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

项目总结

PROJECT SUMMARY This diversity supplement to the funded “Mechanisms and Targeted Therapy of NRF2high Esophageal Squamous Cell Carcinoma” (R01CA244236) will expand the scope of the funded grant to study how levels of reactive oxygen species (ROS) governs global kinase activity in ESCC. In the parent grant, we are characterizing the molecular and phenotypic consequences of NRF2 hyperactivation in ESCC, determining the mechanisms of action and efficacy of NRF2 small molecule inhibitors, and identifying NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. As a complement and extension of this work, the proposed diversity supplement fills a void not studied in the parent project—the role of reactive oxygen species in the regulation of kinase activity and kinase signal transduction in ESCC. This supplement will support Dr. Emily Zarbock’s career development, giving her new scientific skills in cancer cell biology, molecular biology and signal transduction. Dr. Zarbock is an expert in analytical chemistry and mass spectrometry, and new expertise in cancer cell biology will enhance her academic career as she builds her independent research program. In the proposed project, Dr. Zarbock aims to: 1) quantify ROS levels and dynamics in ESCC human cell lines grown in 2D and in 3D as spheroids 2) identify Redox-sensitive kinases in ESCC and 3) determine the role of select redox-sensitive kinases on ESCC signal transduction and cell biology. Dr. Zarbock will work to connect reactive oxygen species to kinases, which while being increasingly appreciated, has not been comprehensively studied or examined in ESCC model systems.