title: Analysis of temozolomide resistance in low-grade gliomas using a mechanistic mathematical model.
abstract: Understanding how tumors develop resistance to chemotherapy is a major issue in oncology. When treated with temozolomide (TMZ), an oral alkylating chemotherapy drug, most low-grade gliomas (LGG) show an initial volume decrease but this effect is rarely long lasting. In addition, it has been suggested that TMZ may drive tumor progression in a subset of patients as a result of acquired resistance. Using longitudinal tumor size measurements from 121 patients, the aim of this study was to develop a semi-mechanistic mathematical model to determine whether resistance of LGG to TMZ was more likely to result from primary and/or from chemotherapy-induced acquired resistance that may contribute to tumor progression. We applied the model to a series of patients treated upfront with TMZ (n = 109) or PCV (procarbazine, CCNU, vincristine) chemotherapy (n = 12) and used a population mixture approach to classify patients according to the mechanism of resistance most likely to explain individual tumor growth dynamics. Our modeling results predicted acquired resistance in 51% of LGG treated with TMZ. In agreement with the different biological effects of nitrosoureas, none of the patients treated with PCV were classified in the acquired resistance group. Consistent with the mutational analysis of recurrent LGG, analysis of growth dynamics using mathematical modeling suggested that in a subset of patients, TMZ might paradoxically contribute to tumor progression as a result of chemotherapy-induced resistance. Identification of patients at risk of developing acquired resistance is warranted to better define the role of TMZ in LGG.
authors.affiliation: U.M.P.A., Ecole Normale Supérieure de Lyon, CNRS UMR 5669, INRIA, Project-team NUMED, 46 Allée d'Italie, 69364, Lyon Cedex 07, France.|SAINBIOSE, INSERM, U1059, Saint-Etienne, F-42023, France.|Laboratoire Jean Kuntzmann, UMR CNRS 5224, Université Grenoble-Alpes, 38401, Saint-Martin-d'Heres, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Ollier
authors.affiliation: U.M.P.A., Ecole Normale Supérieure de Lyon, CNRS UMR 5669, INRIA, Project-team NUMED, 46 Allée d'Italie, 69364, Lyon Cedex 07, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Mazzocco
authors.affiliation: Service de Neurologie, Service de Santé des Armées, Hôpital d'Instruction des Armées du Val-de-Grâce, 75005, Paris, France.|UMR 5782 MD4 Cognac-G, CNRS, Service de Santé des Armées, Université Paris-Descartes, 75270, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Ricard
authors.affiliation: INSERM U975, 47 boulevard de l'Hôpital 75013, Paris, France.|UMR 7225, CNRS, 47, boulevard de l'hôpital 75013, Paris, France.|Service de neurologie 2-Mazarin, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Gentian
authors.initials: G
authors.lastname: Kaloshi
authors.affiliation: INSERM U975, 47 boulevard de l'Hôpital 75013, Paris, France.|UMR 7225, CNRS, 47, boulevard de l'hôpital 75013, Paris, France.|Service de neurologie 2-Mazarin, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: INSERM U975, 47 boulevard de l'Hôpital 75013, Paris, France.|UMR 7225, CNRS, 47, boulevard de l'hôpital 75013, Paris, France.|Service de neurologie 2-Mazarin, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Agusti
authors.initials: A
authors.lastname: Alentorn
authors.affiliation: INSERM U975, 47 boulevard de l'Hôpital 75013, Paris, France.|UMR 7225, CNRS, 47, boulevard de l'hôpital 75013, Paris, France.|Service de neurologie 2-Mazarin, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Psimaras
authors.affiliation: Service de Neuro-oncologie, Hôpital Neurologique, Hospices Civils de Lyon, 59 boulevard Pinel, 69500, Bron, France.|Université Claude Bernard Lyon 1, F-69622, Villeurbanne Cedex, France.|Institut NeuroMyoGene (INMG) INSERM 1217/UMR CNRS 5310, F-69622, Villeurbanne Cedex, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.affiliation: INSERM U975, 47 boulevard de l'Hôpital 75013, Paris, France.|UMR 7225, CNRS, 47, boulevard de l'hôpital 75013, Paris, France.|Service de neurologie 2-Mazarin, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.affiliation: U.M.P.A., Ecole Normale Supérieure de Lyon, CNRS UMR 5669, INRIA, Project-team NUMED, 46 Allée d'Italie, 69364, Lyon Cedex 07, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Grenier
authors.affiliation: Service de Neuro-oncologie, Hôpital Neurologique, Hospices Civils de Lyon, 59 boulevard Pinel, 69500, Bron, France.|Université Claude Bernard Lyon 1, F-69622, Villeurbanne Cedex, France.|Cancer Research Centre of Lyon, INSERM U1052, CNRS UMR5286, 69373, Lyon Cedex 08, France.
authors.forename: François
authors.initials: F
authors.lastname: Ducray
authors.affiliation: Laboratoire Jean Kuntzmann, UMR CNRS 5224, Université Grenoble-Alpes, 38401, Saint-Martin-d'Heres, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Samson
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008962:Models, Theoretical; D011344:Procarbazine / Q000627:therapeutic use; D000077204:Temozolomide; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011344:Procarbazine; D014750:Vincristine; D003606:Dacarbazine; D000077204:Temozolomide
keywords: low-grade glioma; mathematical model; resistance; temozolomide; tumor growth inhibition