Combined anticancer therapies have been gaining an increasing interest in recent years. However, development of proper therapy protocols and their successful application in clinical practice is subject to understanding of intracellular processes that determine cell fate and their regulatory mechanisms. The research devoted to extending our knowledge about these processes involves both experimental work and mathematical modeling, supporting the experiments.

This work is focused on modeling and analysis of two types of stress that can be used as therapeutic actions - heat shock and  chemo- or radiotherapy. The first one is associated with activating Heat Shock Factor (HSF) family of proteins and Heat Shock Proteins (HSP) through a particular signaling pathway. The other stress-inducing actions induce various cellular responses, leading to either cell cycle arrest or cell death. NFkB pathway is one of the most important ones among those that determine cell fate in that case. Analysis of the dynamics of nuclear NFkB can provide valuable information about possible outcome of the therapy on a cellular level.

So far, several models of HSP/HSF pathway have been proposed, much more models of the NFkB pathway have been developed. On the other hand, there are numerous reports of a possible  interplay  between those pathways with some experimental data supporting  that claim. In our work, we combine existing models of these pathways to a single model, in which various types of excitation may be applied. First, we use several hypotheses about possible mechanisms responsible for the interactions between the pathways (competition for IKK protein being the most important one) to build the models  and using mathematical simulations analyze their implications. Additionally, several models of each pathway are used, to check what are the differences in the results which stem from particular model assumptions. Then, a particular experimental setup is used to check system responses, in which heat shock is used first, followed by either irradiation or TNF stimulation. The idea behind this setup is to damp the response of the NFkB pathway by earlier heat shock treatment. We show what should be the length and temperature of the heat shock to obtain the best possible results (with the least possible side effects) and for how long the NFkB pathway is blocked (partially), which could provide hints about the time course for the second part of treatment.

Simulation results are compared to data which is being gathered by our group in experiments currently underway.