A computational systems biology approach to predictive oncology : a computer modeling and bioinformatics study predicting tumor response to therapy and cancer phenotypes
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Technological advances in the recent decades have enabled cancer researchers to probe the disease at multiple resolutions. This wealth of experimental data combined with computational systems biology methods is now leading to predictive models of cancer progression and response to therapy. We begin by presenting our research group’s multis-cale in silico framework for modeling cancer, whose core is a tissue-scale computational model capable of tracking the progression of tumors from a diffusion-limited avascular phase through angiogenesis, and into invasive lesions with realistic, complex morphologies. We adapt this core model to consider the delivery of systemically-administered anticancer agents and their effect on lesions once they reach their intended nuclear target. We calibrate the model parameters using in vitro data from the literature, and demonstrate through simulation that transport limitations affecting drug and oxygen distributions play a significant role in hampering the efficacy of chemotherapy; a result that has since been validated by in vitro experimentation. While this study demonstrates the capability of our adapted core model to predict distributions (e.g., cell density, pressure, oxygen, nutrient, drug) within lesions and consequent tumor morphology, nevertheless, the underlying factors driving tumor-scale behavior occur at finer scales. What is needed in our multi-scale approach is to parallel reality, where molecular signaling models predict cellular behavior, and ultimately drive what is seen at the tumor level. Models of signaling pathways linked to cell models are already beginning to surface in the literature. We next transition our research to the molecular level, where we employ data mining and bioinformatics methods to infer signaling relationships underlying a subset of breast cancer that might benefit from targeted therapy of Androgen Receptor and associated pathways. Defining the architecture of signaling pathways is a critical first step towards development of pathways models underlying tumor models, while also providing valuable insight for drug discovery. Finally, we develop an agent-based, cell-scale model focused on predicting motility in response to chemical signals in the microenvironment, generally accepted to be a necessary feature of cancer invasion and metastasis. This research demonstrates the use of signaling models to predict emergent cell behavior, such as motility. The research studies presented in this dissertation are critical steps towards developing a predictive, in silico computational model for cancer progression and response to therapy. Our Laboratory for Computational & Predictive Oncology, in collaboration with research groups throughout in the United States and Europe are following a computational systems biology paradigm where model development is fueled by biological knowledge, and model predictions are refining experimental focus. The ultimate objective is a virtual cancer simulator capable of accurately simulating cancer progression and response to therapy on a patient-specific basis.