Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization

Abstract

Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to simulate tumor growth and angiogenesis and then employed the model to evaluate an array of single and combination therapy approaches. Treatments included maximum tolerated dose or metronomic (i.e., frequent low doses) scheduling of anti-cancer drugs combined with anti-angiogenic therapy. The results show that metronomic therapy normalizes the tumor vasculature to improve drug delivery, modulates cancer metabolism, decreases interstitial fluid pressure and decreases cancer cell invasion. Further, we find that combining an anti-cancer drug with anti-angiogenic treatment enhances tumor killing and reduces drug accumulation in normal tissues. We also show that combined anti-angiogenic and anti-cancer drugs can decrease cancer invasiveness and normalize the cancer metabolic microenvironment leading to reduced hypoxia and hypoglycemia. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity. Author summary Effective treatment of solid tumors with injected drugs requires that sufficient exposure of cancer cells to the cytotoxic drugs. However, non-uniform and poorly functioning blood vessels make this difficult. The amount of drug that reaches a given cancer cells depends on many factors, including the drug chemistry, its lifetime in the blood circulation, its ability to cross the blood vessel wall and enter the tissue, and the schedule of the injections. We present a mathematical model of tumor growth, angiogenesis, metabolism and drug transport that examines how these processes affect the response to treatment. We find that low dose, high frequency (metronomic) therapy normalizes the tumor vasculature to improve drug delivery and that combining an anti-cancer drug with a drug that specifically enhances vascular function increases tumor killing and reduces drug accumulation in normal tissues. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity.