# Project 1: Race-related RNA splicing in non-small cell lung cancer: functional interrogation and therapeutic targeting

> **NIH NIH P20** · DUKE UNIVERSITY · 2020 · $295,093

## Abstract

ABSTRACT – Project 1
Lung and bronchus cancer is the leading cause of cancer-related deaths in the United States and in our
institution’s state of North Carolina, with blacks having the highest number of deaths and being diagnosed three
years younger on average than whites. Biological drivers of non-small cell lung cancer (NSCLC) in black patients
remain underexplored, with only a small number of studies on race-related differences in actionable mutations
and aggregate gene expression. As a result, these efforts have likely missed other important drivers of race-
related NSCLC biological and clinical heterogeneity. The proposed work addresses the urgent need to
functionally characterize and therapeutically target novel race-related RNA splicing targets in NSCLC. We are
the first team to identify alternative RNA splicing differences in NSCLC between patients of African and
European ancestry. Specifically, in lung squamous cell carcinomas (LUSCs), the number of race-related
differentially spliced genes (DSGs) (4,830) far exceeded the number of genes exhibiting race-related differential
aggregate gene expression (DEGs) (267) in the same tissues. Among the DSGs, 17% are reported to be
oncogenes, tumor suppressor genes and/or drivers and 355 RNA splicing events within DSGs are associated
with LUSC survival. Among the DEGs, 6% are reported to be cancer-related and 18 are associated with LUSC
survival. A number of the DSGs and DEGs involve therapeutically targetable signaling pathways. Furthermore,
we have mined The Cancer Genome Atlas (TCGA) and have identified DSGs and DEGs in additional LUSCs or
lung adenocarcinomas (LUADs). The objectives of the proposed work are to extend this novel area of inquiry
with significance for precision oncology in NSCLC disparities by 1) examining DSGs and DEGs in an expanded
cohort of clinically relevant NSCLC subgroups of patients annotated for survival and smoking status, 2)
functionally characterizing prioritized race-related alternative RNA splicing events, and 3) drugging prioritized
race-related alternative RNA splicing events for therapeutic application. To reach these objectives, we propose
to conduct three aims. Aim 1: To assess the expression of RNA splice variants and genes encoding trans-acting
splicing factors across clinically relevant NSCLC subgroups in patients of African and European ancestry. Aim
2: To interrogate the functional significance of prioritized race-related RNA splice variants for the biology of
NSCLC. Aim 3: A) To develop novel splice-switching oligonucleotide (SSO) morpholino drugs to modulate RNA
splicing events critical to race-related NSCLC for therapeutic application and B) To identify available targeted
therapeutic agents that inhibit race-related NSCLC based on dysregulated RNA splicing pathway(s). The
rationale for and impact of this study is that it will 1) increase understanding of the molecular mechanisms
underlying lung cancer disparities, 2) provide an abundance of novel RNA s...

## Key facts

- **NIH application ID:** 10037508
- **Project number:** 1P20CA251657-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jennifer Ann Freedman
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $295,093
- **Award type:** 1
- **Project period:** 2020-09-14 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10037508

## Citation

> US National Institutes of Health, RePORTER application 10037508, Project 1: Race-related RNA splicing in non-small cell lung cancer: functional interrogation and therapeutic targeting (1P20CA251657-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10037508. Licensed CC0.

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