Dosage strategies for delaying resistance emergence in heterogeneous tumors

Abstract

Drug resistance in cancer treatments is a frequent problem that, when it arises, leads to failure in therapeutic efforts. Tumor heterogeneity is the primary reason for resistance emergence and a precise treatment design that takes heterogeneity into account is required to postpone the rise of resistant subpopulations in the tumor environment. In this paper, we present a mathematical framework involving clonal evolution modeling of drug-sensitive and drug-resistant clones. Using our framework, we examine delaying the rise of resistance in heterogeneous tumors during control phase of therapy in a containment treatment approach. We apply pharmacokinetic/pharmacodynamic (PKPD) modeling and show that dosage strategies can be designed to control the resistant subpopulation. Our results show that the drug dosage and schedule determine the relative dynamics of sensitive and resistant clones. We present an optimal control problem that finds the dosing strategy that maximizes the delay in resistance emergence for a given period of containment treatment.

Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma

“…Increasing research has focused on dose strategies to combat resistance in tumor progression in combination therapy, and both extremes of too high and too low doses may unnecessarily accelerate the spread of resistance ( Kouyos et al, 2014 ; Vakil and Trappe, 2022 ). Some results suggest that maintaining a low-dose treatment strategy is advantageous when the size of the patient‘s tumor is tolerable, as it allows the susceptible clonal population to survive and compete with the resistant subpopulation to prevent the resistant population from propagating uncontrollably and taking over the entire tumor, thus having more feared consequences for the patient ( Vakil and Trappe, 2021 ). In addition, in situations where the patient‘s immune response increases over time, delaying the emergence of resistance may provide sufficient time for immunity to help prevent resistance.…”

Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations

“…Drug resistance is a major contributing factor to treatment failure and disease progression, and sub-optimal concentrations are known to provide selective and/or adaptive pressures for tumor evolution. Dosage strategies (i.e., amount and timing) have been shown to be effective in preventing or delaying acquired resistance 72 . Combination therapy is an alternative method to overcome the drug resistance that is typically seen in sequential monotherapy treatment [72][73][74][75] and has the added benefit of enhanced tumor killing.…”

“…Dosage strategies (i.e., amount and timing) have been shown to be effective in preventing or delaying acquired resistance 72 . Combination therapy is an alternative method to overcome the drug resistance that is typically seen in sequential monotherapy treatment [72][73][74][75] and has the added benefit of enhanced tumor killing. In the era of personalized medicine, clinical trials using a combination of therapeutic interventions are increasing.…”

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“…We then have the following expression for tumor volume: where x ( t ) is the instantaneous drug concentration near the tumor at time t . In practice, γ ( x ) can be expressed as the Hill function, a commly used empirical pharmacodynamic equation 21,25,26 : Given the treatment dynamics, x ( t ), and initial conditions, we can solve for the tumor volume over time. This tumor volume can be used to evaluate the fragility of our tumor in response to different treatment schedules.…”

“…where x(t) is the instantaneous drug concentration near the tumor at time t. In practice, γ(x) can be expressed as the Hill function, a commly used empirical pharmacodynamic equation 21,25,26 :…”