Refine
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
Institute
- Mathematik (2)
Therapy evasion – and subsequent disease progression – is a major challenge in current oncology. An important role in this context seems to be played by various forms of cancer cell dormancy. For example, therapy-induced dormancy, over short timescales, can create serious obstacles to aggressive treatment approaches such as chemotherapy, and long-term dormancy may lead to relapses and metastases even many years after an initially successful treatment. The underlying dormancy-related mechanisms are complex and highly diverse, so that the analysis even of basic patterns of the population-level consequences of dormancy requires abstraction and idealization, as well as the identification of the relevant specific scenarios.
In this paper, we focus on a situation in which individual cancer cells may switch into and out of a dormant state both spontaneously as well as in response to treatment, and over relatively short time-spans. We introduce a mathematical ‘toy model’, based on stochastic agent-based interactions, for the dynamics of cancer cell populations involving individual short-term dormancy, and allow for a range of (multi-drug) therapy protocols. Our analysis shows that in our idealized model, even a small initial population of dormant cells can lead to therapy failure under classical (and in the absence of dormancy successful) single-drug treatments. We further investigate the effectiveness of several multidrug regimes (manipulating dormant cancer cells in specific ways) and provide some basic rules for the design of (multi-)drug treatment protocols depending on the types and parameters of dormancy mechanisms present in the population.
Highlights
• We study dormancy in the ‘rare mutation’ regime of stochastic adaptive dynamics.
• We first derive the polymorphic evolution sequence, based on prior work.
• Our evolutionary branching criterion extends a result by Champagnat and Méléard.
• In a classical model dormancy can favour evolutionary branching.
• Dormancy also affects several more population characteristics.
Abstract
In this paper, we investigate the consequences of dormancy in the ‘rare mutation’ and ‘large population’ regime of stochastic adaptive dynamics. Starting from an individual-based micro-model, we first derive the Polymorphic Evolution Sequence of the population, based on a previous work by Baar and Bovier (2018). After passing to a second ‘small mutations’ limit, we arrive at the Canonical Equation of Adaptive Dynamics, and state a corresponding criterion for evolutionary branching, extending a previous result of Champagnat and Méléard (2011).
The criterion allows a quantitative and qualitative analysis of the effects of dormancy in the well-known model of Dieckmann and Doebeli (1999) for sympatric speciation. In fact, quite an intuitive picture emerges: Dormancy enlarges the parameter range for evolutionary branching, increases the carrying capacity and niche width of the post-branching sub-populations, and, depending on the model parameters, can either increase or decrease the ‘speed of adaptation’ of populations. Finally, dormancy increases diversity by increasing the genetic distance between subpopulations.