Mechanisms and Targeted Therapy of NRF2-high Esophageal Squamous Cell Carcinoma

NRF2高食管鳞癌的机制及靶向治疗

基本信息

批准号：
10407469
负责人：
XIAOXIN Luke CHEN
金额：
$ 16.92万
依托单位：
NORTH CAROLINA CENTRAL 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：
2020-06-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407469
关键词：
3-Dimensional Affect Anabolism Animal Model Apoptosis Architecture Automobile Driving Biochemistry Biological Models Biology CDKN2A gene CUL3 gene Cancer Etiology Cell Line Cell model Cells Cellular biology Cessation of life Clinic Data Data Set Development Diagnosis Drug Metabolic Detoxication Drug Screening Epithelial Epithelial Cells Esophageal Squamous Cell Carcinoma Esophagus Event Experimental Models Expression Profiling Future Genes Genetic Genetic Transcription Growth Human Hyperactivity Hyperplasia In Vitro Lesion Longevity LoxP-flanked allele Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Metabolism Modeling Molecular Mus Mutate Mutation Neoplasm Metastasis Normal Cell Oncogenic Organoids PI3K/AKT PIK3CA gene Pathway interactions Patients Pharmacology Pharmacology Study Phase Phenotype Phosphotransferases Preventive Proteomics Pyrimethamine Pyruvate Kinase Recurrence Regulation Reporting Research Signal Pathway Signal Transduction Stains Stress Surveys Survival Rate TP53 gene Tamoxifen Testing Therapeutic Therapeutic Agents Tissue Microarray Tissues Translating Tumor Promoters United States Validation Work Xenograft procedure advanced disease cancer type design differential expression experimental study genomic locus in vivo inhibitor insight member metabolomics molecular phenotype multiple omics new therapeutic target novel novel therapeutics response small molecule small molecule inhibitor targeted treatment therapeutic evaluation transcription factor transcriptome sequencing tumor progression

项目摘要

This multiple-PI R01 proposal is designed to incorporate genetic and pharmacological approaches to understand the mechanisms of NRF2 hyperactivation in ESCC and to develop targeted therapy for Nrf2high ESCC. We believe Nrf2 and kinases are functionally interrelated, and thus cooperatively contribute to ESCC. In this proposal, we aim to characterize the molecular and phenotypic consequences of NRF2 hyperactivation in ESCC, determine the mechanisms of action and efficacy of NRF2 small molecule inhibitors in ESCC, and identify NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. Through three independent yet tightly related Specific Aims, we will provide novel insights into pathway regulation and novel therapeutic targets/agents for NRF2high ESCC. If proven effective, some compounds may be further translated into the clinic for targeted therapy of NRF2high ESCC in the future.

这个多重 PI R01 提案旨在结合遗传和药理学方法了解 ESCC 中 NRF2 过度激活的机制并开发 Nrf2high 的靶向治疗食管鳞癌。我们相信 Nrf2 和激酶在功能上是相互关联的，因此共同促成 ESCC。在本提案中，我们的目标是描述 NRF2 过度激活的分子和表型后果在 ESCC 中，确定 NRF2 小分子抑制剂在 ESCC 中的作用机制和功效，以及鉴定 NRF2 响应激酶及其在 NRF2 驱动的 ESCC 生物学中的功能。通过三独立但紧密相关的具体目标，我们将为途径调控提供新颖的见解和新颖的 NRF2high ESCC 的治疗靶点/药物。如果被证明有效，一些化合物可能会被进一步转化未来将进入临床针对NRF2high ESCC的靶向治疗。