Fractionated follow-up chemotherapy delays the onset of resistance in bone metastatic prostate cancer

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 doeses 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.keywords: evolutionary game theory -prostate cancer bone metastasis -chemotherapy -heterogeneity -resistance

The Contribution of Evolutionary Game Theory to Understanding and Treating Cancer

“…As original replicator dynamics ( 7) assume that n i=1 q i = 1, extensions have been made to capture situations with a varying total population size. Such extensions involve fictitious freespace strategies [108,192], but also more general dynamics [101,123,186]. A relatively large body of literature models interactions between cancer cells of different types and/or interactions between cancer cells and the environment through the Lotka-Volterra (LV) competition equations and their extensions [30,55,75,206].…”

“…Warman et al focused on a fitness matrix model of the vicious cycle of metastatic prostate cancer cells co-opting bone remodeling [192]. The authors introduced fractionated follow-up therapy-chemotherapy where dosage is administered initially in one solid block followed by alternating smaller doses and holidays-and showed that it is better than either a continuous application or a periodic one.…”

The contribution of evolutionary game theory to understanding and treating cancer

“…As the replicator dynamics ( 9) include frequency dynamics only and cannot capture the changes of cancer cell population, alternative modeling frameworks have been adopted to capture both ecological and evolutionary dynamics of cancer cells. These include expanding replicator dynamics by additional population dynamics elements, such as through fictious free-space strategies [104,187], but also different models capturing population dynamics directly [119,180]. A relatively large body of literature models interactions between cancer cells of different types and/or interactions between cancer cells and the environment through the Lotka-Volterra competition equations and their extensions [29,52,72,200].…”

“…They adopted optimal control theory and showed analytically that to reduce the tumor volume while preserving its heterogeneity, one needs to apply lower than the MTD of drugs. Warman et al (2018) focused on a fitness matrix model of the vicious cycle of metastatic prostate cancer cells co-opting bone remodeling [187].…”

High school Internship Program in Integrated Mathematical Oncology (HIP IMO) – five-year experience at Moffitt Cancer Center

“…Student projects contributed to a number of peer-reviewed and published articles and book chapters in topical and interdisciplinary journals including PLoS Computational Biology [38], Scientific Reports [39], International Journal of Radiation Biology [40], Games [41], Annals of Epidemiology [42], and Encyclopedia of Biomedical Engineering [43], as well as several BioRxiv preprints [44–47].…”