Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer

Jessica Cunningham*, Frank Thuijsman, Ralf Peeters, Yannick Viossat, Joel Brown, Robert Gatenby, Kateřina Staňková

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

10 Citations (Scopus)
40 Downloads (Pure)


In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations.

Original languageEnglish
Article numbere0243386
Number of pages24
JournalPLoS ONE
Issue number12 December
Publication statusPublished - 2020


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