Andrew Raddatz

BME PhD Thesis Proposal Presentation

Date: February 21, 2020

Time: 10:30 AM

Location:Kendeda 210 Classroom

Advisor: Melissa Kemp

Committee Members: Eberhard Voit, Peng Qiu, Cristina Furdui (Wake Forest), Susan Thomas

Title: Multiscale Computational Modeling of ROS-Generating Chemotherapies in Head and Neck Squamous Cell Carcinoma

Abstract:

Head and neck squamous cell carcinoma (HNSCC) affects approximately 50,000 new people each year. Many HNSCC tumors resist standard chemotherapies and radiation treatment due to the upregulation of Nrf2, a transcription factor that controls cellular reactive oxygen species (ROS) levels through transcriptional control over antioxidant enzymes such as catalase, peroxiredoxin, and NQO1. A potential method of treatment is to use NQO1-activatable chemotherapeutic agents, such as β-lapachone and isobutyl-deoxynyboquinone (IB-DNQ), which produce ROS leading to cell death through programmed necrosis. The efficacy of these chemotherapeutics for solid tumors is still under investigation, and currently patient-specific metrics of response have not been identified. HNSCC is a highly heterogeneous cancer, including expression of NQO1 which metabolizes the drug. Work by our collaborators has established in other cancers that tumor heterogeneity can be leveraged for the bystander effect, which is when cells that are not directly affected by the drug are damaged or killed by apoptosis due to the metabolism of the drug in a nearby cell. Even though redox-associated proteins are well characterized in their individual mechanisms, a more thorough approach to elucidate their quantitative significance on a systems level both intracellularly and on the broader tissue scale is necessary for this drug to be effectively utilized in the clinical setting. Ultimately, the objective of this project as executed in three aims will relate antioxidant expression, hypoxia, and ROS-generating chemotherapy efficacy, and utilize this knowledge to engineer personalized, computational models of HNSCC in response to ROS-generating chemotherapies