PCX-miR-1 and cisplatin treated tumor samples.
Altogether, the proposed studies will establish the clinical utility of PCX-miR-1 NPs as a novel therapeutic strategy
for the treatment of SCLC patients who are difficult to treat due to their advanced disease stage and/or
development of drug resis...

## Key facts

- **NIH application ID:** 10439792
- **Project number:** 5R01CA218545-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Mohd Wasim Nasser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $508,682
- **Award type:** 5
- **Project period:** 2018-07-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439792

## Citation

> US National Institutes of Health, RePORTER application 10439792, Novel approach to attenuate small cell lung cancer growth and metastasis (5R01CA218545-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439792. Licensed CC0.

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