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

项目 1：非小细胞肺癌中的种族相关 RNA 剪接：功能询问和治疗靶向

基本信息

批准号：
10037508
负责人：
Jennifer Ann Freedman
金额：
$ 29.51万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10037508
关键词：
Address African African American Age Alternative Splicing Area Biological Biological Markers Biological Specimen Banks Biology Bronchi CRISPR/Cas technology Cancer Etiology Cancer Patient Cellular biology Cessation of life Characteristics Clinical Data Development Developmental Therapeutics Program Diagnosis Drug Targeting Ethnic Origin European Event Exhibits Gene Expression Genes Genetic Transcription Genotype Institution Intervention Intervention Studies Lead Libraries Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Methodology Modeling Molecular Non-Small-Cell Lung Carcinoma North Carolina Oligonucleotides Oncogenic Oncology Organoids Pathology Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Positioning Attribute Pre-Clinical Model RNA Splicing Race Reagent Reporting Research Resistance Resources Scientist Signal Pathway Smoking Status Spliced Genes Squamous Cell Lung Carcinoma Subgroup Technology The Cancer Genome Atlas Therapeutic Therapeutic Agents Tissues Transfection Tumor Suppressor Genes United States Universities Variant Work actionable mutation base biological heterogeneity cancer cell cancer health disparity clinical heterogeneity clinically relevant cohort differential expression driver mutation drug use screening exon skipping high-throughput drug screening improved in vivo interest new therapeutic target novel patient subsets precision oncology response targeted treatment therapeutic target tool transcriptome transcriptome sequencing

项目摘要

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 splicing-related targets for development of new biomarkers and therapeutic agents for NSCLC in patients of African ancestry, 3) when combined with TCGA data, this study will more than double the number of molecularly characterized NSCLC biospecimens from patients of African ancestry, and generate additional preclinical models, making such data and models available to the nationwide cohort of scientists conducting research on lung cancer and lung cancer disparities, and 4) position lead novel RNA splicing-targeted drugs for NSCLC in patients of African ancestry for in vivo studies. Ultimately, such precision oncology interventions and further studies enabled by the molecularly characterized cohort of biospecimens and models will have the potential to mitigate NSCLC disparities.

摘要-项目1