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Data-driven modeling of combination therapy in oncology

Licentiatsavhandling
Författare Tim Cardilin
Datum för examination 2016-10-07
Opponent at public defense Dr. Philip Gerlee, Mathematical Sciences, Chalmers University of Technology and University of Gothenburg
Förlag Chalmers University of Technology
Förlagsort Gothenburg
Publiceringsår 2016
Publicerad vid Institutionen för matematiska vetenskaper, matematik
Språk en
Ämnesord Oncology, Model-Based Drug Development, Pharmacokinetics/Pharmacodynamics, Nonlinear Mixed-Effects Models, Combination Therapy, Mathematical Modeling
Ämneskategorier Matematik, Bioinformatik (beräkningsbiologi), Annan data- och informationsvetenskap, Farmaceutisk vetenskap

Sammanfattning

This thesis contains two manuscripts: Tumor Static Concentration Curves in Combination Therapy and Extending the Tumor Static Concentration Curve to Exposure - A Combination Therapy Example with Radiation Therapy. There is also an introductory chapter presenting some basic facts necessary to understand the appended manuscripts. The manuscripts share the common goal of developing model-based data-driven tools and techniques to quantitatively assess the effectiveness of anticancer combinations. The first paper presents a dynamical systems model for combination therapy with the anticancer drugs cetuximab and cisplatin. Using a mixed-effects approach the model is shown to adequately describe a preclinical dataset. The model is then analyzed by introducing the Tumor Static Concentration (TSC) curve, a curve of cetuximab-cisplatin concentration pairs all of which, if maintained, result in tumor stasis. The TSC analysis reveals a modest gain from combining the compounds. The variability of the TSC curve across the population is also explored. In the second paper we develop a dynamical systems model for combination therapy with ionizing radiation and a test compound. For this combination we introduce an extension of the TSC curve called the (average) Tumor Static Exposure (TSE) curve based on average, as opposed to pointwise, tumor stasis. The TSE analysis for combinations of radiation and the test compound demonstrates a large synergistic effect.

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Utskriftsdatum: 2019-11-15