EPSRC Seminar - A multi-scale systems pharmacology approach for anticancer chemotherapy personalisation - Thursday 9th March 2017

Speaker: Dr Annabelle Ballesta, Systems Biology Centre, University of Warwick

Venue: 3:00PM MATH-103, Department of Mathematical Science Building

Anticancer chemotherapy personalisation needs to reliably account for the activation of molecular pathways triggered by drug administration in each individual patient. Indeed, underlying gene and protein intracellular networks ultimately drive treatment antitumor efficacy and side effects in cancer and healthy tissues respectively, and they highly depend on patient- and tumourspecific genetic mutations or epigenetic alterations. However, clinical molecular data is usually minimally available in individual patients so that physiologically-based models designed through multi-scale approaches integrating preclinical and clinical investigations appears as an adapted solution. The models are based on ordinary differential equations (ODEs), and represent the relevant intracellular protein networks together with the pharmacokinetics-pharmacodynamics (PK-PD) of drugs of interest in both the tumour and the healthy tissues for which chemotherapy is critically toxic. While PK quantifies the transport and metabolism of the drug and its metabolites that are driving exposure concentration over time, PD quantifies drug interactions with cellular targets and subsequent cytotoxicity. Basing mathematical models on physiology allows the use of in vitro studies to design wholebody preclinical rodent models, to be further scaled to patient population data. Partial re calibration of the resulting human model for a given cancer patient according to individual biomarker recordings, genetic background and therapeutic history further allow for chemotherapy personalisation. The patient-specific models would then initiate a novel kind of clinical trial in which each individual patient would receive personalised drug combinations/scheduling computed via mathematical models informed with a continuous flow of multidimensional information obtained and tele-transmitted from patients. I will first present how this multi-scale approach is currently undertaken for designing clinically-relevant models of the PK-PD of temozolomide, the cornerstone of treatments against brain tumours, and how they can be used to personalize combination chemotherapies [1]. Next, I will discuss the promises of personalized cancer chronotherapeutics, that is administering anticancer drugs according to the patient’s biological rhythms over the 24h span. The project focuses on individualizing the circadian delivery of the anticancer drug irinotecan, one of the three drugs of the current gold standard protocols against digestive cancers [2-4] .

References
1. 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.
2. Dulong, S., et al., Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling. Mol Cancer Ther, 2015.
3. Ballesta, A., et al., A systems biomedicine approach for chronotherapeutics optimization: focus on the anticancer drug irinotecan, in New Challenges for Cancer Systems Biomedicine. 2012, Springer.
4. 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.