Stochastic dynamics of leukemic cells under an intermittent targeted therapy

Abstract

The evolutionary dynamics of cancerous cell populations in a model of Chronic Myeloid Leukemia (CML) is investigated in the presence of an intermittent targeted therapy. Cancer development and progression is modeled by simulating the stochastic evolution of initially healthy cells which can experience genetic mutations and modify their reproductive behavior, becoming leukemic clones. Front line therapy for the treatment of patients affected by CML is based on the administration of tyrosine kinase inhibitors, namely imatinib (Gleevec) or, more recently, dasatinib or nilotinib. Despite the fact that they represent the first example of a successful molecular targeted therapy, the development of resistance to these drugs is observed in a proportion of patients, especially those in advanced stages. In this study, we simulate an imatinib-like treatment of CML by modifying the fitness and the death rate of cancerous cells and describe the several scenarios in the evolutionary dynamics of white blood cells as a consequence of the efficacy of the different modeled therapies. The patient response to the therapy is investigated by simulating a drug administration following a continuous or pulsed time scheduling. A permanent disappearance of leukemic clones is achieved with a continuous therapy. This theoretical behavior is in a good agreement with that observed in previous clinical investigations. However, these findings demonstrate that an intermittent therapy could represent a valid alternative in patients with high risk of toxicity. A suitable tuned pulsed therapy can also reduce the probability of developing resistance.

Stability in a system subject to noise with regulated periodicity

“…[25]. There, the stability condition, expressed through high-order spectral densities of the noise signal, turns out to be the same as that of this work when the truncated expansion (15), valid for narrow distribution, is used. The general idea that the stability is related to the variance of the noise fluctuations was given in Ref.…”

“…Specifically, random variations of species concentrations in natural ecosystems [1,2,[11][12][13], the role of molecular noise in the growth of bacteria that are present in food products [14], and the stochastic dynamics of diseases connected with genetic mutations [15] are fundamental aspects that cannot be neglected when seeking a better understanding of the dynamics of complex living systems. In particular, in these systems the random variations of temperature, food resources, and other environmental parameters can be described using models in which multiplicative noise sources are present [8,16,17].…”

Intermittent targeted therapies and stochastic evolution in patients affected by chronic myeloid leukemia

“…In this section we describe the model used to reproduce the dynamics of leukemic cells in patients aected by CML. The time evolution of CML has been analyzed using deterministic approaches [30][31][32][33] as much as models based on stochastic approaches [2,5,8,10,14,[34][35][36][37][38]. According to clinical studies on cancer genetics [39,40], which analyze the time behaviour of the level of BCR-ABL positive cells in patients treated with imatinib, both deterministic and stochastic models consider that leukemia initiation coincides with the occurrence of multiple mutations in a single non-dierentiated blood cell.…”

Noise-induced bistability in the fate of cancer phenotypic quasispecies: a bit-strings approach

“…Other extrinsic sources of noise affecting the complexity of tumorigenesis can be given by random variations in nutrients supply or in the availability of oxygen, among others. Stochastic evolutionary dynamics has been explored for leukemic cells under different targeted therapies using MonteCarlo simulations 44 . Also, the Langevin equation has been employed to characterize stochastic cancer evolution for chronic myeloid leukemia 45 .…”