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Populational adaptive evolution, chemotherapeutic resistanceand multiple anti-cancer therapies

Published online by Cambridge University Press:  11 January 2013

Alexander Lorz
Affiliation:
UPMC Univ. Paris 06, CNRS UMR 7598, Laboratoire Jacques-Louis Lions, 4, pl. Jussieu 75252 Paris Cedex 05, France.. lorz@ann.jussieu.frINRIA-Rocquencourt, EPI BANG, France.; jean.clairambault@inria.fr
Tommaso Lorenzi
Affiliation:
Department of Mathematics, Politecnico di Torino, Corso Duca degli Abruzzi 24, I10129 Torino, Italy.; tommaso.lorenzi@polito.it
Michael E. Hochberg
Affiliation:
Institut des Sciences de l’Evolution, CNRS, Université Montpellier 2, Place Eugene Bataillon, 34095 Montpellier, France.Santa Fe Institute, 1399 Hyde Park Rd, Santa Fe, New Mexico, USA.; mhochber@univ-montp2.fr
Jean Clairambault
Affiliation:
UPMC Univ. Paris 06, CNRS UMR 7598, Laboratoire Jacques-Louis Lions, 4, pl. Jussieu 75252 Paris Cedex 05, France.. lorz@ann.jussieu.frINRIA-Rocquencourt, EPI BANG, France.; jean.clairambault@inria.fr
Benoît Perthame
Affiliation:
UPMC Univ. Paris 06, CNRS UMR 7598, Laboratoire Jacques-Louis Lions, 4, pl. Jussieu 75252 Paris Cedex 05, France.. lorz@ann.jussieu.frINRIA-Rocquencourt, EPI BANG, France.; jean.clairambault@inria.frInstitut Universitaire de France, France. ; benoit.perthame@upmc.fr

Abstract

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Resistance to chemotherapies, particularly to anticancer treatments, is an increasingmedical concern. Among the many mechanisms at work in cancers, one of the most importantis the selection of tumor cells expressing resistance genes or phenotypes. Motivated bythe theory of mutation-selection in adaptive evolution, we propose a model based on acontinuous variable that represents the expression level of a resistance gene (or genes,yielding a phenotype) influencing in healthy and tumor cells birth/death rates, effects ofchemotherapies (both cytotoxic and cytostatic) and mutations. We extend previous work bydemonstrating how qualitatively different actions of chemotherapeutic and cytostatictreatments may induce different levels of resistance. The mathematical interest of ourstudy is in the formalism of constrained Hamilton–Jacobi equations in the framework ofviscosity solutions. We derive the long-term temporal dynamics of the fittest traits inthe regime of small mutations. In the context of adaptive cancer management, we alsoanalyse whether an optimal drug level is better than the maximal tolerated dose.

Information

Type
Research Article
Copyright
© EDP Sciences, SMAI, 2013