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Abstract
Rapid evolution is ubiquitous in nature. We briefly review some of this quite broadly, particularly in the context of response to anthropogenic disturbances. Nowhere is this more evident, replicated and accessible to study than in cancer. Curiously cancer has been late - relative to fisheries, antibiotic resistance, pest management and evolution in human dominated landscapes - in recognizing the need for evolutionarily informed management strategies. The speed of evolution matters. Here, we employ game-theoretic modeling to compare time to progression with continuous maximum tolerable dose to that of adaptive therapy where treatment is discontinued when the population of cancer cells gets below half of its initial size and re-administered when the cancer cells recover, forming cycles with and without treatment. We show that the success of adaptive therapy relative to continuous maximum tolerable dose therapy is much higher if the population of cancer cells is defined by two cell types (sensitive vs. resistant in a polymorphic population). Additionally, the relative increase in time to progression increases with the speed of evolution. These results hold with and without a cost of resistance in cancer cells. On the other hand, treatment-induced resistance can be modeled as a quantitative trait in a monomorphic population of cancer cells. In that case, when evolution is rapid, there is no advantage to adaptive therapy. Initial responses to therapy are blunted by the cancer cells evolving too quickly. Our study emphasizes how cancer provides a unique system for studying rapid evolutionary changes within tumor ecosystems in response to human interventions; and allows us to contrast and compare this system to other human managed or dominated systems in nature.
Highlights
Organisms can respond rapidly to contingencies and changes in their environment
We model this in the context of monomorphic and polymorphic cancer cell populations, and in the context of having no cost of resistance, a cost of resistance manifested in intrinsic growth rates, and a cost of resistance manifested in the carrying capacities
We compare time to progression (TTP) under maximum tolerable dose (MTD) vs. adaptive therapy (AT) for each of our eco-evolutionary models introduced in the previous section
Summary
Organisms can respond rapidly to contingencies and changes in their environment. When they cannot extinction may follow. Cancers provide a unique study of rapid evolution because within a matter of months or years, cancer within its host will evolve adaptations for evading the immune system, increasing vasculature, co-opting the signaling pathways of normal cells, and gathering scarce nutrients more quickly and efficiently (Hanahan and Weinberg, 2000, 2011). We analyze the consequences of evolutionary speed in determining the efficacy of a standard form of AT relative to continuous drug delivery at maximum tolerable dose (MTD) (section 5) We model this in the context of monomorphic and polymorphic cancer cell populations, and in the context of having no cost of resistance, a cost of resistance manifested in intrinsic growth rates, and a cost of resistance manifested in the carrying capacities. In addition to adding to the modeling results for AT in cancers, we hope to show evolutionary biologists and ecologists just how similar resistance management in cancer is to managing evolving species (that may be pests or resources), and to show cancer biologists how the challenge of therapy resistance is kindred to conservators and managers of biodiversity and pests in nature
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