An in vitro systems pharmacology approach to personalize temozolomide –
based combination chemotherapy against glioblastoma.
Dr Annabelle Ballesta1, Dr Maité Verreault2, Dr Ahmed Idbaih 2,3.
1 Warwick Systems Biology Centre & Medical School, UK
2 Institut du Cerveau et de la Moelle épinière, Hôpital La Pitité Salpétrière, Paris, France
3 Assistance Publique Hopitaux de Paris (AP-HP), Hôpital La Pitité Salpétrière , service de
Neuro-oncologie, Paris, France
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumour currently
associated with a median patient survival of 18 months and no major therapeutic advance has been
accomplished within the past 10 years. This dismal prognosis may partially be explained by the
intrinsic resistance of cancer cells to chemotherapy and radiotherapy. Nowadays, multiple
innovative molecules are being developed with promising perspectives in neuro-oncology. Those
compounds are mainly targeted drugs acting on a particular protein that may be mutated in cancer
cells but not in healthy tissues so that low treatment toxicities are expected. However, the selection
of drug candidates and their optimal combination and administration timing constitute a current
challenge that cannot be addressed by time-consuming traditional in vitro/in vivo studies. Thus, this
project aims at combining experimental and mathematical means to design optimal drug
combinations achieving safe antitumor activity against GBM.
The only anticancer drug clinically-approved for the treatment of GBM is temozolomide
(TMZ), so that this investigation will focus on designing optimal combinations of TMZ with targeted
molecules. Seven GBM cell lines derived from patient’s tumor samples are available at Hôpital La
Pitié-Salpétrière and were characterized for genetic mutations and mRNA levels. As a first in vitro
proof of concept, optimal combination chemotherapies will be designed for each cell line.
The mathematical model based on ordinary differential equations will be composed of
subunits representing i) TMZ pharmacokinetics-pharmacodynamics, adapted from [1] , ii) DNA
damage response and p53 network adapted from [2], and iii) a minimal model of the cell cycle. First,
parameter estimation will be performed through a weighted least-square approach based on
qualitative and quantitative information from the literature. Then, for each cell line, protein levels
will be re-calibrated according to genetic mutations and mRNA levels datasets. Existing optimization
procedures will be utilized to develop optimal scheduling of TMZ combined to targeted molecules, in
order to achieve maximal antitumor efficacy for a predefined dose of TMZ [3]. A particular interest
will be given to the combination of TMZ with a new Mdm2 inhibitor developed by Roche. The
validation of the theoretically-optimal drug sequence will require new in vitro experiments to be
performed by the collaborators in France. Overall, this systems pharmacology approach will foster
the development of an innovative physiologically-based model enabling GBM treatment
personalization.
References
1.
2.
3.
Ballesta, A., et al., Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic
models for personalized medicine: application to temozolomide in brain tumors. CPT
Pharmacometrics Syst Pharmacol, 2014. 3: p. e112.
Elias, J., et al., The p53 protein and its molecular network: modelling a missing link between
DNA damage and cell fate. Biochim Biophys Acta, 2014. 1844(1 Pt B): p. 232-47.
Ballesta, A., et al., A combined experimental and mathematical approach for molecularbased optimization of irinotecan circadian delivery. PLoS Comput Biol, 2011. 7(9): p.
e1002143.