Evolution of resistance to anti-cancer therapy during general dosing schedules.

Anti-cancer drugs targeted to specific oncogenic pathways have shown promising therapeutic results in the past few years; however, drug resistance remains an important obstacle for these therapies. Resistance to these drugs can emerge due to a variety of reasons including genetic or epigenetic changes which alter the binding site of the drug target, cellular metabolism or export mechanisms. Obtaining a better understanding of the evolution of resistant populations during therapy may enable the design of more effective therapeutic regimens which prevent or delay progression of disease due to resistance. In this paper, we use stochastic mathematical models to study the evolutionary dynamics of resistance under time-varying dosing schedules and pharmacokinetic effects. The populations of sensitive and resistant cells are modeled as multi-type non-homogeneous birth-death processes in which the drug concentration affects the birth and death rates of both the sensitive and resistant cell populations in continuous time. This flexible model allows us to consider the effects of generalized treatment strategies as well as detailed pharmacokinetic phenomena such as drug elimination and accumulation over multiple doses. We develop estimates for the probability of developing resistance and moments of the size of the resistant cell population. With these estimates, we optimize treatment schedules over a subspace of tolerated schedules to minimize the risk of disease progression due to resistance as well as locate ideal schedules for controlling the population size of resistant clones in situations where resistance is inevitable. Our methodology can be used to describe dynamics of resistance arising due to a single (epi)genetic alteration in any tumor type. Copyright 2009 Elsevier Ltd. All rights reserved.