DEVELOPMENT OF HYBRID INTRACELLULAR/EXTRACELLULAR MODELS OF BRAIN TUMOR PROGRESSION AND MEDICATION STRATEGIES

Open Access
Author:
Vital-Lopez, Francisco Gamaliel
Graduate Program:
Chemical Engineering
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
October 11, 2010
Committee Members:
  • Antonios Armaou, Dissertation Advisor
  • Antonios Armaou, Committee Chair
  • Costas D Maranas, Committee Chair
  • Ali Borhan, Committee Member
  • Patrick Cirino, Committee Member
  • Christine Dolan Keating, Committee Member
  • Andrew Zydney, Committee Member
Keywords:
  • Modeling
  • Brain tumor
  • Angiogenesis
  • Temozolomide
  • Chemotaxis
  • Simulation
Abstract:
High grade brain tumors such as glioblastomas are among the most lethal and difficult to treat cancers. Currently there is no curative treatment for this disease and the median survival time for patients with this cancer is about 15 months. The progression of these tumors depends on the intricate interplay between biological processes that span the molecular and macroscopic scales. In this research, we develop a mathematical model that describes determinant processes of tumor progression at the cellular and tumor levels including signal transduction, proliferation and migration of individual tumor cells, vasculature degeneration and angiogenesis. The model is based in the agent based modeling framework, which is combined with a realistic description of the spatial-temporal distribution of the biochemical cues that affect the behavior of the tumor cells. We deploy the model to investigate different underlying mechanisms of tumor progression. We start by analyzing the effect of the tumor cells response to chemotactic cues on the progression of the tumors. Subsequently, we focus on the role of angiogenesis, which is believed to be essential for the progression of these tumors. Finally, we simulate the effect of different treatment strategies of a chemotherapeutic agent on two tumors mimicking real orthotopic models of glioma. Simulation results suggest that the response of the tumor cells to chemotactic cues is a major determinant of tumor invasion. Moreover, the chemotactic response is tightly coupled with the tumor-induced remodeling of the vasculature, especially with the vessel occlusion. The model is able to quantitatively recapitulate experimental data from treatments of orthotopic models of glioma with a chemotherapeutic agent. Simulation results suggest an intricate relationship between tumor growth, vasculature remodeling and the anti-tumor activity of the chemotherapy. Notably, simulations reveal the emergence of a resistance mechanism to the treatment. The overall goal of this modeling effort is to develop a computational platform to perform in silico experiments that would help understand the complex behavior emerging from multiple interdependent biological processes in the progression of these brain tumors.