{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:26:36Z","timestamp":1772252796502,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T00:00:00Z","timestamp":1524441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Games"],"abstract":"<jats:p>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 \u201cvicious cycle\u201d 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\u2014chemotherapy where dosage is administered initially in one solid block followed by alternating smaller doses and holidays\u2014and 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.<\/jats:p>","DOI":"10.3390\/g9020019","type":"journal-article","created":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T04:44:48Z","timestamp":1524545088000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Fractionated Follow-Up Chemotherapy Delays the Onset of Resistance in Bone Metastatic Prostate Cancer"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5199-2474","authenticated-orcid":false,"given":"Pranav I.","family":"Warman","sequence":"first","affiliation":[{"name":"Department of Cumputer Science, Duke University, Durham, NC 27708, USA"},{"name":"Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}]},{"given":"Artem","family":"Kaznatcheev","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK"},{"name":"Department of Translational Hematology &amp; Oncology Research, Cleveland Clinic, Cleveland, OH 44195, USA"}]},{"given":"Arturo","family":"Araujo","sequence":"additional","affiliation":[{"name":"Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}]},{"given":"Conor C.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}]},{"given":"David","family":"Basanta","sequence":"additional","affiliation":[{"name":"Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,23]]},"reference":[{"key":"ref_1","unstructured":"National Cancer Institute (2017, August 01). Cancer Stat Facts: Prostate Cancer, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/prost.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1158\/0008-5472.CAN-13-2652","article-title":"An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer","volume":"74","author":"Araujo","year":"2014","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29384","DOI":"10.1038\/srep29384","article-title":"Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer","volume":"6","author":"Cook","year":"2016","journal-title":"Sci. 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