Microenvironment-Mediated Modeling of Tumor Response to Vascular-Targeting Drugs
The tumor-associated microvasculature is one of the key elements of the microenvironment that helps shape, and is shaped by, tumor progression. Given the important role of the vasculature in tumor progression, and the fact that tumor and normal vasculatur
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Jana L. Gevertz
Abstract
The tumor-associated microvasculature is one of the key elements of the microenvironment that helps shape, and is shaped by, tumor progression. Given the important role of the vasculature in tumor progression, and the fact that tumor and normal vasculature are physiologically and molecularly distinct, much effort has gone into the development of vascular-targeting drugs that in theory should target tumors without significant risk to normal tissue. In this chapter, a multiscale hybrid mathematical model of tumor-vascular interactions is presented to provide a theoretical basis for assessing tumor response to vascular-targeting drugs. Model performance is calibrated to quantitative clinical data on tumor response to angiogenesis inhibitors (AIs), preclinical data on response to a cytotoxic chemotherapy, and qualitative preclinical data on response to vascular disrupting agents (VDAs). The calibrated model is then used to explore two questions of clinical interest. First, the hypothesis that AIs and VDAs are complementary treatments, rather than redundant, is explored. The model predicts a minimal increase in antitumor activity as a result of adding a VDA to an AI treatment regimen, and in fact at times the combination can exert less antitumor activity than stand-alone AI treatment. Second, the question of identifying an optimal dosing strategy for treating with an AI and a cytotoxic agent is addressed. Using a stochastic optimization scheme, an intermittent schedule for both chemotherapy and AI administration is identified that can eradicate the simulated tumors. We propose that this schedule may have increased clinical antitumor activity compared to currently used treatment protocols.
J.L. Gevertz () Department of Mathematics and Statistics, The College of New Jersey, Ewing, NJ 08628, USA e-mail: [email protected] © Springer International Publishing Switzerland 2016 K.A. Rejniak (ed.), Systems Biology of Tumor Microenvironment, Advances in Experimental Medicine and Biology 936, DOI 10.1007/978-3-319-42023-3_10
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J.L. Gevertz
Keywords
Tumor-vasculature interactions • Hybrid cellular automaton model • Angiogenesis inhibitors • Vascular disrupting agents • Cytotoxic chemotherapy
10.1
Introduction
Solid tumors maintain their vascular needs through a combination of co-option of existing host blood vessels and the creation of new blood vessels from existing ones in a process termed angiogenesis. While a tumor can partially fill its vascular needs through vessel co-option, growth beyond a few millimeters in diameter and invasion beyond the primary tumor site requires angiogenesis [4]. Therefore, the tumorassociated vasculature is a key component of the microenvironment that helps shape, and is shaped by, tumor progression. The angiogenic process is influenced by a broad range of pro- and anti-angiogenic molecules, and can also be triggered by microenvironmental cues such as hypoxia and mechanical stress [4]. While angiogenesis is a speedy process for directing oxygen and nutri
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