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.

Biomechanical modelling of tumor growth with chemotherapeutic treatment: a review

“…The two aspects described above are related to the administration scheduling that has an effect on tumor progression, regression, and the evolution of resistant cells. To determine the optimal chemotherapy schedule, mathematical models have been employed for personalized cancer treatment [30,[229][230][231][232][233][234][235][236][237][238][239].…”

Transport Barriers Influence the Activation of Anti‐Tumor Immunity: A Systems Biology Analysis

“…Such models represent each component of the system and how those components interact with one another over several length scales. [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] There is a rich literature of pharmacokinetic‐pharmacodynamic (PKPD) or quantitative systems pharmacology (QSP) models of the circulation of therapeutic agents, antigens, and immune cells in the blood and lymph. [ 31 , 32 , 33 , 34 ] The simplest of these consider only a single tumor and a single lymph node, while more detailed models include several additional organs.…”

“…Blood flow follows anatomically‐accurate pathways and is distributed to the various organs via branches in the arterial tree, according to flow volumes reported in the literature. [ 26 , 30 , 42 ] Each compartment of the model contains a sub‐compartment for the organ and another sub‐compartment representing the lymph node(s) draining that organ. Each sub‐compartment receives a fraction of the blood flow entering that organ, and a fraction of interstitial fluid collected from the tissue is assumed to flow into the draining lymph nodes (LNs).…”