First Strike-Second Strike Strategies in Metastatic Cancer: Lessons from the Evolutionary Dynamics of Extinction.

While clinical cancer research has produced many highly effective drugs, the diversity and evolutionary capacity of most cancer populations remain insurmountable barriers to cure. Here, we propose that curative outcomes may, nevertheless, be achieved by sequencing therapies that are individually effective but noncurative. Basic principles for such an approach are derived from the eco-evolutionary dynamics of background extinctions in which a "first strike" reduces the size and heterogeneity of the population. When followed immediately by demographic and ecological "second strikes," the population can be reduced below some minimum threshold, leading inevitably to extinction. This strategy bears strong similarity to the empirically-derived curative therapy in childhood acute lymphocytic leukemia. ©2019 American Association for Cancer Research.