Preventing competitive release

Seton-Rogers, Sarah

doi:10.1038/nrc.2016.28

Cited by 31 publications

(17 citation statements)

References 1 publication

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“…The numerical values in (16) are chosen for convenience and satisfy the constraints (17)- (19). In each cell-cell interaction, the healthy cells x 1 (healthy H) are cooperators, and the two-species of cancer cells, x 2 (sensitive S), and x 3 (resistant R), are the defectors.…”

Section: A the Prisoner's Dilemma As A Cancer Modelmentioning

confidence: 99%

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Nonlinear dynamics of chemotherapeutic resistance

Newton¹,

Ma²

2018

Preprint

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We use a three-component replicator dynamical system with healthy cells, sensitive cells, and resistant cells, with a prisoner's dilemma payoff matrix from evolutionary game theory to understand the phenomenon of competitive release, which is the main mechanism by which tumors develop chemotherapeutic resistance. By comparing the phase portraits of the system without therapy compared to continuous therapy above a certain threshold, we show that chemotherapeutic resistance develops if there are pre-exisiting resistance cells in the population. We examine the basin boundaries of attraction associated with the chemo-sensitive population and the chemo-resistant population for increasing values of chemo-concentrations and show their spiral intertwined structure. We also examine the fitness landscapes both with and without continuous therapy and show that with therapy, the average fitness as well as the fitness functions of each of the subpopulations initially increases, but eventually decreases monotonically as the resistant subpopulation saturates the tumor.

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Section: A the Prisoner's Dilemma As A Cancer Modelmentioning

confidence: 99%

“…Filled corners are stable, unfilled corners are unstable. This is the basic mechanism of competitive release induced by sufficiently strong chemotherapeutic dose [19].…”

Section: B Chemotherapy Modelmentioning

confidence: 99%

Nonlinear dynamics of chemotherapeutic resistance

Newton¹,

Ma²

2018

Preprint

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“…After months of fixed periodic cycles, the cancer often recurs and the tumor begins to regrow. Because of the genetic and cellular heterogeneity of a typical tumor [5], instead of killing all of the cancer cells and therby elimi-nating the tumor, the chemotherapeutic regime actually selects for a resistant phenotype, a phenomenon known as competitive release [6][7][8][9]. The diversity of cells within a tumor effectively protects the tumor from single-line or pre-scheduled chemotherapeutic assaults by allowing for elimination of the chemo-sensitive population in order to accomplish the subsequent release of the chemo-resistant population.…”

Section: Introductionmentioning

confidence: 99%

“…The characterization of a typical tumor as an adaptive landscape made up of competing cells of varying degrees of fitness, which determine growth rates of the various sub-populations is a more accurate characterization of a tumor and suggests an ecological or evolutionary approach [11][12][13][14][15][16][17][18][19]. If one had access to timeresolved information [20] on the relative balance of the sub-populations of cells making up the tumor, then one could use chemotherapy as a control device (accuator) to keep the sub-populations in balance, competing with each other indefinitely, without any one of the cancerous sub-populations dominating the landscape [6].…”

Section: Introductionmentioning

confidence: 99%

On the design of treatment schedules that avoid chemotherapeutic resistance

Newton¹,

Ma²

2018

Preprint

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We introduce a method of designing treatment schedules for a model three-component replicator dynamical system that avoids chemotherapeutic resistance by controlling and managing the competitive release of resistant cells in the tumor. We use an evolutionary game theory model with prisoner's dilemma payoff matrix that governs the competition among healthy cells, chemo-sensitive cells, and chemo-resistant cells and the goal is to control the evolution of chemo-resistance via the competitive release mechanism. The method is based on nonlinear trajectory design and energy transfer methods first introduced in the orbital mechanics literature for Hamiltonian systems. By using the structure of the trajectories defined by solutions of the replicator system for different constant chemotherapeutic concentrations (which produces a curvilinear coordinate system spanning the full region), we construct periodic (closed) orbits by switching the chemo-dose at carefully chosen times and appropriate levels to design schedules that are superior to both maximum tolerated dose (MTD) schedules and low-dose metronomic (LDM) schedules, both of which ultimately lead to fixation of either sensitive cells or resistant cells. By keeping the three sub-populations of cells in competition with each other, neither the sensitive cell population nor the resitant cell population are able to dominate as we balance the populations indefinitely (closed periodic orbits), thereby avoiding fixation of the cancer cell population and re-growth of a resistant tumor. The schedules we design have the feature that they maintain a higher average population fitness than either the MTD or the LDM schedules.

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“…Effective use of this concept relies on both a working understanding of how the many interacting sub-species coevolve, as well as the ability to continually monitor the different sub-populations so that adaptive adjustments can be made to the delivery schedule of toxins to shape the fitness landscape on a timescale shorter than the timescale on which the population develops resistance to the pesticide. Many of these same ideas can also be used for the control of the heterogeneous population of cancer cells comprising an evolving and growing tumor [2][3][4][5][6][7][8][9][10]. The concept, known generically as adaptive therapeutics [10] is an exciting avenue for avoiding chemo-resistance in a tumor which is one of the main stumbling blocks associated with the efficacy of many cancer treatments.…”

Section: Introduction To the Type Of Problem In Cancermentioning

confidence: 99%

Competitive release in tumors

West

2018

Preprint

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Abstract.Competitive release is a bedrock principle of coevolutionary ecology and population dynamics. It is also the main mechanism by which heterogeneous tumors develop chemotherapeutic resistance. Understanding, controlling, and exploiting this important mechanism represents one of the key challenges and potential opportunities of current medical oncology. The development of sophisticated mathematical and computational models of coevolution among clonal and sub-clonal cell populations in the tumor ecosystem can guide us in predicting and shaping various responses to perturbations in the fitness landscape which is altered by chemo-toxic agents. This in turn can help us design adaptive chemotherapeutic strategies to combat the release resistant cells.

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Preventing competitive release

Cited by 31 publications

References 1 publication

Nonlinear dynamics of chemotherapeutic resistance

Nonlinear dynamics of chemotherapeutic resistance

On the design of treatment schedules that avoid chemotherapeutic resistance

Competitive release in tumors

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