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.
Journal of theoretical biology. 2018 Jul 23 [Epub ahead of print]
Jeffrey West, Yongqian Ma, Paul K Newton
Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4 Rm 24000H Tampa, Florida, 33612, USA. Electronic address: ., Department of Physics and Astronomy, University of Southern California, Los Angeles, CA, USA. Electronic address: ., Department of Aerospace & Mechanical Engineering and Mathematics, University of Southern California, Los Angeles, CA, 90089-1234, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089-1234, USA. Electronic address: .