Limiting the development of anti-cancer drug resistance in a spatial model of micrometastases

DOI10.3934/MBE.2016038zbMATH Open1352.92085OpenAlexW2962732437WikidataQ38738084 ScholiaQ38738084MaRDI QIDQ326548FDOQ326548

Authors A. Shah, Katarzyna A. Rejniak, Jana L. Gevertz 

Publication date 12 October 2016

Published in Mathematical Biosciences and Engineering (Search for Journal in Brave)

Full work available at URL https://arxiv.org/abs/1601.03412

zbMATH Keywords

maximum tolerated dosehybrid modelmetronomic chemotherapychemoresistancefractionated therapymicrometastases

Mathematics Subject Classification ID

Medical applications (general) (92C50) Dynamical systems in biology (37N25)

Abstract: While chemoresistance in primary tumors is well-studied, much less is known about the influence of systemic chemotherapy on the development of drug resistance at metastatic sites. In this work, we use a hybrid spatial model of tumor response to a DNA damaging drug to study how the development of chemoresistance in micrometastases depends on the drug dosing schedule. We separately consider cell populations that harbor pre-existing resistance to the drug, and those that acquire resistance during the course of treatment. For each of these independent scenarios, we consider one hypothetical cell line that is responsive to metronomic chemotherapy, and another that with high probability cannot be eradicated by a metronomic protocol. Motivated by experimental work on ovarian cancer xenografts, we consider all possible combinations of a one week treatment protocol, repeated for three weeks, and constrained by the total weekly drug dose. Simulations reveal a small number of fractionated-dose protocols that are at least as effective as metronomic therapy in eradicating micrometastases with acquired resistance (weak or strong), while also being at least as effective on those that harbor weakly pre-existing resistant cells. Given the responsiveness of very different theoretical cell lines to these few fractionated-dose protocols, these may represent more effective ways to schedule chemotherapy with the goal of limiting metastatic tumor progression.

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Cites Work

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Cited In (4)

• Including blood vasculature into a game-theoretic model of cancer dynamics
• Emergence of anti-cancer drug resistance: exploring the importance of the microenvironmental niche via a spatial model
• Comparison of drug inhibitory effects \((\mathrm{IC}_{50})\) in monolayer and spheroid cultures
• Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives

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