Multiscale Computational Modeling of ROS-Generating Chemotherapies in Head and Neck Squamous Cell Carcinoma
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Raddatz, Andrew
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Abstract
To expand the community’s knowledge of head and neck cancer in response to chemotherapeutic treatment and the impact that tumor heterogeneity plays in this process, a dynamic intracellular drug metabolism model and a microscopy-based pipeline to analyze and simulate the impact of tumor heterogeneity on drug response was developed. In the dynamic intracellular drug metabolism model, ROS-generating chemotherapies were focused on, specifically beta-lapachone, and the reduction of these ROS by constructing an ordinary differential equation system representing the enzymatic reactions of drug metabolism and ROS reduction on a single cell level. Patients’ healthy and cancer cells were compared by their simulated production rates of ROS during beta-lapachone treatment and it was found that treatment could be cancer-targeting depending on the patient and the enzyme profiles of their cells. Furthermore, the output features of these simulations in machine learning algorithms identified which combinations of enzymes were most important to the model, providing potential biomarkers to be probed for when applying these drugs to animal or human studies.
To probe how spatial distribution of heterogeneous redox enzymes could impact beta-lapachone potency non-uniformly within tumors, an agent-based model that accounts for diffusion for drug metabolized H2O2 to simulate how neighboring cells interact with one another under treatment was developed. The agent-based model used experimentally-determined location and expression values of enzymes as input to predict oxygen and ROS concentration profiles as well as cell viability at various time points. The model demonstrated that spatial tumor heterogeneity impacted drug potency depending on the expression of the antioxidant enzymes and location within a tumor, reflecting known bystander effect of beta-lapachone. Agent-based simulations suggest that the more heterogeneous a tumor is, the more effective beta-lapachone will be due to an increased bystander effect given similar bulk phenotypes.
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2023-04-30
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Dissertation