Integrating Cell-level Kinetic Modeling into
the Optimization of Cancer Therapeutics.
PhD thesis, National University of Ireland Maynooth.
Cancer therapy benefits today from the availability of new promising classes of drugs such as
therapeutic proteins. Due to their ability to specifically bind targets in the body they allow to
modulate specific chemical reactions and ultimately to modify the functional response of the
cell, such as cell growth or cell division. Targeting receptor systems by competitive inhibition
is the objective of various protein drugs in development and on the market. Many targeted
receptor systems also constitute a degradation mechanism for the drug via endocytosis and a
thorough understanding of the complex interplay between the drug's pharmacokinetics and
its effect, is largely missing.
For complex diseases such as cancer, systems biology models of therapeutically relevant
cellular processes have proven valuable for identifying potent drug targets. So far, such
information about the dynamics of the targeted system is neglected in later stages of the drug
development process when pharmacokinetic modeling is used to guide dose finding and analyze
preclinical or clinical in vivo data. This is especially critical for therapeutic proteins where,
due to the degradation mediated by the targeted receptor, drug effect and pharmacokinetics
are inherently interdependent.
This thesis combines the points of view of systems biology and pharmacokinetics. We
present a detailed mechanistic model of the targeted cellular system that explicitly takes into
account receptor binding and trafficking inside the cell and that is used to derive reduced
models of drug degradation which retain a mechanistic interpretation. By integrating cell-level
models with established pharmacokinetic models, we translate biophysical properties
of protein drugs into a transient drug effect in vivo. We illustrate the approach for antibodies
against the epidermal growth factor receptor used in cancer therapy. The cell-level
pharmacokinetic/pharmacodynamic model identifies options and limits for future therapeutic
antibodies and links their inhibitory effect with genomic alteration of tumor cells.
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