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A multiscale model to design therapeutic strategies that overcome drug resistance to tyrosine kinase inhibitors in multiple myeloma.

Authors
  • Bouchnita, Anass1
  • Volpert, Vitaly2
  • Koury, Mark J3
  • Hellander, Andreas4
  • 1 Division of Scientific Computing, Department of Information Technology, Uppsala University, Uppsala 75105, Sweden; Ecole Centrale Casablanca, Ville Verte, Bouskoura, 20000 Casablanca, Morocco. Electronic address: [email protected] , (Morocco)
  • 2 Institut Camille Jordan, Université Lyon 1, Villeurbanne 69622, France; INRIA Team Dracula, INRIA Lyon La Doua, Villeurbanne 69603, France; Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow 117198, Russian Federation. , (France)
  • 3 Vanderbilt University Medical Center, Nashville, TN 37232-6307, USA.
  • 4 Division of Scientific Computing, Department of Information Technology, Uppsala University, Uppsala 75105, Sweden. , (Sweden)
Type
Published Article
Journal
Mathematical biosciences
Publication Date
Dec 03, 2019
Volume
319
Pages
108293–108293
Identifiers
DOI: 10.1016/j.mbs.2019.108293
PMID: 31809782
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Drug resistance (DR) is a phenomenon characterized by the tolerance of a disease to pharmaceutical treatment. In cancer patients, DR is one of the main challenges that limit the therapeutic potential of the existing treatments. Therefore, overcoming DR by restoring the sensitivity of cancer cells would be greatly beneficial. In this context, mathematical modeling can be used to provide novel therapeutic strategies that maximize the efficiency of anti-cancer agents and potentially overcome DR. In this paper, we present a new multiscale model devoted to the interaction of potential treatments with multiple myeloma (MM) development. In this model, MM cells are represented as individual objects that move, divide, and die by apoptosis. The fate of each cell depends on intracellular and extracellular regulation, as well as the administered treatment. The model is used to explore the combined effects of a tyrosine-kinase inhibitor (TKI) with a pentose phosphate pathway (PPP) inhibitor. We use numerical simulations to tailor effective and safe treatment regimens that may eradicate the MM tumors. The model suggests that an interval for the daily dose of the PPP inhibitor can maximize the responsiveness of MM cells to the treatment with TKIs. Then, it demonstrates that the combination of high-dose pulsatile TKI treatment with high-dose daily PPP inhibitor therapy can potentially eradicate the tumor.The predictions of numerical simulations using such a model can be considered as testable hypotheses in future pre-clinical experiments and clinical studies. Copyright © 2019 Elsevier Inc. All rights reserved.

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