Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma

Rabé, Marion; Dumont, Solenne; Álvarez-Arenas, Arturo; Janati, Hicham; Belmonte-Beitia, Juan; Calvo, Gabriel F.; Thibault-Carpentier, Christelle; Séry, Quentin; Chauvin, Cynthia; Joalland, Noémie; Briand, Floriane; Blandin, Stéphanie; Scotet, Emmanuel; Pecqueur, Claire; Clairambault, Jean; Oliver, Lisa; Pérez-Garcı́a, Vı́ctor M.; Nadaradjane, Arulraj; Cartron, Pierre-François; Gratas, Catherine; Vallette, François M.

doi:10.1038/s41419-019-2200-2

Cited by 64 publications

(78 citation statements)

References 42 publications

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“…The induction of persisters in glioma cells has been known to be partially reverted by ‘drug wash-out’ suggesting the contribution of epigenetic mechanisms in drug resistance and supporting the possibility of TMZ rechallenge in glioma patients after prior drug exposure [39], provided there is a sufficiently long waiting time between treatments. Recent experimental results support this hypothesis [40]. In our case, the fact that the maintenance phase of the treatment leaves a time spacing of three months within cycles could be optimal not only in terms of survival but also to avoid persisters becoming resistant tumor cells.…”

Section: Discussionsupporting

confidence: 65%

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas

et al. 2019

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Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the ‘in-silico twins’ of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits.

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Section: Discussionsupporting

confidence: 65%

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas

et al. 2019

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“…Moreover, we assume that once sensitive cells have acquired a resistant phenotype they irreversibly remain in that state, and thus do not return to a sensitive state after any subsequent time elapsed. This assumption is in agreement with several works dealing with resistances in tumours (see for instance [38] and [41]).…”

supporting

confidence: 92%

Ultimate dynamics and optimal control of a multi-compartment model of tumor resistance to chemotherapy

Álvarez-Arenas¹,

Starkov²,

Calvo³

et al. 2019

Discrete &Amp; Continuous Dynamical Systems - B

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In this paper, a non-trivial generalization of a mathematical model put forward in [35] to account for the development of resistance by tumors to chemotherapy is presented. A study of the existence and local stability of the solutions, as well as the ultimate dynamics of the model, is addressed. An analysis of different chemotherapeutical protocols using discretization and optimization methods is carried out. A number of objective functionals are considered and the necessary optimality conditions are provided. Since the control variable appears linearly in the associated problem, optimal controls are concatenations of bang-bang and singular arcs. A formula of the singular control in terms of state and adjoint variables is derived analytically. Bangbang and singular controls from the numerical simulations are obtained where, in particular, singular controls illustrate the metronomic chemotherapy.

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“…For each of the four biological replicates per condition, the library construction was performed from 500 ng of total RNA with SureSelect Strand-Specific RNA Library Prep for Illumina Multiplexed kit (#5190-6410, Agilent Technologies) according to manufacturer' protocol as previously described [50]. Purifications were carried out with NucleoMag NGS Clean-up and Size Select (#744970.50, Macherey-Nagel, Hoerdt, France).…”

Section: Library Construction and Rna-seq Analysismentioning

confidence: 99%

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Chénais

Cornec

Dumont

et al. 2020

IJERPH

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Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 12 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.

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Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma

Cited by 64 publications

References 42 publications

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas

Ultimate dynamics and optimal control of a multi-compartment model of tumor resistance to chemotherapy

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

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