A Predictive Mathematical Modeling Approach for the Study of Doxorubicin Treatment in Triple Negative Breast Cancer

Sci Rep. 2017 Jul 18;7(1):5725. doi: 10.1038/s41598-017-05902-z.

Abstract

Doxorubicin forms the basis of chemotherapy regimens for several malignancies, including triple negative breast cancer (TNBC). Here, we present a coupled experimental/modeling approach to establish an in vitro pharmacokinetic/pharmacodynamic model to describe how the concentration and duration of doxorubicin therapy shape subsequent cell population dynamics. This work features a series of longitudinal fluorescence microscopy experiments that characterize (1) doxorubicin uptake dynamics in a panel of TNBC cell lines, and (2) cell population response to doxorubicin over 30 days. We propose a treatment response model, fully parameterized with experimental imaging data, to describe doxorubicin uptake and predict subsequent population dynamics. We found that a three compartment model can describe doxorubicin pharmacokinetics, and pharmacokinetic parameters vary significantly among the cell lines investigated. The proposed model effectively captures population dynamics and translates well to a predictive framework. In a representative cell line (SUM-149PT) treated for 12 hours with doxorubicin, the mean percent errors of the best-fit and predicted models were 14% (±10%) and 16% (±12%), which are notable considering these statistics represent errors over 30 days following treatment. More generally, this work provides both a template for studies quantitatively investigating treatment response and a scalable approach toward predictions of tumor response in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology
  • Biostatistics*
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Humans
  • Longitudinal Studies
  • Models, Biological
  • Models, Theoretical*
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / drug therapy*

Substances

  • Antibiotics, Antineoplastic
  • Doxorubicin