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Games 2018, 9(2), 19; https://doi.org/10.3390/g9020019

Fractionated Follow-Up Chemotherapy Delays the Onset of Resistance in Bone Metastatic Prostate Cancer

1
Department of Cumputer Science, Duke University, Durham, NC 27708, USA
2
Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
3
Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK
4
Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, OH 44195, USA
5
Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
*
Author to whom correspondence should be addressed.
Received: 28 February 2018 / Revised: 11 April 2018 / Accepted: 18 April 2018 / Published: 23 April 2018
(This article belongs to the Special Issue Game Theory and Cancer)
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Abstract

Prostate cancer to bone metastases are almost always lethal. This results from the ability of metastatic prostate cancer cells to co-opt bone remodeling, leading to what is known as the vicious cycle. Understanding how tumor cells can disrupt bone homeostasis through their interactions with the stroma and how metastatic tumors respond to treatment is key to the development of new treatments for what remains an incurable disease. Here we describe an evolutionary game theoretical model of both the homeostatic bone remodeling and its co-option by prostate cancer metastases. This model extends past the evolutionary aspects typically considered in game theoretical models by also including ecological factors such as the physical microenvironment of the bone. Our model recapitulates the current paradigm of the “vicious cycle” driving tumor growth and sheds light on the interactions of heterogeneous tumor cells with the bone microenvironment and treatment response. Our results show that resistant populations naturally become dominant in the metastases under conventional cytotoxic treatment and that novel schedules could be used to better control the tumor and the associated bone disease compared to the current standard of care. Specifically, we introduce fractionated follow up therapy—chemotherapy where dosage is administered initially in one solid block followed by alternating smaller doses and holidays—and argue that it is better than either a continuous application or a periodic one. Furthermore, we also show that different regimens of chemotherapy can lead to different amounts of pathological bone that are known to correlate with poor quality of life for bone metastatic prostate cancer patients. View Full-Text
Keywords: evolutionary game theory; prostate cancer bone metastasis; chemotherapy; heterogeneity; resistance evolutionary game theory; prostate cancer bone metastasis; chemotherapy; heterogeneity; resistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Warman, P.I.; Kaznatcheev, A.; Araujo, A.; Lynch, C.C.; Basanta, D. Fractionated Follow-Up Chemotherapy Delays the Onset of Resistance in Bone Metastatic Prostate Cancer. Games 2018, 9, 19.

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