6533b870fe1ef96bd12d055e
RESEARCH PRODUCT
Intermittent targeted therapies and stochastic evolution in patients affected by chronic myeloid leukemia
D. Persano AdornoBernardo SpagnoloBernardo SpagnoloNicola PizzolatoDavide Valentisubject
0301 basic medicineOncologyDrugStatistics and Probabilitymedicine.medical_specialtymedicine.medical_treatmentmedia_common.quotation_subjectTargeted therapy03 medical and health sciencesClassical Monte Carlo simulations; computational biology; models for evolution (theory); mutational and evolutionary processes (theory); Statistical and Nonlinear Physics; Statistics and Probability; Statistics Probability and Uncertainty0302 clinical medicinecomputational biologyInternal medicinemedicineClassical Monte Carlo simulationmutational and evolutionary processes (theory)media_commonbusiness.industryMyeloid leukemiaStatistical and Nonlinear PhysicsImatinibSettore FIS/07 - Fisica Applicata(Beni Culturali Ambientali Biol.e Medicin)Axitinib030104 developmental biology030220 oncology & carcinogenesisCancer cellToxicityStatistics Probability and Uncertaintybusinessmodels for evolution (theory)Tyrosine kinasemedicine.drugStatistical and Nonlinear Physicdescription
Front line therapy for the treatment of patients affected by chronic myeloid leukemia (CML) is based on the administration of tyrosine kinase inhibitors, namely imatinib or, more recently, axitinib. Although imatinib is highly effective and represents an example of a successful molecular targeted therapy, the appearance of resistance is observed in a proportion of patients, especially those in advanced stages. In this work, we investigate the appearance of resistance in patients affected by CML, by modeling the evolutionary dynamics of cancerous cell populations in a simulated patient treated by an intermittent targeted therapy. We simulate, with the Monte Carlo method, the stochastic evolution of initially healthy cells to leukemic clones, due to genetic mutations and changes in their reproductive behavior. We first present the model and its validation with experimental data by considering a continuous therapy. Then, we investigate how fluctuations in the number of leukemic cells affect patient response to the therapy when the drug is administered with an intermittent time scheduling. Here we show that an intermittent therapy (IT) represents a valid choice in patients with high risk of toxicity, despite an associated delay to the complete restoration of healthy cells. Moreover, a suitably tuned IT can reduce the probability of developing resistance.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-05-20 |