Capitalizing on competition: An evolutionary model of competitive release in metastatic castration resistant prostate cancer treatment

JOURNAL OF THEORETICAL BIOLOGY

卷:455

Article

West, Jeffrey¹  Ma, Yongqian²  Newton, Paul K.^3,4 

[1] H Lee Moffitt Canc Ctr & Res Inst, Integrated Math Oncol Dept, 12902 Magnolia Dr,SRB 4 Rm 24000H, Tampa, FL 33612 USA

[2] Univ Southern Calif, Dept Phys & Astron, Los Angeles, CA USA

[3] Univ Southern Calif, Dept Aerosp & Mech Engn & Math, Los Angeles, CA 90089 USA

[4] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90089 USA

关键词: Metastatic castration-resistant prostate cancer;    Competitive release;    Evolutionary dynamics;    Adaptive therapy;    Chemotherapeutic resistance;    Prisoner's dilemma;    Replicator dynamics;    Evolutionary game theory;    Adaptive control;   

DOI  :  10.1016/j.jtbi.2018.07.028

来源: Elsevier

【 摘 要 】

The development of chemotherapeutic resistance resulting in tumor relapse is largely the consequence of the mechanism of competitive release of pre-existing resistant tumor cells selected for regrowth after chemotherapeutic agents attack the previously dominant chemo-sensitive population. We introduce a prisoner's dilemma game theoretic mathematical model based on the replicator of three competing cell populations: healthy (cooperators), sensitive (defectors), and resistant (defectors) cells. The model is shown to recapitulate prostate-specific antigen measurement data from three clinical trials for metastatic castration-resistant prostate cancer patients treated with 1) prednisone, 2) mitoxantrone and prednisone and 3) docetaxel and prednisone. Continuous maximum tolerated dose schedules reduce the sensitive cell population, initially shrinking tumor burden, but subsequently release the resistant cells from competition to re-populate and re-grow the tumor in a resistant form. The evolutionary model allows us to quantify responses to conventional (continuous) therapeutic strategies as well as to design adaptive strategies. These novel adaptive strategies are robust to small perturbations in timing and extend simulated time to relapse from continuous therapy administration. (C) 2018 Published by Elsevier Ltd.

【 授权许可】

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